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CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Zhou Yu,Won Jaejoon,Karlsson Mikael Guzman,Zhou Miou,Rogerson Thomas,Balaji Jayaprakash,Neve Rachael,Poirazi Panayiota,Silva Alcino J Nature neuroscience The mechanisms that determine how information is allocated to specific regions and cells in the brain are important for memory capacity, storage and retrieval, but are poorly understood. We manipulated CREB in a subset of lateral amygdala neurons in mice with a modified herpes simplex virus (HSV) and reversibly inactivated transfected neurons with the Drosophila allatostatin G protein-coupled receptor (AlstR)/ligand system. We found that inactivation of the neurons transfected with HSV-CREB during training disrupted memory for tone conditioning, whereas inactivation of a similar proportion of transfected control neurons did not. Whole-cell recordings of fluorescently tagged transfected neurons revealed that neurons with higher CREB levels are more excitable than neighboring neurons and showed larger synaptic efficacy changes following conditioning. Our findings demonstrate that CREB modulates the allocation of fear memory to specific cells in lateral amygdala and suggest that neuronal excitability is important in this process. 10.1038/nn.2405
The other side of the engram: experience-driven changes in neuronal intrinsic excitability. Zhang Wei,Linden David J Nature reviews. Neuroscience 10.1038/nrn1248
The hippocampus and inferential reasoning: building memories to navigate future decisions. Frontiers in human neuroscience A critical aspect of inferential reasoning is the ability to form relationships between items or events that were not experienced together. This review considers different perspectives on the role of the hippocampus in successful inferential reasoning during both memory encoding and retrieval. Intuitively, inference can be thought of as a logical process by which elements of individual existing memories are retrieved and recombined to answer novel questions. Such flexible retrieval is sub-served by the hippocampus and is thought to require specialized hippocampal encoding mechanisms that discretely code events such that event elements are individually accessible from memory. In addition to retrieval-based inference, recent research has also focused on hippocampal processes that support the combination of information acquired across multiple experiences during encoding. This mechanism suggests that by recalling past events during new experiences, connections can be created between newly formed and existing memories. Such hippocampally mediated memory integration would thus underlie the formation of networks of related memories that extend beyond direct experience to anticipate future judgments about the relationships between items and events. We also discuss integrative encoding in the context of emerging evidence linking the hippocampus to the formation of schemas as well as prospective theories of hippocampal function that suggest memories are actively constructed to anticipate future decisions and actions. 10.3389/fnhum.2012.00070
Temporal Proximity Promotes Integration of Overlapping Events. Zeithamova Dagmar,Preston Alison R Journal of cognitive neuroscience Events with overlapping elements can be encoded as two separate representations or linked into an integrated representation, yet we know little about the conditions that promote one form of representation over the other. Here, we tested the hypothesis that the proximity of overlapping events would increase the probability of integration. Participants first established memories for house-object and face-object pairs; half of the pairs were learned 24 hr before an fMRI session, and the other half 30 min before the session. During scanning, participants encoded object-object pairs that overlapped with the initial pairs acquired on the same or prior day. Participants were also scanned as they made inference judgments about the relationships among overlapping pairs learned on the same or different day. Participants were more accurate and faster when inferring relationships among memories learned on the same day relative to those acquired across days, suggesting that temporal proximity promotes integration. Evidence for reactivation of existing memories-as measured by a visual content classifier-was equivalent during encoding of overlapping pairs from the two temporal conditions. In contrast, evidence for integration-as measured by a mnemonic strategy classifier from an independent study [Richter, F. R., Chanales, A. J. H., & Kuhl, B. A. Predicting the integration of overlapping memories by decoding mnemonic processing states during learning. Neuroimage, 124, 323-335, 2016]-was greater for same-day overlapping events, paralleling the behavioral results. During inference itself, activation patterns further differentiated when participants were making inferences about events acquired on the same day versus across days. These findings indicate that temporal proximity of events promotes integration and further influences the neural mechanisms engaged during inference. 10.1162/jocn_a_01116
Overlapping memory trace indispensable for linking, but not recalling, individual memories. Yokose Jun,Okubo-Suzuki Reiko,Nomoto Masanori,Ohkawa Noriaki,Nishizono Hirofumi,Suzuki Akinobu,Matsuo Mina,Tsujimura Shuhei,Takahashi Yukari,Nagase Masashi,Watabe Ayako M,Sasahara Masakiyo,Kato Fusao,Inokuchi Kaoru Science (New York, N.Y.) Memories are not stored in isolation from other memories but are integrated into associative networks. However, the mechanisms underlying memory association remain elusive. Using two amygdala-dependent behavioral paradigms-conditioned taste aversion (CTA) and auditory-cued fear conditioning (AFC)-in mice, we found that presenting the conditioned stimulus used for the CTA task triggered the conditioned response of the AFC task after natural coreactivation of the memories. This was accompanied through an increase in the overlapping neuronal ensemble in the basolateral amygdala. Silencing of the overlapping ensemble suppressed CTA retrieval-induced freezing. However, retrieval of the original CTA or AFC memory was not affected. A small population of coshared neurons thus mediates the link between memories. They are not necessary for recalling individual memories. 10.1126/science.aal2690
Pattern separation in the hippocampus. Yassa Michael A,Stark Craig E L Trends in neurosciences The ability to discriminate among similar experiences is a crucial feature of episodic memory. This ability has long been hypothesized to require the hippocampus, and computational models suggest that it is dependent on pattern separation. However, empirical data for the role of the hippocampus in pattern separation have not been available until recently. This review summarizes data from electrophysiological recordings, lesion studies, immediate-early gene imaging, transgenic mouse models, as well as human functional neuroimaging, that provide convergent evidence for the involvement of particular hippocampal subfields in this key process. We discuss the impact of aging and adult neurogenesis on pattern separation, and also highlight several challenges to linking across species and approaches, and suggest future directions for investigation. 10.1016/j.tins.2011.06.006
Selective synaptic remodeling of amygdalocortical connections associated with fear memory. Yang Yang,Liu Dan-Qian,Huang Wei,Deng Juan,Sun Yangang,Zuo Yi,Poo Mu-Ming Nature neuroscience Neural circuits underlying auditory fear conditioning have been extensively studied. Here we identified a previously unexplored pathway from the lateral amygdala (LA) to the auditory cortex (ACx) and found that selective silencing of this pathway using chemo- and optogenetic approaches impaired fear memory retrieval. Dual-color in vivo two-photon imaging of mouse ACx showed pathway-specific increases in the formation of LA axon boutons, dendritic spines of ACx layer 5 pyramidal cells, and putative LA-ACx synaptic pairs after auditory fear conditioning. Furthermore, joint imaging of pre- and postsynaptic structures showed that essentially all new synaptic contacts were made by adding new partners to existing synaptic elements. Together, these findings identify an amygdalocortical projection that is important to fear memory expression and is selectively modified by associative fear learning, and unravel a distinct architectural rule for synapse formation in the adult brain. 10.1038/nn.4370
Differences in excitability of cortical neurons as a function of motor projection in conditioned cats. Woody C D,Black-Cleworth P Journal of neurophysiology 10.1152/jn.1973.36.6.1104
Sparse and powerful cortical spikes. Wolfe Jason,Houweling Arthur R,Brecht Michael Current opinion in neurobiology Activity in cortical networks is heterogeneous, sparse and often precisely timed. The functional significance of sparseness and precise spike timing is debated, but our understanding of the developmental and synaptic mechanisms that shape neuronal discharge patterns has improved. Evidence for highly specialized, selective and abstract cortical response properties is accumulating. Singe-cell stimulation experiments demonstrate a high sensitivity of cortical networks to the action potentials of some, but not all, single neurons. It is unclear how this sensitivity of cortical networks to small perturbations comes about and whether it is a generic property of cortex. The unforeseen sensitivity to cortical spikes puts serious constraints on the nature of neural coding schemes. 10.1016/j.conb.2010.03.006
Retrieval induces adaptive forgetting of competing memories via cortical pattern suppression. Wimber Maria,Alink Arjen,Charest Ian,Kriegeskorte Nikolaus,Anderson Michael C Nature neuroscience Remembering a past experience can, surprisingly, cause forgetting. Forgetting arises when other competing traces interfere with retrieval and inhibitory control mechanisms are engaged to suppress the distraction they cause. This form of forgetting is considered to be adaptive because it reduces future interference. The effect of this proposed inhibition process on competing memories has, however, never been observed, as behavioral methods are 'blind' to retrieval dynamics and neuroimaging methods have not isolated retrieval of individual memories. We developed a canonical template tracking method to quantify the activation state of individual target memories and competitors during retrieval. This method revealed that repeatedly retrieving target memories suppressed cortical patterns unique to competitors. Pattern suppression was related to engagement of prefrontal regions that have been implicated in resolving retrieval competition and, critically, predicted later forgetting. Thus, our findings demonstrate a cortical pattern suppression mechanism through which remembering adaptively shapes which aspects of our past remain accessible. 10.1038/nn.3973
Dynamics of the hippocampal ensemble code for space. Wilson M A,McNaughton B L Science (New York, N.Y.) Ensemble recordings of 73 to 148 rat hippocampal neurons were used to predict accurately the animals' movement through their environment, which confirms that the hippocampus transmits an ensemble code for location. In a novel space, the ensemble code was initially less robust but improved rapidly with exploration. During this period, the activity of many inhibitory cells was suppressed, which suggests that new spatial information creates conditions in the hippocampal circuitry that are conducive to the synaptic modification presumed to be involved in learning. Development of a new population code for a novel environment did not substantially alter the code for a familiar one, which suggests that the interference between the two spatial representations was very small. The parallel recording methods outlined here make possible the study of the dynamics of neuronal interactions during unique behavioral events. 10.1126/science.8351520
Dissociation of memory systems: The story unfolds. White Norman M,Packard Mark G,McDonald Robert J Behavioral neuroscience In this article we describe the ideas and circumstances that led to the experiment demonstrating a triple dissociation of memory systems. We then move on to discuss the results of 20 years of investigation of those ideas. First, evidence is described from animal studies consistent with the ideas that memory for different kinds of information is stored in different brain systems, and that the hippocampus, amygdala, and dorsal striatum are each central structures in one of the systems. We then focus on the 3 tasks used in the original triple dissociation: win-stay learning, conditioned cue preference, and win-shift learning. Each of these tasks is specific to behavior resulting from the type of information stored in one of the systems, but the use of other behavioral tests that are sensitive to the types of information stored in other systems has revealed that, in each case, other types of information are acquired in parallel. Next, evidence consistent with the idea that the outputs of the systems compete for control of behavior is discussed together with alternative forms of more direct interactions among the systems. Finally, some evidence that many of these ideas about multiple parallel memory systems may apply to humans is reviewed. 10.1037/a0034859
CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Wallace Deanna L,Han Ming-Hu,Graham Danielle L,Green Thomas A,Vialou Vincent,Iñiguez Sergio D,Cao Jun-Li,Kirk Anne,Chakravarty Sumana,Kumar Arvind,Krishnan Vaishnav,Neve Rachael L,Cooper Don C,Bolaños Carlos A,Barrot Michel,McClung Colleen A,Nestler Eric J Nature neuroscience Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element-binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K(+) channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation. 10.1038/nn.2257
Effects of cyclic adenosine monophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety. Wallace Tanya L,Stellitano Kathryn E,Neve Rachael L,Duman Ronald S Biological psychiatry BACKGROUND:Chronic antidepressant administration increases the cyclic adenosine monophosphate response element binding protein (CREB) in the amygdala, a critical neural substrate involved in the physiologic responses to stress, fear, and anxiety. METHODS:To determine the role of CREB in the amygdala in animal models of depression and anxiety, a viral gene transfer approach was used to selectively express CREB in this region of the rat brain. RESULTS:In the learned helplessness model of depression, induction of CREB in the basolateral amygdala after training decreased the number of escape failures, an antidepressant response. However, expression of CREB before training increased escape failures, and increased immobility in the forced swim test, depressive effects. Expression of CREB in the basolateral amygdala also increased behavioral measures of anxiety in both the open field test and the elevated plus maze, and enhanced cued fear conditioning. CONCLUSIONS:Taken together, these data demonstrate that CREB expression in the basolateral amygdala influences behavior in models of depression, anxiety, and fear. Moreover, in the basolateral amygdala, the temporal expression of CREB in relation to learned helplessness training, determines the qualitative outcome in this animal model of depression. 10.1016/j.biopsych.2004.04.010
Chronic enhancement of CREB activity in the hippocampus interferes with the retrieval of spatial information. Viosca Jose,Malleret Gaël,Bourtchouladze Rusiko,Benito Eva,Vronskava Svetlana,Kandel Eric R,Barco Angel Learning & memory (Cold Spring Harbor, N.Y.) The activation of cAMP-responsive element-binding protein (CREB)-dependent gene expression is thought to be critical for the formation of different types of long-term memory. To explore the consequences of chronic enhancement of CREB function on spatial memory in mammals, we examined spatial navigation in bitransgenic mice that express in a regulated and restricted manner a constitutively active form of CREB, VP16-CREB, in forebrain neurons. We found that chronic enhancement of CREB activity delayed the acquisition of an allocentric strategy to solve the hidden platform task. The ability to turn on and off transgene expression allowed us to dissect the role of CREB in dissociable memory processes. In mice in which transgene expression was turned on during memory acquisition, turning off the transgene re-established the access to the memory trace, whereas in mice in which transgene expression was turned off during acquisition, turning on the transgene impaired memory expression in a reversible manner, indicating that CREB enhancement specifically interfered with the retrieval of spatial information. The defects on spatial navigation in mice with chronic enhancement of CREB function were not corrected by conditions that increased further CREB-dependent activation of hippocampal memory systems, such as housing in an enriched environment. These results along with previous findings in CREB-deficient mutants indicate that the relationship of CREB-mediated plasticity to spatial memory is an inverted-U function, and that optimal learning in the water maze requires accurate regulation of this pathway. 10.1101/lm.1220309
Spatial exploration induces ARC, a plasticity-related immediate-early gene, only in calcium/calmodulin-dependent protein kinase II-positive principal excitatory and inhibitory neurons of the rat forebrain. Vazdarjanova Almira,Ramirez-Amaya Victor,Insel Nathan,Plummer Thane K,Rosi Susanna,Chowdhury Shoaib,Mikhael Dalia,Worley Paul F,Guzowski John F,Barnes Carol A The Journal of comparative neurology Active behavior, such as exploring a novel environment, induces the expression of the immediate-early gene Arc (activity-regulated cytoskeletal associated protein, or Arg 3.1) in many brain regions, including the hippocampus, neocortex, and striatum. Arc messenger ribonucleic acid and protein are localized in activated dendrites, and Arc protein is required for the maintenance of long-term potentiation and memory consolidation. Although previous evidence suggests that Arc is expressed in neurons, there is no direct demonstration that only neurons can express Arc. Furthermore, there is no characterization of the main neuronal types that express Arc. The data reported here show that behavior- or seizure-induced Arc expression in the hippocampus, primary somatosensory cortex, and dorsal striatum of rats colocalizes only with neuronal (NeuN-positive) and not with glial (GFAP-positive) cells. Furthermore, Arc was found exclusively in non-GABAergic alpha-CaMKII-positive hippocampal and neocortical neurons of rats that had explored a novel environment. Some GAD65/67-positive neurons in these regions were observed to express Arc, but only after a very strong stimulus (electroconvulsive seizure). In the dorsal striatum, spatial exploration induced Arc only in GABAergic and alpha-CaMKII-positive neurons. Combined, these results show that although a very strong stimulus (seizure) can induce Arc in a variety of neurons, behavior induces Arc in the CaMKII-positive principal neurons of the hippocampus, neocortex, and dorsal striatum. These results, coupled with recent in vitro findings of interactions between Arc and CaMKII, are consistent with the hypothesis that Arc and CaMKII act as plasticity partners to promote functional and/or structural synaptic modifications that accompany learning. 10.1002/cne.21003
The tagging and capture hypothesis from synapse to memory. Viola Haydée,Ballarini Fabricio,Martínez María Cecilia,Moncada Diego Progress in molecular biology and translational science The synaptic tagging and capture theory (STC) was postulated by Frey and Morris in 1997 and provided a strong framework to explain how to achieve synaptic specificity and persistence of electrophysiological-induced plasticity changes. Ten years later, the same argument was applied on learning and memory models to explain the formation of long-term memories, resulting in the behavioral tagging hypothesis (BT). These hypotheses are able to explain how a weak event that induces transient changes in the brain can establish long-lasting phenomena through a tagging and capture process. In this framework, it was postulated that the weak event sets a tag that captures plasticity-related proteins/products (PRPs) synthesized by an independent strong event. The tagging and capture processes exhibit symmetry, and therefore, PRPs can be captured if they are synthesized either before or after the setting of the tag. In summary, the hypothesis provides a wide framework that gives a solid explanation of how lasting changes occur and how the interaction between different events leads to promotion, reinforcement, or impairment of such changes. In this chapter, we will summarize the postulates of STC hypothesis, the common features between synaptic plasticity and memory, as well as a detailed compilation of the findings supporting the existence of BT process. At the end, we pose some questions related to BT mechanism and LTM formation, which probably will be answered in the near future. 10.1016/B978-0-12-420170-5.00013-1
Schemas and memory consolidation. Tse Dorothy,Langston Rosamund F,Kakeyama Masaki,Bethus Ingrid,Spooner Patrick A,Wood Emma R,Witter Menno P,Morris Richard G M Science (New York, N.Y.) Memory encoding occurs rapidly, but the consolidation of memory in the neocortex has long been held to be a more gradual process. We now report, however, that systems consolidation can occur extremely quickly if an associative "schema" into which new information is incorporated has previously been created. In experiments using a hippocampal-dependent paired-associate task for rats, the memory of flavor-place associations became persistent over time as a putative neocortical schema gradually developed. New traces, trained for only one trial, then became assimilated and rapidly hippocampal-independent. Schemas also played a causal role in the creation of lasting associative memory representations during one-trial learning. The concept of neocortical schemas may unite psychological accounts of knowledge structures with neurobiological theories of systems memory consolidation. 10.1126/science.1135935
Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. Turrigiano Gina Annual review of neuroscience Maintaining the proper balance between excitation and inhibition is critical for the normal function of cortical circuits. This balance is thought to be maintained by an array of homeostatic mechanisms that regulate neuronal and circuit excitability, including mechanisms that target excitatory and inhibitory synapses, and mechanisms that target intrinsic neuronal excitability. In this review, I discuss where and when these mechanisms are used in complex microcircuits, what is currently known about the signaling pathways that underlie them, and how these different ways of achieving network stability cooperate and/or compete. An important challenge for the field of homeostatic plasticity is to assemble our understanding of these individual mechanisms into a coherent view of how microcircuit stability is maintained during experience-dependent circuit refinement. 10.1146/annurev-neuro-060909-153238
Memory Engram Cells Have Come of Age. Tonegawa Susumu,Liu Xu,Ramirez Steve,Redondo Roger Neuron The idea that memory is stored in the brain as physical alterations goes back at least as far as Plato, but further conceptualization of this idea had to wait until the 20(th) century when two guiding theories were presented: the "engram theory" of Richard Semon and Donald Hebb's "synaptic plasticity theory." While a large number of studies have been conducted since, each supporting some aspect of each of these theories, until recently integrative evidence for the existence of engram cells and circuits as defined by the theories was lacking. In the past few years, the combination of transgenics, optogenetics, and other technologies has allowed neuroscientists to begin identifying memory engram cells by detecting specific populations of cells activated during specific learning epochs and by engineering them not only to evoke recall of the original memory, but also to alter the content of the memory. 10.1016/j.neuron.2015.08.002
Toward a Neurocentric View of Learning. Neuron Synaptic plasticity (e.g., long-term potentiation [LTP]) is considered the cellular correlate of learning. Recent optogenetic studies on memory engram formation assign a critical role in learning to suprathreshold activation of neurons and their integration into active engrams ("engram cells"). Here we review evidence that ensemble integration may result from LTP but also from cell-autonomous changes in membrane excitability. We propose that synaptic plasticity determines synaptic connectivity maps, whereas intrinsic plasticity-possibly separated in time-amplifies neuronal responsiveness and acutely drives engram integration. Our proposal marks a move away from an exclusively synaptocentric toward a non-exclusive, neurocentric view of learning. 10.1016/j.neuron.2017.05.021
Transient changes in excitability of rabbit CA3 neurons with a time course appropriate to support memory consolidation. Thompson L T,Moyer J R,Disterhoft J F Journal of neurophysiology 1. The excitability of CA3 pyramidal neurons was assessed with intracellular recordings in hippocampal slices from behaviorally naive rabbits. CA3 pyramidal neurons had large (-13.1 +/- 0.3 mV; mean +/- SE) postburst afterhyperpolarization (AHPs) and exhibited robust spike-frequency adaptation (accommodation) to prolonged (800-ms) depolarizing current injection at resting potentials of -68 mV. AHP and accommodation measures differed in scale but not in kind from those obtained in stable recordings from CA1 pyramidal neurons in the same slices or from the same rabbits, with CA3 neurons having larger longer AHPs but fewer spikes during accommodation. 2. Groups of rabbits were trained in a simple, associative-learning task, trace eye-blink conditioning, which required an intact hippocampus for successful acquisition. Memory consolidation in this task also involves the hippocampus, whereas long-term retention of the learned response does not. The time course and magnitude of learning-specific changes in excitability were assessed in 201 CA3 pyramidal neurons. 3. Learning increased the excitability of CA3 pyramidal neurons soon after acquisition (within 1-24 h). The mean postburst AHP was reduced to approximately half (-6.4 +/- 0.3 mV) the basal amplitude of the AHP observed in naive controls. The area and duration of the postburst AHP similarly were reduced. Approximately half of all pyramidal neurons tested soon after learning exhibited significantly reduced AHPs, whereas none exhibited enhanced AHPs. 4. Trace conditioning also reduced accommodation of CA3 pyramidal neurons 1-24 h after learning. Neurons from successfully trained rabbits fired significantly more action potentials (5.6 +/- 1.5) in response to prolonged depolarization than did neurons from naive controls (4.1 +/- 0.2). The magnitude of the learning-specific change in accommodation was less than that for the AHP. Approximately 45% of neurons tested exhibited significantly reduced accommodation soon after learning. 5. Both learning-specific changes in CA3 increased neuronal excitability. Both changes were highly time dependent. AHPs were reduced maximally 1-24 h after learning, then increased, returning to basal (naive) levels within 7 days and remaining basal thereafter. The decay rate of accommodation to basal levels preceded that of the AHP by several days. 6. Other membrane properties, including action potential characteristics, resting potential, and input resistance, were unchanged by learning. The restriction of the observed changes to two interrelated measures of excitability concurs with earlier reports that learning-specific changes in the mammalian hippocampus are linked to changes in a limited number of membrane conductances. 7. Learning, not long-term memory or performance of the learned behavior, was linked to the excitability changes. Neurons from rabbits that failed to acquire the task after considerable training exhibited no excitability changes. Neurons from pseudoconditioned rabbits were indistinguishable from neurons of behaviorally naive controls. Finally, neurons from rabbits that explicitly demonstrated long-term retention of the conditioned response were indistinguishable from those of naive controls. 8. Behavioral changes persisted for extremely long periods, but the observed changes in hippocampal excitability were transient and greatest soon after learning. Excitability was enhanced for a period of a few days, a period demonstrated in other eyeblink studies to be required for memory consolidation. Because hippocampal excitability then returned to basal levels but memory of the learned task persisted, postconsolidation memory traces (the "engram") must be extrahippocampal. 10.1152/jn.1996.76.3.1836
Evidence for an Evolutionarily Conserved Memory Coding Scheme in the Mammalian Hippocampus. Thome Alexander,Marrone Diano F,Ellmore Timothy M,Chawla Monica K,Lipa Peter,Ramirez-Amaya Victor,Lisanby Sarah H,McNaughton Bruce L,Barnes Carol A The Journal of neuroscience : the official journal of the Society for Neuroscience Decades of research identify the hippocampal formation as central to memory storage and recall. Events are stored via distributed population codes, the parameters of which (e.g., sparsity and overlap) determine both storage capacity and fidelity. However, it remains unclear whether the parameters governing information storage are similar between species. Because episodic memories are rooted in the space in which they are experienced, the hippocampal response to navigation is often used as a proxy to study memory. Critically, recent studies in rodents that mimic the conditions typical of navigation studies in humans and nonhuman primates (i.e., virtual reality) show that reduced sensory input alters hippocampal representations of space. The goal of this study was to quantify this effect and determine whether there are commonalities in information storage across species. Using functional molecular imaging, we observe that navigation in virtual environments elicits activity in fewer CA1 neurons relative to real-world conditions. Conversely, comparable neuronal activity is observed in hippocampus region CA3 and the dentate gyrus under both conditions. Surprisingly, we also find evidence that the absolute number of neurons used to represent an experience is relatively stable between nonhuman primates and rodents. We propose that this convergence reflects an optimal ensemble size for episodic memories. One primary factor constraining memory capacity is the sparsity of the engram, the proportion of neurons that encode a single experience. Investigating sparsity in humans is hampered by the lack of single-cell resolution and differences in behavioral protocols. Sparsity can be quantified in freely moving rodents, but extrapolating these data to humans assumes that information storage is comparable across species and is robust to restraint-induced reduction in sensory input. Here, we test these assumptions and show that species differences in brain size build memory capacity without altering the structure of the data being stored. Furthermore, sparsity in most of the hippocampus is resilient to reduced sensory information. This information is vital to integrating animal data with human imaging navigation studies. 10.1523/JNEUROSCI.3057-16.2017
Reactivation of neural ensembles during the retrieval of recent and remote memory. Tayler Kaycie K,Tanaka Kazumasa Z,Reijmers Leon G,Wiltgen Brian J Current biology : CB BACKGROUND:Episodic memories are encoded within hippocampal and neocortical circuits. Retrieving these memories is assumed to involve reactivation of neural ensembles that were established during learning. Although it has been possible to follow the activity of individual neurons shortly after learning, it has not been possible to examine their activity weeks later during retrieval. We addressed this issue by using a stable form of GFP (H2B-GFP) to permanently tag neurons that are active during contextual fear conditioning. RESULTS:H2B-GFP expression in transgenic mice was increased by learning and could be regulated by doxycycline (DOX). Using this system, we found a large network of neurons in the hippocampus, amygdala, and neocortex that were active during context fear conditioning and subsequent memory retrieval 2 days later. Reactivation was contingent on memory retrieval and was not observed when animals were trained and tested in different environments. When memory was retrieved several weeks after learning, reactivation was altered in the hippocampus and amygdala but remained unchanged in the cortex. CONCLUSIONS:Retrieving a recently formed context fear memory reactivates neurons in the hippocampus, amygdala, and cortex. Several weeks after learning, the degree of reactivation is altered in hippocampal and amygdala networks but remains stable in the cortex. 10.1016/j.cub.2012.11.019
Cortical representations are reinstated by the hippocampus during memory retrieval. Tanaka Kazumasa Z,Pevzner Aleksandr,Hamidi Anahita B,Nakazawa Yuki,Graham Jalina,Wiltgen Brian J Neuron The hippocampus is assumed to retrieve memory by reinstating patterns of cortical activity that were observed during learning. To test this idea, we monitored the activity of individual cortical neurons while simultaneously inactivating the hippocampus. Neurons that were active during context fear conditioning were tagged with the long-lasting fluorescent protein H2B-GFP and the light-activated proton pump ArchT. These proteins allowed us to identify encoding neurons several days after learning and silence them with laser stimulation. When tagged CA1 cells were silenced, we found that memory retrieval was impaired and representations in the cortex (entorhinal, retrosplenial, perirhinal) and the amygdala could not be reactivated. Importantly, hippocampal inactivation did not alter the total amount of activity in most brain regions. Instead, it selectively prevented neurons that were active during learning from being reactivated during retrieval. These data provide functional evidence that the hippocampus reactivates specific memory representations during retrieval. 10.1016/j.neuron.2014.09.037
Retrieval-induced forgetting predicts failure to recall negative autobiographical memories. Storm Benjamin C,Jobe Tara A Psychological science There is a positivity bias in autobiographical memory such that people are more likely to remember positive events from their past than they are to remember negative ones. Inhibition may promote this positivity bias by deterring negative memories from being retrieved. In our first experiment, we measured individual differences in retrieval-induced forgetting, a phenomenon believed to be the consequence of retrieval inhibition, and correlated that measure with individual differences in the recall of positive and negative autobiographical memories. Participants who exhibited lower levels of retrieval-induced forgetting recalled significantly more negative memories despite recalling fewer positive memories. In our second experiment, participants attempted to recall negative memories from childhood and from the previous month. Participants who exhibited lower levels of retrieval-induced forgetting recalled significantly more negative memories in both conditions. These results suggest that inhibition plays a key role in preventing the retrieval of negative autobiographical memories. 10.1177/0956797612443837
Hippocampal Somatostatin Interneurons Control the Size of Neuronal Memory Ensembles. Stefanelli Thomas,Bertollini Cristina,Lüscher Christian,Muller Dominique,Mendez Pablo Neuron Hippocampal neurons activated during encoding drive the recall of contextual fear memory. Little is known about how such ensembles emerge during acquisition and eventually form the cellular engram. Manipulating the activity of granule cells (GCs) of the dentate gyrus (DG), we reveal a mechanism of lateral inhibition that modulates the size of the cellular engram. GCs engage somatostatin-positive interneurons that inhibit the dendrites of surrounding GCs. Our findings reveal a microcircuit within the DG that controls the size of the cellular engram and the stability of contextual fear memory. 10.1016/j.neuron.2016.01.024
Declarative and nondeclarative memory: multiple brain systems supporting learning and memory. Squire L R Journal of cognitive neuroscience Abstract The topic of multiple forms of memory is considered from a biological point of view. Fact-and-event (declarative, explicit) memory is contrasted with a collection of non conscious (non-declarative, implicit) memory abilities including skills and habits, priming, and simple conditioning. Recent evidence is reviewed indicating that declarative and non declarative forms of memory have different operating characteristics and depend on separate brain systems. A brain-systems framework for understanding memory phenomena is developed in light of lesion studies involving rats, monkeys, and humans, as well as recent studies with normal humans using the divided visual field technique, event-related potentials, and positron emission tomography (PET). 10.1162/jocn.1992.4.3.232
Trace fear conditioning enhances synaptic and intrinsic plasticity in rat hippocampus. Song Chenghui,Detert Julia A,Sehgal Megha,Moyer James R Journal of neurophysiology Experience-dependent synaptic and intrinsic plasticity are thought to be important substrates for learning-related changes in behavior. The present study combined trace fear conditioning with both extracellular and intracellular hippocampal recordings to study learning-related synaptic and intrinsic plasticity. Rats received one session of trace fear conditioning, followed by a brief conditioned stimulus (CS) test the next day. To relate behavioral performance with measures of hippocampal CA1 physiology, brain slices were prepared within 1 h of the CS test. In trace-conditioned rats, both synaptic plasticity and intrinsic excitability were significantly correlated with behavior such that better learning corresponded with enhanced long-term potentiation (LTP; r = 0.64, P < 0.05) and a smaller postburst afterhyperpolarization (AHP; r = -0.62, P < 0.05). Such correlations were not observed in pseudoconditioned rats, whose physiological data were comparable to those of poor learners and naive and chamber-exposed control rats. In addition, acquisition of trace fear conditioning did not enhance basal synaptic responses. Thus these data suggest that within the hippocampus both synaptic and intrinsic mechanisms are involved in the acquisition of trace fear conditioning. 10.1152/jn.00692.2011
Integrating memories in the human brain: hippocampal-midbrain encoding of overlapping events. Shohamy Daphna,Wagner Anthony D Neuron Decisions are often guided by generalizing from past experiences. Fundamental questions remain regarding the cognitive and neural mechanisms by which generalization takes place. Prior data suggest that generalization may stem from inference-based processes at the time of generalization. By contrast, generalization may emerge from mnemonic processes occurring while premise events are encoded. Here, participants engaged in a two-phase learning and generalization task, wherein they learned a series of overlapping associations and subsequently generalized what they learned to novel stimulus combinations. Functional MRI revealed that successful generalization was associated with coupled changes in learning-phase activity in the hippocampus and midbrain (ventral tegmental area/substantia nigra). These findings provide evidence for generalization based on integrative encoding, whereby overlapping past events are integrated into a linked mnemonic representation. Hippocampal-midbrain interactions support the dynamic integration of experiences, providing a powerful mechanism for building a rich associative history that extends beyond individual events. 10.1016/j.neuron.2008.09.023
Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies. The Journal of neuroscience : the official journal of the Society for Neuroscience It is well established that the basolateral amygdala is critically involved in the association between an unconditioned stimulus (US), such as a foot shock, and a conditioned stimulus (CS), such as a light, during classic fear conditioning. However, little is known about how the US (pain) inputs are relayed to the basolateral amygdala. The present studies were designed to define potential US pathways to the amygdala using lesion methods. Electrolytic lesions before or after training were placed in caudal granular/dysgranular insular cortex (IC) alone or in conjunction with the posterior intralaminar nuclei of the thalamus (PoT/PIL), and the effects on fear conditioning were examined. Pretraining lesions of both IC and PoT/PIL, but not lesions of IC alone, blocked the acquisition of fear-potentiated startle. However, post-training combined lesions of IC and PoT/PIL did not prevent expression of conditioned fear. Given that previous studies have shown that lesions of PoT/PIL alone had no effect on acquisition of conditioned fear, these results suggest that two parallel cortical (insula-amygdala) and subcortical (PoT/PIL-amygdala) pathways are involved in relaying shock information to the basolateral amygdala during fear conditioning.
Dorsal hippocampal CREB is both necessary and sufficient for spatial memory. Sekeres Melanie J,Neve Rachael L,Frankland Paul W,Josselyn Sheena A Learning & memory (Cold Spring Harbor, N.Y.) Although the transcription factor CREB has been widely implicated in memory, whether it is sufficient to produce spatial memory under conditions that do not normally support memory formation in mammals is unknown. We found that locally and acutely increasing CREB levels in the dorsal hippocampus using viral vectors is sufficient to induce robust spatial memory in two conditions that do not normally support spatial memory, weakly trained wild-type (WT) mice and strongly trained mutant mice with a brain-wide disruption of CREB function. Together with previous results, these findings indicate that CREB is both necessary and sufficient for spatial memory formation, and highlight its pivotal role in the hippocampal molecular machinery underlying the formation of spatial memory. 10.1101/lm.1785510
Increasing CRTC1 function in the dentate gyrus during memory formation or reactivation increases memory strength without compromising memory quality. Sekeres Melanie J,Mercaldo Valentina,Richards Blake,Sargin Derya,Mahadevan Vivek,Woodin Melanie A,Frankland Paul W,Josselyn Sheena A The Journal of neuroscience : the official journal of the Society for Neuroscience Memory stabilization following encoding (synaptic consolidation) or memory reactivation (reconsolidation) requires gene expression and protein synthesis (Dudai and Eisenberg, 2004; Tronson and Taylor, 2007; Nader and Einarsson, 2010; Alberini, 2011). Although consolidation and reconsolidation may be mediated by distinct molecular mechanisms (Lee et al., 2004), disrupting the function of the transcription factor CREB impairs both processes (Kida et al., 2002; Mamiya et al., 2009). Phosphorylation of CREB at Ser133 recruits CREB binding protein (CBP)/p300 coactivators to activate transcription (Chrivia et al., 1993; Parker et al., 1996). In addition to this well known mechanism, CREB regulated transcription coactivators (CRTCs), previously called transducers of regulated CREB (TORC) activity, stimulate CREB-mediated transcription, even in the absence of CREB phosphorylation. Recently, CRTC1 has been shown to undergo activity-dependent trafficking from synapses and dendrites to the nucleus in excitatory hippocampal neurons (Ch'ng et al., 2012). Despite being a powerful and specific coactivator of CREB, the role of CRTC in memory is virtually unexplored. To examine the effects of increasing CRTC levels, we used viral vectors to locally and acutely increase CRTC1 in the dorsal hippocampus dentate gyrus region of mice before training or memory reactivation in context fear conditioning. Overexpressing CRTC1 enhanced both memory consolidation and reconsolidation; CRTC1-mediated memory facilitation was context specific (did not generalize to nontrained context) and long lasting (observed after virally expressed CRTC1 dissipated). CREB overexpression produced strikingly similar effects. Therefore, increasing CRTC1 or CREB function is sufficient to enhance the strength of new, as well as established reactivated, memories without compromising memory quality. 10.1523/JNEUROSCI.1419-12.2012
Learning to learn - intrinsic plasticity as a metaplasticity mechanism for memory formation. Sehgal Megha,Song Chenghui,Ehlers Vanessa L,Moyer James R Neurobiology of learning and memory "Use it or lose it" is a popular adage often associated with use-dependent enhancement of cognitive abilities. Much research has focused on understanding exactly how the brain changes as a function of experience. Such experience-dependent plasticity involves both structural and functional alterations that contribute to adaptive behaviors, such as learning and memory, as well as maladaptive behaviors, including anxiety disorders, phobias, and posttraumatic stress disorder. With the advancing age of our population, understanding how use-dependent plasticity changes across the lifespan may also help to promote healthy brain aging. A common misconception is that such experience-dependent plasticity (e.g., associative learning) is synonymous with synaptic plasticity. Other forms of plasticity also play a critical role in shaping adaptive changes within the nervous system, including intrinsic plasticity - a change in the intrinsic excitability of a neuron. Intrinsic plasticity can result from a change in the number, distribution or activity of various ion channels located throughout the neuron. Here, we review evidence that intrinsic plasticity is an important and evolutionarily conserved neural correlate of learning. Intrinsic plasticity acts as a metaplasticity mechanism by lowering the threshold for synaptic changes. Thus, learning-related intrinsic changes can facilitate future synaptic plasticity and learning. Such intrinsic changes can impact the allocation of a memory trace within a brain structure, and when compromised, can contribute to cognitive decline during the aging process. This unique role of intrinsic excitability can provide insight into how memories are formed and, more interestingly, how neurons that participate in a memory trace are selected. Most importantly, modulation of intrinsic excitability can allow for regulation of learning ability - this can prevent or provide treatment for cognitive decline not only in patients with clinical disorders but also in the aging population. 10.1016/j.nlm.2013.07.008
Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Schroeder B C,Kubisch C,Stein V,Jentsch T J Nature Epilepsy affects more than 0.5% of the world's population and has a large genetic component. It is due to an electrical hyperexcitability in the central nervous system. Potassium channels are important regulators of electrical signalling, and benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes. Here we show that KCNQ2 and KCNQ3 are distributed broadly in brain with expression patterns that largely overlap. Expression in Xenopus oocytes indicates the formation of heteromeric KCNQ2/KCNQ3 potassium channels with currents that are at least tenfold larger than those of the respective homomeric channels. KCNQ2/KCNQ3 currents can be increased by intracellular cyclic AMP, an effect that depends on an intact phosphorylation site in the KCNQ2 amino terminus. KCNQ2 and KCNQ3 mutations identified in BFNC pedigrees compromised the function of the respective subunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC. Drugs raising intracellular cAMP may prove beneficial in this form of epilepsy. 10.1038/25367
Loss of recent memory after bilateral hippocampal lesions. SCOVILLE W B,MILNER B Journal of neurology, neurosurgery, and psychiatry 10.1136/jnnp.20.1.11
Long-term sensitization in Aplysia: biophysical correlates in tail sensory neurons. Scholz K P,Byrne J H Science (New York, N.Y.) A fundamental problem in the cellular analysis of learning and memory is the identification of the neuronal substrates of long-term information storage and their relation to short-term cellular alterations. In this report, biophysical correlates of long-term sensitization of a simple withdrawal reflex in the mollusc Aplysia were examined. A voltage-clamp analysis of the sensory neurons that control the reflex, 24 hours after sensitization training, revealed a significant reduction in net outward current. The results indicate that one mechanism for the storage of long-term sensitization is the regulation of membrane currents that influence the characteristics of the action potential and the excitability of individual neurons. The results also provide insights into the relation between short- and long-term sensitization in that the biophysical loci involved in the storage of long-term sensitization appear similar to those involved in short-term sensitization. 10.1126/science.2433766
CA1 subfield contributions to memory integration and inference. Hippocampus The ability to combine information acquired at different times to make novel inferences is a powerful function of episodic memory. One perspective suggests that by retrieving related knowledge during new experiences, existing memories can be linked to the new, overlapping information as it is encoded. The resulting memory traces would thus incorporate content across event boundaries, representing important relationships among items encountered during separate experiences. While prior work suggests that the hippocampus is involved in linking memories experienced at different times, the involvement of specific subfields in this process remains unknown. Using both univariate and multivariate analyses of high-resolution functional magnetic resonance imaging (fMRI) data, we localized this specialized encoding mechanism to human CA1 . Specifically, right CA1 responses during encoding of events that overlapped with prior experience predicted subsequent success on a test requiring inferences about the relationships among events. Furthermore, we employed neural pattern similarity analysis to show that patterns of activation evoked during overlapping event encoding were later reinstated in CA1 during successful inference. The reinstatement of CA1 patterns during inference was specific to those trials that were performed quickly and accurately, consistent with the notion that linking memories during learning facilitates novel judgments. These analyses provide converging evidence that CA1 plays a unique role in encoding overlapping events and highlight the dynamic interactions between hippocampal-mediated encoding and retrieval processes. More broadly, our data reflect the adaptive nature of episodic memories, in which representations are derived across events in anticipation of future judgments. 10.1002/hipo.22310
Memory integration: neural mechanisms and implications for behavior. Schlichting Margaret L,Preston Alison R Current opinion in behavioral sciences Everyday behaviors require a high degree of flexibility, in which prior knowledge is applied to inform behavior in new situations. Such flexibility is thought to be supported in part by memory integration, a process whereby related memories become interconnected in the brain through recruitment of overlapping neuronal populations. Recent advances in cognitive and behavioral neuroscience highlight the importance of a hippocampal-medial prefrontal circuit in memory integration. Emerging evidence suggests that abstracted representations in medial prefrontal cortex guide reactivation of related memories during new encoding events, thus promoting hippocampal integration of related experiences. Moreover, recent work indicates that integrated memories are called upon during novel situations to facilitate a host of behaviors, from spatial navigation to imagination. 10.1016/j.cobeha.2014.07.005
Memory distortion: an adaptive perspective. Schacter Daniel L,Guerin Scott A,St Jacques Peggy L Trends in cognitive sciences Memory is prone to distortions that can have serious consequences in everyday life. Here we integrate emerging evidence that several types of memory distortions - imagination inflation, gist-based and associative memory errors, and post-event misinformation - reflect adaptive cognitive processes that contribute to the efficient functioning of memory, but produce distortions as a consequence of doing so. We consider recent cognitive and neuroimaging studies that link these distortions with adaptive processes, including simulation of future events, semantic and contextual encoding, creativity, and memory updating. We also discuss new evidence concerning factors that can influence the occurrence of memory distortions, such as sleep and retrieval conditions, as well as conceptual issues related to the development of an adaptive perspective. 10.1016/j.tics.2011.08.004
CREB regulates spine density of lateral amygdala neurons: implications for memory allocation. Sargin Derya,Mercaldo Valentina,Yiu Adelaide P,Higgs Gemma,Han Jin-Hee,Frankland Paul W,Josselyn Sheena A Frontiers in behavioral neuroscience Neurons may compete against one another for integration into a memory trace. Specifically, neurons in the lateral nucleus of the amygdala with relatively higher levels of cAMP Responsive Element Binding Protein (CREB) seem to be preferentially allocated to a fear memory trace, while neurons with relatively decreased CREB function seem to be excluded from a fear memory trace. CREB is a ubiquitous transcription factor that modulates many diverse cellular processes, raising the question as to which of these CREB-mediated processes underlie memory allocation. CREB is implicated in modulating dendritic spine number and morphology. As dendritic spines are intimately involved in memory formation, we investigated whether manipulations of CREB function alter spine number or morphology of neurons at the time of fear conditioning. We used viral vectors to manipulate CREB function in the lateral amygdala (LA) principal neurons in mice maintained in their homecages. At the time that fear conditioning normally occurs, we observed that neurons with high levels of CREB had more dendritic spines, while neurons with low CREB function had relatively fewer spines compared to control neurons. These results suggest that the modulation of spine density provides a potential mechanism for preferential allocation of a subset of neurons to the memory trace. 10.3389/fnbeh.2013.00209
Postsynaptic receptor trafficking underlying a form of associative learning. Rumpel Simon,LeDoux Joseph,Zador Anthony,Malinow Roberto Science (New York, N.Y.) To elucidate molecular, cellular, and circuit changes that occur in the brain during learning, we investigated the role of a glutamate receptor subtype in fear conditioning. In this form of learning, animals associate two stimuli, such as a tone and a shock. Here we report that fear conditioning drives AMPA-type glutamate receptors into the synapse of a large fraction of postsynaptic neurons in the lateral amygdala, a brain structure essential for this learning process. Furthermore, memory was reduced if AMPA receptor synaptic incorporation was blocked in as few as 10 to 20% of lateral amygdala neurons. Thus, the encoding of memories in the lateral amygdala is mediated by AMPA receptor trafficking, is widely distributed, and displays little redundancy. 10.1126/science.1103944
Neural networks in the brain involved in memory and recall. Rolls E T,Treves A Progress in brain research We have considered how the neuronal network architecture of the hippocampus may enable it to act as an intermediate term buffer store for recent memories, and how information may be recalled from it to the cerebral cortex using modified synapses in back-projection pathways from the hippocampus to the cerebral cortex. The recalled information in the cerebral neocortex could then be used by the neocortex in the formation of long-term memories, which is severely impaired by damage to the hippocampus. 10.1016/S0079-6123(08)60550-6
Synaptic tagging during memory allocation. Rogerson Thomas,Cai Denise J,Frank Adam,Sano Yoshitake,Shobe Justin,Lopez-Aranda Manuel F,Silva Alcino J Nature reviews. Neuroscience There is now compelling evidence that the allocation of memory to specific neurons (neuronal allocation) and synapses (synaptic allocation) in a neurocircuit is not random and that instead specific mechanisms, such as increases in neuronal excitability and synaptic tagging and capture, determine the exact sites where memories are stored. We propose an integrated view of these processes, such that neuronal allocation, synaptic tagging and capture, spine clustering and metaplasticity reflect related aspects of memory allocation mechanisms. Importantly, the properties of these mechanisms suggest a set of rules that profoundly affect how memories are stored and recalled. 10.1038/nrn3667
Simultaneous cellular-resolution optical perturbation and imaging of place cell firing fields. Nature neuroscience Linking neural microcircuit function to emergent properties of the mammalian brain requires fine-scale manipulation and measurement of neural activity during behavior, where each neuron's coding and dynamics can be characterized. We developed an optical method for simultaneous cellular-resolution stimulation and large-scale recording of neuronal activity in behaving mice. Dual-wavelength two-photon excitation allowed largely independent functional imaging with a green fluorescent calcium sensor (GCaMP3, λ = 920 ± 6 nm) and single-neuron photostimulation with a red-shifted optogenetic probe (C1V1, λ = 1,064 ± 6 nm) in neurons coexpressing the two proteins. We manipulated task-modulated activity in individual hippocampal CA1 place cells during spatial navigation in a virtual reality environment, mimicking natural place-field activity, or 'biasing', to reveal subthreshold dynamics. Notably, manipulating single place-cell activity also affected activity in small groups of other place cells that were active around the same time in the task, suggesting a functional role for local place cell interactions in shaping firing fields. 10.1038/nn.3866
Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation. Rexach Jessica E,Clark Peter M,Mason Daniel E,Neve Rachael L,Peters Eric C,Hsieh-Wilson Linda C Nature chemical biology The transcription factor cyclic AMP-response element binding protein (CREB) is a key regulator of many neuronal processes, including brain development, circadian rhythm and long-term memory. Studies of CREB have focused on its phosphorylation, although the diversity of CREB functions in the brain suggests additional forms of regulation. Here we expand on a chemoenzymatic strategy for quantifying glycosylation stoichiometries to characterize the functional roles of CREB glycosylation in neurons. We show that CREB is dynamically modified with an O-linked β-N-acetyl-D-glucosamine sugar in response to neuronal activity and that glycosylation represses CREB-dependent transcription by impairing its association with CREB-regulated transcription coactivator (CRTC; also known as transducer of regulated CREB activity). Blocking glycosylation of CREB alters cellular function and behavioral plasticity, enhancing both axonal and dendritic growth and long-term memory consolidation. Our findings demonstrate a new role for O-glycosylation in memory formation and provide a mechanistic understanding of how glycosylation contributes to critical neuronal functions. Moreover, we identify a previously unknown mechanism for the regulation of activity-dependent gene expression, neural development and memory. 10.1038/nchembio.770
Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Repa J C,Muller J,Apergis J,Desrochers T M,Zhou Y,LeDoux J E Nature neuroscience Single-cell activity was recorded in the dorsal subnucleus of the lateral amygdala (LAd) of freely behaving rats during Pavlovian fear conditioning, to determine the relationship between neuronal activity and behavioral learning. Neuronal responses elicited by the conditioned stimulus typically increased before behavioral fear was evident, supporting the hypothesis that neural changes in LAd account for the conditioning of behavior. Furthermore, two types of these rapidly modified cells were found. Some, located in the dorsal tip of LAd, exhibited short-latency responses (<20 ms) that were only transiently changed. A second class of cells, most commonly found in ventral regions of LAd, had longer latency responses, but maintained enhanced responding throughout training and even through extinction. These anatomically distinct cells in LAd may be differentially involved in the initiation of learning and long-term memory storage. 10.1038/89512
Localization of a stable neural correlate of associative memory. Reijmers Leon G,Perkins Brian L,Matsuo Naoki,Mayford Mark Science (New York, N.Y.) Do learning and retrieval of a memory activate the same neurons? Does the number of reactivated neurons correlate with memory strength? We developed a transgenic mouse that enables the long-lasting genetic tagging of c-fos-active neurons. We found neurons in the basolateral amygdala that are activated during Pavlovian fear conditioning and are reactivated during memory retrieval. The number of reactivated neurons correlated positively with the behavioral expression of the fear memory, indicating a stable neural correlate of associative memory. The ability to manipulate these neurons genetically should allow a more precise dissection of the molecular mechanisms of memory encoding within a distributed neuronal network. 10.1126/science.1143839
Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature The valence of memories is malleable because of their intrinsic reconstructive property. This property of memory has been used clinically to treat maladaptive behaviours. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory. 10.1038/nature13725
Creating a false memory in the hippocampus. Ramirez Steve,Liu Xu,Lin Pei-Ann,Suh Junghyup,Pignatelli Michele,Redondo Roger L,Ryan Tomás J,Tonegawa Susumu Science (New York, N.Y.) Memories can be unreliable. We created a false memory in mice by optogenetically manipulating memory engram-bearing cells in the hippocampus. Dentate gyrus (DG) or CA1 neurons activated by exposure to a particular context were labeled with channelrhodopsin-2. These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context, in which a foot shock was never delivered. The recall of this false memory was context-specific, activated similar downstream regions engaged during natural fear memory recall, and was also capable of driving an active fear response. Our data demonstrate that it is possible to generate an internally represented and behaviorally expressed fear memory via artificial means. 10.1126/science.1239073
Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Quirk G J,Repa C,LeDoux J E Neuron The lateral nucleus of the amygdala (LA) is the first site in the amygdala where the plasticity underlying fear conditioning could occur. We simultaneously recorded from multiple LA neurons in freely moving rats during fear conditioning trials in which tones were paired with foot shocks. Conditioning significantly increased the magnitude of tone-elicited responses (often within the first several trials), converted unresponsive cells into tone-responsive ones, and altered functional couplings between LA neurons. The effects of conditioning were greatest on the shortest latency (less than 15 ms) components of the tone-elicited responses, consistent with the hypothesis that direct projections from the auditory thalamus to LA are an important link in the circuitry through which rapid behavioral responses are controlled in the presence of conditioned fear stimuli.
Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Quirk G J,Armony J L,LeDoux J E Neuron Single neurons were recorded in freely behaving rats during fear conditioning from areas of auditory cortex that project to the lateral nucleus of the amygdala (LA). The latency and rate of conditioning and extinction were analyzed, and the results were compared to previous recordings from LA itself. Auditory cortex neurons took more trials to learn, and they responded more slowly than LA neurons within trials. Short-latency plasticity in LA, therefore, reflects inputs from the auditory thalamus rather than the auditory cortex. Unlike LA cells, some auditory cortex cells showed late conditioned responses that seemed to anticipate the unconditioned stimulus, while others showed extinction-resistant memory storage. Thus, rapid conditioning of fear responses to potentially dangerous stimuli depends on plasticity in the amygdala, while cortical areas may be particularly involved in higher cognitive (mnemonic and attentional) processing of fear experiences.
A metaplasticity-like mechanism supports the selection of fear memories: role of protein kinase a in the amygdala. The Journal of neuroscience : the official journal of the Society for Neuroscience How the brain determines which memories are selected for long-term storage is critical for a full understanding of memory. One possibility is that memories are selected based on the history of activity and current state of neurons within a given memory circuit. Many in vitro studies have demonstrated metaplasticity-like effects whereby prior neuronal activity can affect the ability of cells to express synaptic plasticity in the future; however, the significance of these findings to memory is less clear. Here we show in rats that a single pairing of a light with shock, insufficient to support either short- or long-term fear memory, primes future learning such that another trial delivered within a circumscribed time window lasting from ∼60 min to 3 d results in the formation of a long-lasting and robust fear memory. Two adequately spaced training trials support long-term fear memory only if the two trials are signaled by the same cue. Furthermore, although a single training trial does not support formation of an observable fear memory, it does result in the phosphorylation of several targets of protein kinase A (PKA) in the amygdala. Accordingly, blocking PKA signaling in the amygdala before the first training trial completely prevents the ability of that trial to facilitate the formation of long-term fear memory when a second trial is delivered 24 h later. These findings may provide insight into how memories are selected for long-term storage. 10.1523/JNEUROSCI.0939-12.2012
Neuronal Allocation to a Hippocampal Engram. Park Sungmo,Kramer Emily E,Mercaldo Valentina,Rashid Asim J,Insel Nathan,Frankland Paul W,Josselyn Sheena A Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology The dentate gyrus (DG) is important for encoding contextual memories, but little is known about how a population of DG neurons comes to encode and support a particular memory. One possibility is that recruitment into an engram depends on a neuron's excitability. Here, we manipulated excitability by overexpressing CREB in a random population of DG neurons and examined whether this biased their recruitment to an engram supporting a contextual fear memory. To directly assess whether neurons overexpressing CREB at the time of training became critical components of the engram, we examined memory expression while the activity of these neurons was silenced. Chemogenetically (hM4Di, an inhibitory DREADD receptor) or optogenetically (iC++, a light-activated chloride channel) silencing the small number of CREB-overexpressing DG neurons attenuated memory expression, whereas silencing a similar number of random neurons not overexpressing CREB at the time of training did not. As post-encoding reactivation of the activity patterns present during initial experience is thought to be important in memory consolidation, we investigated whether post-training silencing of neurons allocated to an engram disrupted subsequent memory expression. We found that silencing neurons 5 min (but not 24 h) following training disrupted memory expression. Together these results indicate that the rules of neuronal allocation to an engram originally described in the lateral amygdala are followed in different brain regions including DG, and moreover, that disrupting the post-training activity pattern of these neurons prevents memory consolidation. 10.1038/npp.2016.73
Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Pape Hans-Christian,Pare Denis Physiological reviews The last 10 years have witnessed a surge of interest for the mechanisms underlying the acquisition and extinction of classically conditioned fear responses. In part, this results from the realization that abnormalities in fear learning mechanisms likely participate in the development and/or maintenance of human anxiety disorders. The simplicity and robustness of this learning paradigm, coupled with the fact that the underlying circuitry is evolutionarily well conserved, make it an ideal model to study the basic biology of memory and identify genetic factors and neuronal systems that regulate the normal and pathological expressions of learned fear. Critical advances have been made in determining how modified neuronal functions upon fear acquisition become stabilized during fear memory consolidation and how these processes are controlled in the course of fear memory extinction. With these advances came the realization that activity in remote neuronal networks must be coordinated for these events to take place. In this paper, we review these mechanisms of coordinated network activity and the molecular cascades leading to enduring fear memory, and allowing for their extinction. We will focus on Pavlovian fear conditioning as a model and the amygdala as a key component for the acquisition and extinction of fear responses. 10.1152/physrev.00037.2009
The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. O'Keefe J,Dostrovsky J Brain research 10.1016/0006-8993(71)90358-1
Watermaze learning enhances excitability of CA1 pyramidal neurons. Oh M Matthew,Kuo Amy G,Wu Wendy W,Sametsky Evgeny A,Disterhoft John F Journal of neurophysiology The dorsal hippocampus is crucial for learning the hidden-platform location in the hippocampus-dependent, spatial watermaze task. We have previously demonstrated that the postburst afterhyperpolarization (AHP) of hippocampal pyramidal neurons is reduced after acquisition of the hippocampus-dependent, temporal trace eyeblink conditioning task. We report here that the AHP and one or more of its associated currents (IAHP and/or sIAHP) are reduced in dorsal hippocampal CA1 pyramidal neurons from rats that learned the watermaze task as compared with neurons from control rats. This reduction was a learning-induced phenomenon as the AHP of CA1 neurons from rats that failed to learn the hidden-platform location was similar to that of neurons from control rats. We propose that reduction of the AHP in pyramidal neurons in regions crucial for learning is a cellular mechanism of learning that is conserved across species and tasks. 10.1152/jn.01177.2002
Modeling hippocampal and neocortical contributions to recognition memory: a complementary-learning-systems approach. Norman Kenneth A,O'Reilly Randall C Psychological review The authors present a computational neural-network model of how the hippocampus and medial temporal lobe cortex (MTLC) contribute to recognition memory. The hippocampal component contributes by recalling studied details. The MTLC component cannot support recall, but one can extract a scalar familiarity signal from MTLC that tracks how well a test item matches studied items. The authors present simulations that establish key differences in the operating characteristics of the hippocampal-recall and MTLC-familiarity signals and identify several manipulations (e.g., target-lure similarity, interference) that differentially affect the 2 signals. They also use the model to address the stochastic relationship between recall and familiarity and the effects of partial versus complete hippocampal lesions on recognition. 10.1037/0033-295X.110.4.611
A circuit mechanism for differentiating positive and negative associations. Namburi Praneeth,Beyeler Anna,Yorozu Suzuko,Calhoon Gwendolyn G,Halbert Sarah A,Wichmann Romy,Holden Stephanie S,Mertens Kim L,Anahtar Melodi,Felix-Ortiz Ada C,Wickersham Ian R,Gray Jesse M,Tye Kay M Nature The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive and negative. Different populations of BLA neurons may encode fearful or rewarding associations, but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained unknown. Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning. We find that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impairs fear conditioning and enhances reward conditioning. We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala. 10.1038/nature14366
More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory. Mozzachiodi Riccardo,Byrne John H Trends in neurosciences Decades of research on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories might also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes can function as part of the engram itself, they might also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage. 10.1016/j.tins.2009.10.001
Trace eyeblink conditioning increases CA1 excitability in a transient and learning-specific manner. Moyer J R,Thompson L T,Disterhoft J F The Journal of neuroscience : the official journal of the Society for Neuroscience Time-dependent, learning-related changes in hippocampal excitability were evaluated by recording from rabbit CA1 pyramidal neurons in slices prepared at various times after acquisition of trace eyeblink conditioning. Increased excitability (reduced postburst afterhyperpolarizations and reduced spike-frequency adaptation) was seen as early as 1 hr after acquisition to behavioral criterion, was maximal in neurons studied 24 hr later, and returned to baseline within 7 d, whereas behavioral performance remained asymptotic for months. Neurons were held at -67 mV to equate voltage-dependent effects. No learning-related effects were observed on input resistance, action-potential amplitude or duration, or resting membrane potential. The excitability changes were learning-specific, because they were not seen in neurons from very slow learning (exhibited < 30% conditioned responses after 15 training sessions) or from pseudoconditioned control rabbits. Neurons from rabbits that displayed asymptotic behavioral performance after long-term retention testing (an additional training session 14 d after learning) were also indistinguishable from control neurons. Thus, the increased excitability of CA1 neurons was not performance- or memory-dependent. Rather, the time course of increased excitability may represent a critical window during which learning-specific alterations in postsynaptic excitability of hippocampal neurons are important for consolidation of the learned association elsewhere in the brain.
Parvalbumin interneurons constrain the size of the lateral amygdala engram. Morrison Dano J,Rashid Asim J,Yiu Adelaide P,Yan Chen,Frankland Paul W,Josselyn Sheena A Neurobiology of learning and memory Memories are thought to be represented by discrete physiological changes in the brain, collectively referred to as an engram, that allow patterns of activity present during learning to be reactivated in the future. During the formation of a conditioned fear memory, a subset of principal (excitatory) neurons in the lateral amygdala (LA) are allocated to a neuronal ensemble that encodes an association between an initially neutral stimulus and a threatening aversive stimulus. Previous experimental and computational work suggests that this subset consists of only a small proportion of all LA neurons, and that this proportion remains constant across different memories. Here we examine the mechanisms that contribute to the stability of the size of the LA component of an engram supporting a fear memory. Visualizing expression of the activity-dependent gene Arc following memory retrieval to identify neurons allocated to an engram, we first show that the overall size of the LA engram remains constant across conditions of different memory strength. That is, the strength of a memory was not correlated with the number of LA neurons allocated to the engram supporting that memory. We then examine potential mechanisms constraining the size of the LA engram by expressing inhibitory DREADDS (designer receptors exclusively activated by designer drugs) in parvalbumin-positive (PV) interneurons of the amygdala. We find that silencing PV neurons during conditioning increases the size of the engram, especially in the dorsal subnucleus of the LA. These results confirm predictions from modeling studies regarding the role of inhibition in shaping the size of neuronal memory ensembles and provide additional support for the idea that neurons in the LA are sparsely allocated to the engram based on relative neuronal excitability. 10.1016/j.nlm.2016.07.007
Place navigation impaired in rats with hippocampal lesions. Morris R G,Garrud P,Rawlins J N,O'Keefe J Nature 10.1038/297681a0
Induction of long-term memory by exposure to novelty requires protein synthesis: evidence for a behavioral tagging. The Journal of neuroscience : the official journal of the Society for Neuroscience A behavioral analog of the synaptic tagging and capture process, a key property of synaptic plasticity, has been predicted recently. Here, we demonstrate that weak inhibitory avoidance training, which induces short- but not long-term memory (LTM), can be consolidated into LTM by an exploration to a novel, but not a familiar, environment occurring close in time to the training session. This memory-promoting effect caused by novelty depends on activation of dopamine D1/D5 receptors and requires newly synthesized proteins in the dorsal hippocampus. Thus, our results indicate the existence of a behavioral tagging process in which the exploration to a novel environment provides the plasticity-related proteins to stabilize the inhibitory avoidance memory trace. 10.1523/JNEUROSCI.1083-07.2007
Phosphorylation state of CREB in the rat hippocampus: a molecular switch between spatial novelty and spatial familiarity? Moncada Diego,Viola Haydée Neurobiology of learning and memory The activation of cAMP response element-binding protein (CREB) after a learning experience is a common feature in the formation of several associative memories. We recently demonstrated that the increase in the hippocampal phosphorylated CREB (pCREB) levels 1 h after a short exploration of an open field (OF) was associated to detection of spatial novelty and was not related to the memory formation of habituation in this non-associative learning paradigm. Moreover, after a long training of three OF sessions, hippocampal pCREB levels were below to that observed in control rats. The present results show that such decrease does not correlate with memory retrieval or improvement in long-term memory of habituation. Instead, it is associated with the familiarity to the arena. Our experiments revealed that the relevant variable to induce CREB deactivation was the prolonged exploration of the arena (30 min). A 15 min OF exploration was ineffective. Furthermore, the last 5 min period of a prolonged exploration was crucial to change CREB phosphorylation state: when exploration took place in a novel arena the level of pCREB increased; in contrast, when it was performed in the familiar OF, pCREB levels decreased. Taken as a whole, our results suggest that CREB phosphorylation state in the hippocampus switches in response to exposure to a novel or to a familiar spatial environment. 10.1016/j.nlm.2005.12.002
Cognitive neuroscience and the study of memory. Milner B,Squire L R,Kandel E R Neuron
Hippocampal synaptic enhancement and spatial learning in the Morris swim task. Korol D L,Abel T W,Church L T,Barnes C A,McNaughton B L Hippocampus The authors attempted to replicate the study of Castro, Silbert, McNaughton, and Barnes (1989) in which it was concluded that bilateral saturation of hippocampal synaptic enhancement produced a deficit in acquisition of a spatial navigation problem in the Morris swim task. The original protocol was followed as closely as possible, but no effect of long-term enhancement (LTE) saturation on spatial performance in this task was found. This negative result suggests either that the previous finding using the swim task reflected statistical error or that some as yet undetermined variable is of critical importance in this phenomenon. The present negative finding also raises a question concerning the reproducibility of the earlier results of McNaughton, Barnes, Rao, Baldwin, and Rasmussen (1986) in which LTE saturation apparently led to a prolonged deficit on a different spatial task. Although negative results in such experiments do not constitute grounds for rejecting the underlying hypothesis, the present lack of a positive effect renders uncertain, for the time being, one of the lines of experimental support for the theory that LTE at hippocampal synapses reflects a mechanism for the associative, distributed storage of new spatial information. 10.1002/hipo.450030204
Consolidation and reconsolidation: two lives of memories? McKenzie Sam,Eichenbaum Howard Neuron Most studies on memory consolidation consider the new information as if it were imposed on a tabula rasa, but considerable evidence indicates that new memories must be interleaved within a large network of relevant pre-existing knowledge. Early studies on reconsolidation highlighted that a newly consolidated memory could be erased after reactivation, but new evidence has shown that an effective reactivation experience must also involve memory reorganization to incorporate new learning. The combination of these observations on consolidation and reconsolidation highlights the fundamental similarities of both phenomena as the integration of new information and old, and it suggests reconsolidation = consolidation as a neverending process of schema modification. 10.1016/j.neuron.2011.06.037
Cortical pathways to the mammalian amygdala. McDonald A J Progress in neurobiology The amygdaloid nuclear complex is critical for producing appropriate emotional and behavioral responses to biologically relevant sensory stimuli. It constitutes an essential link between sensory and limbic areas of the cerebral cortex and subcortical brain regions, such as the hypothalamus, brainstem, and striatum, that are responsible for eliciting emotional and motivational responses. This review summarizes the anatomy and physiology of the cortical pathways to the amygdala in the rat, cat and monkey. Although the basic anatomy of these systems in the cat and monkey was largely delineated in studies conducted during the 1970s and 1980s, detailed information regarding the cortico-amygdalar pathways in the rat was only obtained in the past several years. The purpose of this review is to describe the results of recent studies in the rat and to compare the organization of cortico-amygdalar projections in this species with that seen in the cat and monkey. In all three species visual, auditory, and somatosensory information is transmitted to the amygdala by a series of modality-specific cortico-cortical pathways ("cascades") that originate in the primary sensory cortices and flow toward higher order association areas. The cortical areas in the more distal portions of these cascades have stronger and more extensive projections to the amygdala than the more proximal areas. In all three species olfactory and gustatory/visceral information has access to the amygdala at an earlier stage of cortical processing than visual, auditory and somatosensory information. There are also important polysensory cortical inputs to the mammalian amygdala from the prefrontal and hippocampal regions. Whereas the overall organization of cortical pathways is basically similar in all mammalian species, there is anatomical evidence which suggests that there are important differences in the extent of convergence of cortical projections in the primate versus the nonprimate amygdala. 10.1016/s0301-0082(98)00003-3
Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Marie Hélène,Morishita Wade,Yu Xiang,Calakos Nicole,Malenka Robert C Neuron The transcription factor CREB is critical for several forms of experience-dependent plasticity in a range of species and is commonly activated in neurons by calcium/calmodulin-dependent protein kinase IV (CaMKIV). Surprisingly, little is known about the neural circuit adaptations caused by activation of CaMKIV and CREB. Here, we use viral-mediated gene transfer in vivo to examine the consequences of acute expression of constitutively active forms of CaMKIV and CREB on synaptic function in the rodent hippocampus. Acute expression of active CaMKIV or CREB caused an enhancement of both NMDA receptor-mediated synaptic responses and long-term potentiation (LTP). This was accompanied by electrophysiological and morphological changes consistent with the generation of "silent synapses," which provide an ideal substrate for further experience-dependent modifications of neural circuitry and which may also be important for the consolidation of long-term synaptic plasticity and memories. 10.1016/j.neuron.2005.01.039
Simple memory: a theory for archicortex. Marr D Philosophical transactions of the Royal Society of London. Series B, Biological sciences 10.1098/rstb.1971.0078
Building concepts one episode at a time: The hippocampus and concept formation. Mack Michael L,Love Bradley C,Preston Alison R Neuroscience letters Concepts organize our experiences and allow for meaningful inferences in novel situations. Acquiring new concepts requires extracting regularities across multiple learning experiences, a process formalized in mathematical models of learning. These models posit a computational framework that has increasingly aligned with the expanding repertoire of functions associated with the hippocampus. Here, we propose the Episodes-to-Concepts (EpCon) theoretical model of hippocampal function in concept learning and review evidence for the hippocampal computations that support concept formation including memory integration, attentional biasing, and memory-based prediction error. We focus on recent studies that have directly assessed the hippocampal role in concept learning with an innovative approach that combines computational modeling and sophisticated neuroimaging measures. Collectively, this work suggests that the hippocampus does much more than encode individual episodes; rather, it adaptively transforms initially-encoded episodic memories into organized conceptual knowledge that drives novel behavior. 10.1016/j.neulet.2017.07.061
Function and regulation of CREB family transcription factors in the nervous system. Lonze Bonnie E,Ginty David D Neuron CREB and its close relatives are now widely accepted as prototypical stimulus-inducible transcription factors. In many cell types, these factors function as effector molecules that bring about cellular changes in response to discrete sets of instructions. In neurons, a wide range of extracellular stimuli are capable of activating CREB family members, and CREB-dependent gene expression has been implicated in complex and diverse processes ranging from development to plasticity to disease. In this review, we focus on the current level of understanding of where, when, and how CREB family members function in the nervous system.
Planting misinformation in the human mind: a 30-year investigation of the malleability of memory. Loftus Elizabeth F Learning & memory (Cold Spring Harbor, N.Y.) The misinformation effect refers to the impairment in memory for the past that arises after exposure to misleading information. The phenomenon has been investigated for at least 30 years, as investigators have addressed a number of issues. These include the conditions under which people are especially susceptible to the negative impact of misinformation, and conversely when are they resistant. Warnings about the potential for misinformation sometimes work to inhibit its damaging effects, but only under limited circumstances. The misinformation effect has been observed in a variety of human and nonhuman species. And some groups of individuals are more susceptible than others. At a more theoretical level, investigators have explored the fate of the original memory traces after exposure to misinformation appears to have made them inaccessible. This review of the field ends with a brief discussion of the newer work involving misinformation that has explored the processes by which people come to believe falsely that they experienced rich complex events that never, in fact, occurred. 10.1101/lm.94705
Differential projection of the posterior paralaminar thalamic nuclei to the amygdaloid complex in the rat. Linke R,Braune G,Schwegler H Experimental brain research The thalamic paralaminar nuclei that border the medial and ventral edges of the medial geniculate body, viz. the suprageniculate nucleus (SG), the posterior intralaminar nucleus (PIN), the medial division of the medial geniculate nucleus (MGm), and the peripeduncular nucleus (PP), are regarded as important extralemniscal relay nuclei for sensory stimuli and as an important link for the direct transmission of sensory stimuli to the amygdala. Each of these thalamic nuclei receives a unique pattern of afferent input but an unresolved question is, how each of these thalamic nuclei project to the amygdala and whether there are zones of convergence and/or non-overlapping regions within amygdaloid target nuclei. Small injections of PHA-L or Miniruby, which were made into single thalamic nuclei at different rostrocaudal levels, revealed a non-uniform distribution of anterogradely labeled axons within the amygdaloid complex. Injections into the SG, MGm, and rostral PIN predominantly labeled axons in the laterodorsal and lateroventral portions of the lateral nucleus of the amygdala (LA). Axons from the MGm were located rather in the dorsal part of the LA, whereas SG-derived axons were concentrated in the ventrolateral part of the LA. Injections into the PP labeled axons predominantly in the medial part of the LA, whereas after injections into the caudal PIN axons were seen in the entire LA. In addition, the PIN projects heavily to the anterior basomedial nucleus and medial division of the central nucleus, whereas this projection is virtually absent from the other thalamic nuclei. The lateral part of the central nucleus and the basal nucleus of the amygdala are spared by axons from the thalamic paralaminar nuclei. The present results suggest that, despite a considerable degree of convergence of the thalamoamygdaloid projection in the lateral nucleus, each thalamic nucleus plays a unique role in the transmission of sensory stimuli to the amygdala and in the modulation of intraamygdaloid circuits. 10.1007/s002210000475
Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Lewis David A,Curley Allison A,Glausier Jill R,Volk David W Trends in neurosciences Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and postsynaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control. 10.1016/j.tins.2011.10.004
Measuring Memory Reactivation With Functional MRI: Implications for Psychological Theory. Levy Benjamin J,Wagner Anthony D Perspectives on psychological science : a journal of the Association for Psychological Science Environmental cues often remind us of earlier experiences by triggering the reactivation of memories of events past. Recent evidence suggests that memory reactivation can be observed using functional MRI and that distributed pattern analyses can even provide evidence of reactivation on individual trials. The ability to measure memory reactivation offers unique and powerful leverage on theoretical issues of long-standing interest in cognitive psychology, providing a means to address questions that have proven difficult to answer with behavioral data alone. In this article, we consider three instances. First, reactivation measures can indicate whether memory-based inferences (i.e., generalization) arise through the encoding of integrated cross-event representations or through the flexible expression of separable event memories. Second, online measures of memory reactivation may inform theories of forgetting by providing information about when competing memories are reactivated during competitive retrieval situations. Finally, neural reactivation may provide a window onto the role of replay in memory consolidation. The ability to track memory reactivation, including at the individual trial level, provides unique leverage that is not afforded by behavioral measures and thus promises to shed light on such varied topics as generalization, integration, forgetting, and consolidation. 10.1177/1745691612469031
Distinct ensemble codes in hippocampal areas CA3 and CA1. Leutgeb Stefan,Leutgeb Jill K,Treves Alessandro,Moser May-Britt,Moser Edvard I Science (New York, N.Y.) The hippocampus has differentiated into an extensively connected recurrent stage (CA3) followed by a feed-forward stage (CA1). We examined the function of this structural differentiation by determining how cell ensembles in rat CA3 and CA1 generate representations of rooms with common spatial elements. In CA3, distinct subsets of pyramidal cells were activated in each room, regardless of the similarity of the testing enclosure. In CA1, the activated populations overlapped, and the overlap increased in similar enclosures. After exposure to a novel room, ensemble activity developed slower in CA3 than CA1, suggesting that the representations emerged independently. 10.1126/science.1100265
Pattern separation in the dentate gyrus and CA3 of the hippocampus. Leutgeb Jill K,Leutgeb Stefan,Moser May-Britt,Moser Edvard I Science (New York, N.Y.) Theoretical models have long pointed to the dentate gyrus as a possible source of neuronal pattern separation. In agreement with predictions from these models, we show that minimal changes in the shape of the environment in which rats are exploring can substantially alter correlated activity patterns among place-modulated granule cells in the dentate gyrus. When the environments are made more different, new cell populations are recruited in CA3 but not in the dentate gyrus. These results imply a dual mechanism for pattern separation in which signals from the entorhinal cortex can be decorrelated both by changes in coincidence patterns in the dentate gyrus and by recruitment of nonoverlapping cell assemblies in CA3. 10.1126/science.1135801
Hippocampal place fields emerge upon single-cell manipulation of excitability during behavior. Lee Doyun,Lin Bei-Jung,Lee Albert K Science (New York, N.Y.) The origin of the spatial receptive fields of hippocampal place cells has not been established. A hippocampal CA1 pyramidal cell receives thousands of synaptic inputs, mostly from other spatially tuned neurons; however, how the postsynaptic neuron's cellular properties determine the response to these inputs during behavior is unknown. We discovered that, contrary to expectations from basic models of place cells and neuronal integration, a small, spatially uniform depolarization of the spatially untuned somatic membrane potential of a silent cell leads to the sudden and reversible emergence of a spatially tuned subthreshold response and place-field spiking. Such gating of inputs by postsynaptic neuronal excitability reveals a cellular mechanism for receptive field origin and may be critical for the formation of hippocampal memory representations. 10.1126/science.1221489
Projections to the subcortical forebrain from anatomically defined regions of the medial geniculate body in the rat. LeDoux J E,Ruggiero D A,Reis D J The Journal of comparative neurology Although the auditory cortex is believed to be the principal efferent target of the medial geniculate body (MG), our recent behavioral studies indicate that in rats the conditioned coupling of emotional responses to an acoustic stimulus is mediated by subcortical projections of the MG. In the present study we have therefore used WGA-HRP as an anterograde and retrograde axonal marker to (1) define the full range of subcortical efferent projections of the MG; (2) identify the cells of origin within the MG of each projection; and (3) determine whether the subregions of the MG that project to subcortical areas receive inputs from acoustic relay nuclei of the mid-brain, particularly the inferior colliculus. The rat MG was first parcelled into three major cytoarchitectural areas: the ventral, medial, and dorsal divisions. The suprageniculate nucleus, located within the body of the MG just dorsal to the medial division, was also identified. Efferent projections of the MG were determined by combined anterograde and retrograde tracing methods. Injections of WGA-HRP in the MG produced anterograde transport to cortex and several subcortical areas, including the posterior caudate-putamen and amygdala, the ventromedial nucleus of the hypothalamus, and the subparafascicular thalamic nucleus. The cells of origin of the subcortical projections were then mapped retrogradely after injections in the anterogradely labeled areas. Injections in the caudate-putamen or amygdala retrogradely labeled the medial division of the MG and the suprageniculate nucleus, as well as several adjacent areas of the posterior thalamus surrounding the MG. In contrast, injections in the ventromedial nucleus of the hypothalamus or the subparafascicular thalamic nucleus only produced labeling in the areas surrounding MG. Afferents to MG from the inferior colliculus were then identified. The central nucleus of the inferior colliculus, the main lemniscal acoustic relay nucleus in the midbrain, was found to project to the ventral and medial divisions of the MG. In contrast, the dorsal cortex and external nucleus of the inferior colliculus project to each division of the MG and to several additional nuclei in adjacent areas of the posterior thalamus. These data demonstrate that the medial division of MG, the suprageniculate nucleus, and immediately adjacent areas of the posterior thalamus provide a direct linkage between auditory neurons in the inferior colliculus and subcortical areas of the forebrain and thereby support the view that thalamic sensory nuclei relay afferent signals to subcortical as well as cortical areas. 10.1002/cne.902420204
The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. LeDoux J E,Cicchetti P,Xagoraris A,Romanski L M The Journal of neuroscience : the official journal of the Society for Neuroscience Previous work has implicated projections from the acoustic thalamus to the amygdala in the classical conditioning of emotional responses to auditory stimuli. The purpose of the present studies was to determine whether the lateral amygdaloid nucleus (AL), which is a major subcortical target of projections from the acoustic thalamus, might be the sensory interface of the amygdala in emotional conditioning. Lesions were placed in AL of rats and the effects on emotional conditioning were examined. Lesions of AL, but not lesions of the striatum above or the cortex adjacent to the AL, interfered with emotional conditioning. Lesions that only partially destroyed AL or lesions placed too ventrally that completely missed AL had no effect. AL lesions did not affect the responses elicited following nonassociative (random) training. AL is thus an essential link in the circuitry through which auditory stimuli are endowed with affective properties and may function as the sensory interface of the amygdala during emotional learning.
Emotion circuits in the brain. LeDoux J E Annual review of neuroscience The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pinpointed the amygdala as an important component of the system involved in the acquisition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emotion, avoided vague and poorly defined concepts such as "affect," "hedonic tone," or "emotional feelings," and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior. 10.1146/annurev.neuro.23.1.155
Unconditioned stimulus pathways to the amygdala: effects of lesions of the posterior intralaminar thalamus on foot-shock-induced c-Fos expression in the subdivisions of the lateral amygdala. Lanuza E,Moncho-Bogani J,Ledoux J E Neuroscience The lateral nucleus of the amygdala (LA) is a site of convergence for auditory (conditioned stimulus) and foot-shock (unconditioned stimulus) inputs during fear conditioning. The auditory pathways to LA are well characterized, but less is known about the pathways through which foot shock is transmitted. Anatomical tracing and physiological recording studies suggest that the posterior intralaminar thalamic nucleus, which projects to LA, receives both auditory and somatosensory inputs. In the present study we examined the expression of the immediate-early gene c-fos in the LA in rats in response to foot-shock stimulation. We then determined the effects of posterior intralaminar thalamic lesions on foot-shock-induced c-Fos expression in the LA. Foot-shock stimulation led to an increase in the density of c-Fos-positive cells in all LA subnuclei in comparison to controls exposed to the conditioning box but not shocked. However, some differences among the dorsolateral, ventrolateral and ventromedial subnuclei were observed. The ventrolateral subnucleus showed a homogeneous activation throughout its antero-posterior extension. In contrast, only the rostral aspect of the ventromedial subnucleus and the central aspect of the dorsolateral subnucleus showed a significant increment in c-Fos expression. The density of c-Fos-labeled cells in all LA subnuclei was also increased in animals placed in the box in comparison to untreated animals. Unilateral electrolytic lesions of the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body reduced foot-shock-induced c-Fos activation in the LA ipsilateral to the lesion. The number of c-Fos labeled cells on the lesioned side was reduced to the levels observed in the animals exposed only to the box. These results indicate that the LA is involved in processing information about the foot-shock unconditioned stimulus and receives this kind of somatosensory information from the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body. 10.1016/j.neuroscience.2008.06.028
Representational similarity analysis - connecting the branches of systems neuroscience. Kriegeskorte Nikolaus,Mur Marieke,Bandettini Peter Frontiers in systems neuroscience A FUNDAMENTAL CHALLENGE FOR SYSTEMS NEUROSCIENCE IS TO QUANTITATIVELY RELATE ITS THREE MAJOR BRANCHES OF RESEARCH: brain-activity measurement, behavioral measurement, and computational modeling. Using measured brain-activity patterns to evaluate computational network models is complicated by the need to define the correspondency between the units of the model and the channels of the brain-activity data, e.g., single-cell recordings or voxels from functional magnetic resonance imaging (fMRI). Similar correspondency problems complicate relating activity patterns between different modalities of brain-activity measurement (e.g., fMRI and invasive or scalp electrophysiology), and between subjects and species. In order to bridge these divides, we suggest abstracting from the activity patterns themselves and computing representational dissimilarity matrices (RDMs), which characterize the information carried by a given representation in a brain or model. Building on a rich psychological and mathematical literature on similarity analysis, we propose a new experimental and data-analytical framework called representational similarity analysis (RSA), in which multi-channel measures of neural activity are quantitatively related to each other and to computational theory and behavior by comparing RDMs. We demonstrate RSA by relating representations of visual objects as measured with fMRI in early visual cortex and the fusiform face area to computational models spanning a wide range of complexities. The RDMs are simultaneously related via second-level application of multidimensional scaling and tested using randomization and bootstrap techniques. We discuss the broad potential of RSA, including novel approaches to experimental design, and argue that these ideas, which have deep roots in psychology and neuroscience, will allow the integrated quantitative analysis of data from all three branches, thus contributing to a more unified systems neuroscience. 10.3389/neuro.06.004.2008
Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization. Nature neuroscience Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors. 10.1038/nn.2364
Overcoming interference: an fMRI investigation of pattern separation in the medial temporal lobe. Kirwan C Brock,Stark Craig E L Learning & memory (Cold Spring Harbor, N.Y.) The medial temporal lobe (MTL) supports the formation and retrieval of long-term declarative memories, or memories for facts and everyday events. One challenge posed for this type of memory stems from the highly overlapping nature of common episodes. Within cognitive psychology, it is widely accepted that interference between information learned at different times is a major limitation on memory. In spite of several decades of intense research in the fields of interference theory and the neurobiological underpinnings of declarative memory, there is little direct evidence bearing on how the MTL resolves this interference to form accurate memories of everyday facts and events. Computational models of MTL function have proposed a mechanism in which the MTL, specifically the hippocampus, performs pattern separation, whereby overlapping representations are made less similar. However, there is little evidence bearing on how this process is carried out in the intact human MTL. Using high-resolution fMRI, we conducted a set of experiments that taxed behavioral pattern separation by using highly similar, interfering stimuli in a modified continuous recognition task. Regions within the parahippocampal gyrus demonstrated activity consistent with a "recall to reject" strategy. In contrast and critical to performing the task, activity within the hippocampus distinguished between correctly identified true stimulus repetitions, correctly rejected presentations of similar lure stimuli, and false alarms to similar lures. These data support the computational models' assertion that the hippocampus plays a key role in pattern separation. 10.1101/lm.663507
Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors. Kim Joshua,Zhang Xiangyu,Muralidhar Shruti,LeBlanc Sarah A,Tonegawa Susumu Neuron Basolateral amygdala (BLA) principal cells are capable of driving and antagonizing behaviors of opposing valence. BLA neurons project to the central amygdala (CeA), which also participates in negative and positive behaviors. However, the CeA has primarily been studied as the site for negative behaviors, and the causal role for CeA circuits underlying appetitive behaviors is poorly understood. Here, we identify several genetically distinct populations of CeA neurons that mediate appetitive behaviors and dissect the BLA-to-CeA circuit for appetitive behaviors. Protein phosphatase 1 regulatory subunit 1B BLA pyramidal neurons to dopamine receptor 1 CeA neurons define a pathway for promoting appetitive behaviors, while R-spondin 2 BLA pyramidal neurons to dopamine receptor 2 CeA neurons define a pathway for suppressing appetitive behaviors. These data reveal genetically defined neural circuits in the amygdala that promote and suppress appetitive behaviors analogous to the direct and indirect pathways of the basal ganglia. VIDEO ABSTRACT. 10.1016/j.neuron.2017.02.034
Antagonistic negative and positive neurons of the basolateral amygdala. Kim Joshua,Pignatelli Michele,Xu Sangyu,Itohara Shigeyoshi,Tonegawa Susumu Nature neuroscience The basolateral amygdala (BLA) is a site of convergence of negative and positive stimuli and is critical for emotional behaviors and associations. However, the neural substrate for negative and positive behaviors and relationship between negative and positive representations in the basolateral amygdala are unknown. Here we identify two genetically distinct, spatially segregated populations of excitatory neurons in the mouse BLA that participate in valence-specific behaviors and are connected through mutual inhibition. These results identify a genetically defined neural circuit for the antagonistic control of emotional behaviors and memories. 10.1038/nn.4414
Memory recall and modifications by activating neurons with elevated CREB. Kim Jieun,Kwon Jeong-Tae,Kim Hyung-Su,Josselyn Sheena A,Han Jin-Hee Nature neuroscience Memory is supported by a specific ensemble of neurons distributed in the brain that form a unique memory trace. We previously showed that neurons in the lateral amygdala expressing elevated levels of cAMP response-element binding protein are preferentially recruited into fear memory traces and are necessary for the expression of those memories. However, it is unknown whether artificially activating just these selected neurons in the absence of behavioral cues is sufficient to recall that fear memory. Using an ectopic rat vanilloid receptor TRPV1 and capsaicin system, we found that activating this specific ensemble of neurons was sufficient to recall established fear memory. Furthermore, this neuronal activation induced a reconsolidation-like reorganization process, or strengthening of the fear memory. Thus, our findings establish a direct link between the activation of specific ensemble of neurons in the lateral amygdala and the recall of fear memory and its subsequent modifications. 10.1038/nn.3592
Synaptic competition in the lateral amygdala and the stimulus specificity of conditioned fear: a biophysical modeling study. Brain structure & function Competitive synaptic interactions between principal neurons (PNs) with differing intrinsic excitability were recently shown to determine which dorsal lateral amygdala (LAd) neurons are recruited into a fear memory trace. Here, we explored the contribution of these competitive interactions in determining the stimulus specificity of conditioned fear associations. To this end, we used a realistic biophysical computational model of LAd that included multi-compartment conductance-based models of 800 PNs and 200 interneurons. To reproduce the continuum of spike frequency adaptation displayed by PNs, the model included three subtypes of PNs with high, intermediate, and low spike frequency adaptation. In addition, the model network integrated spatially differentiated patterns of excitatory and inhibitory connections within LA, dopaminergic and noradrenergic inputs, extrinsic thalamic and cortical tone afferents to simulate conditioned stimuli as well as shock inputs for the unconditioned stimulus. Last, glutamatergic synapses in the model could undergo activity-dependent plasticity. Our results suggest that plasticity at both excitatory (PN-PN) and di-synaptic inhibitory (PN-ITN and, particularly, ITN-PN) connections are major determinants of the synaptic competition governing the assignment of PNs to the memory trace. The model also revealed that training-induced potentiation of PN-PN synapses promotes, whereas that of ITN-PN synapses opposes, stimulus generalization. Indeed, suppressing plasticity of PN-PN synapses increased, whereas preventing plasticity of interneuronal synapses decreased the CS specificity of PN recruitment. Overall, our results indicate that the plasticity configuration imprinted in the network by synaptic competition ensures memory specificity. Given that anxiety disorders are characterized by tendency to generalize learned fear to safe stimuli or situations, understanding how plasticity of intrinsic LAd synapses regulates the specificity of learned fear is an important challenge for future experimental studies. 10.1007/s00429-015-1037-4
Assignment of model amygdala neurons to the fear memory trace depends on competitive synaptic interactions. Kim Dongbeom,Paré Denis,Nair Satish S The Journal of neuroscience : the official journal of the Society for Neuroscience We used biophysical modeling to examine a fundamental, yet unresolved, question regarding how particular lateral amygdala (LA) neurons are assigned to fear memory traces. This revealed that neurons with high intrinsic excitability are more likely to be integrated into the memory trace, but that competitive synaptic interactions also play a critical role. Indeed, when the ratio of intrinsically excitable cells was increased or decreased, the number of plastic cells remained relatively constant. Analysis of the connectivity of plastic and nonplastic cells revealed that subsets of principal LA neurons effectively band together by virtue of their excitatory interconnections to suppress plasticity in other principal cells via the recruitment of inhibitory interneurons. 10.1523/JNEUROSCI.2430-13.2013
Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential for synapse-to-nucleus signaling in activated neurons. Kawashima Takashi,Okuno Hiroyuki,Nonaka Mio,Adachi-Morishima Aki,Kyo Nan,Okamura Michiko,Takemoto-Kimura Sayaka,Worley Paul F,Bito Haruhiko Proceedings of the National Academy of Sciences of the United States of America The neuronal immediate early gene Arc/Arg-3.1 is widely used as one of the most reliable molecular markers for intense synaptic activity in vivo. However, the cis-acting elements responsible for such stringent activity dependence have not been firmly identified. Here we combined luciferase reporter assays in cultured cortical neurons and comparative genome mapping to identify the critical synaptic activity-responsive elements (SARE) of the Arc/Arg-3.1 gene. A major SARE was found as a unique approximately 100-bp element located at >5 kb upstream of the Arc/Arg-3.1 transcription initiation site in the mouse genome. This single element, when positioned immediately upstream of a minimal promoter, was necessary and sufficient to replicate crucial properties of endogenous Arc/Arg-3.1's transcriptional regulation, including rapid onset of transcription triggered by synaptic activity and low basal expression during synaptic inactivity. We identified the major determinants of SARE as a unique cluster of neuronal activity-dependent cis-regulatory elements consisting of closely localized binding sites for CREB, MEF2, and SRF. Consistently, a SARE reporter could readily trace and mark an ensemble of cells that have experienced intense activity in the recent past in vivo. Taken together, our work uncovers a novel transcriptional mechanism by which a critical 100-bp element, SARE, mediates a predominant component of the synapse-to-nucleus signaling in ensembles of Arc/Arg-3.1-positive activated neurons. 10.1073/pnas.0806518106
Age dissociates recency and lag recency effects in free recall. Kahana Michael J,Howard Marc W,Zaromb Franklin,Wingfield Arthur Journal of experimental psychology. Learning, memory, and cognition The temporal relations among word-list items exert a powerful influence on episodic memory retrieval. Two experiments were conducted with younger and older adults in which the age-related recall deficit was examined by using a decomposition method to the serial position curve, partitioning performance into (a) the probability of first recall, illustrating the recency effect, and (b) the conditional response probability, illustrating the lag recency effect (M. W. Howard & M. J. Kahana, 1999). Although the older adults initiated recall in the same manner in both immediate and delayed free recall, temporal proximity of study items (contiguity) exerted a much weaker influence on recall transitions in older adults. This finding suggests that an associative deficit may be an important contributor to older adults' well-known impairment in free recall. 10.1037//0278-7393.28.3.530
Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. The Journal of neuroscience : the official journal of the Society for Neuroscience At least two temporally and mechanistically distinct forms of memory are conserved across many species: short-term memory that persists minutes to hours after training and long-term memory (LTM) that persists days or longer. In general, repeated training trials presented with intervening rest intervals (spaced training) is more effective than massed training (the same number of training trials presented with no or short intervening rest intervals) in producing LTM. LTM requires de novo protein synthesis, and cAMP response element-binding protein (CREB) may be one of the transcription factors regulating the synthesis of new proteins necessary for the formation of LTM. Here we show that rats given massed fear conditioning training show no or weak LTM, as measured by fear-potentiated startle, compared with rats given the same amount of training but presented in a spaced manner. Increasing CREB levels specifically in the basolateral amygdala via viral vector-mediated gene transfer significantly increases LTM after massed fear training. The enhancing effect of CREB overexpression on LTM formation is shown to be specific in terms of biochemistry, anatomy, time course, and the training procedure used. These results suggest that CREB activity in the amygdala serves as a molecular switch for the formation of LTM in fear conditioning.
Heroes of the Engram. Josselyn Sheena A,Köhler Stefan,Frankland Paul W The Journal of neuroscience : the official journal of the Society for Neuroscience In 1904, Richard Semon introduced the term "engram" to describe the neural substrate responsible for (or at least important in) storing and recalling memories (i.e., a memory trace). The recent introduction of a vast array of powerful new tools to probe and manipulate memory function at the cell and neuronal circuit level has spurred an explosion of interest in studying the engram. However, the present "engram renaissance" was not borne in isolation but rather builds on a long tradition of memory research. We believe it is important to acknowledge the debts our current generation of scientists owes to those scientists who have offered key ideas, persevered through failed experiments and made important discoveries before us. Examining the past can also offer a fresh perspective on the present state and future promise of the field. Given the large amount of empirical advances made in recent years, it seems particularly timely to look back and review the scientists who introduced the seminal terminology, concepts, methodological approaches, and initial data pertaining to engrams. Rather than simply list their many accomplishments, here we color in some details of the lives and milestone contributions of our seven personal heroes of the engram (Richard Semon, Karl Lashley, Donald Hebb, Wilder Penfield, Brenda Milner, James McConnell, and Richard Thompson). In reviewing their historic role, we also illustrate how their work remains relevant to today's studies. 10.1523/JNEUROSCI.0056-17.2017
Finding the engram. Josselyn Sheena A,Köhler Stefan,Frankland Paul W Nature reviews. Neuroscience Many attempts have been made to localize the physical trace of a memory, or engram, in the brain. However, until recently, engrams have remained largely elusive. In this Review, we develop four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram. Recent 'capture' studies use novel approaches to tag populations of neurons that are active during memory encoding, thereby allowing these engram-associated neurons to be manipulated at later times. We propose that findings from these capture studies represent considerable progress in allowing us to observe, erase and express the engram. 10.1038/nrn4000
Continuing the search for the engram: examining the mechanism of fear memories. Josselyn Sheena A Journal of psychiatry & neuroscience : JPN The goal of my research is to gain insight using rodent models into the fundamental molecular, cellular and systems that make up the base of memory formation. My work focuses on fear memories. Aberrant fear and/or anxiety may be at the heart of many psychiatric disorders. In this article, I review the results of my research group; these results show that particular neurons in the lateral amygdala, a brain region important for fear, are specifically involved in particular fear memories. We started by showing that the transcription factor CREB (cAMP/Ca(2+) response element binding protein) plays a key role in the formation of fear memories. Next, we used viral vectors to overexpress CREB in a subset of lateral amygdala neurons. This not only facilitated fear memory formation but also "drove" the memory into the neurons with relatively increased CREB function. Finally, we showed that selective ablation of the neurons overexpressing CREB in the lateral amygdala selectively erased the fear memory. These findings are the first to show disruption of a specific memory by disrupting select neurons within a distributed network. 10.1503/jpn.100015
The operation of pattern separation and pattern completion processes associated with different attributes or domains of memory. Hunsaker Michael R,Kesner Raymond P Neuroscience and biobehavioral reviews Pattern separation and pattern completion processes are central to how the brain processes information in an efficient manner. Research into these processes is escalating and deficient pattern separation is being implicated in a wide array of genetic disorders as well as in neurocognitive aging. Despite the quantity of research, there remains a controversy as to precisely which behavioral paradigms should be used to best tap into pattern separation and pattern completion processes, as well as to what constitute legitimate outcome measures reflecting impairments in pattern separation and pattern completion. This review will discuss a theory based on multiple memory systems that provides a framework upon which behavioral tasks can be designed and their results interpreted. Furthermore, this review will discuss the nature of pattern separation and pattern completion and extend these processes outside the hippocampus and across all domains of information processing. After these discussions, an optimal strategy for designing behavioral paradigms to evaluate pattern separation and pattern completion processes will be provided. 10.1016/j.neubiorev.2012.09.014
Manipulating a "cocaine engram" in mice. Hsiang Hwa-Lin Liz,Epp Jonathan R,van den Oever Michel C,Yan Chen,Rashid Asim J,Insel Nathan,Ye Li,Niibori Yosuke,Deisseroth Karl,Frankland Paul W,Josselyn Sheena A The Journal of neuroscience : the official journal of the Society for Neuroscience Experience with drugs of abuse (such as cocaine) produces powerful, long-lasting memories that may be important in the development and persistence of drug addiction. The neural mechanisms that mediate how and where these cocaine memories are encoded, consolidated and stored are unknown. Here we used conditioned place preference in mice to examine the precise neural circuits that support the memory of a cocaine-cue association (the "cocaine memory trace" or "cocaine engram"). We found that a small population of neurons (∼10%) in the lateral nucleus of amygdala (LA) were recruited at the time of cocaine-conditioning to become part of this cocaine engram. Neurons with increased levels of the transcription factor CREB were preferentially recruited or allocated to the cocaine engram. Ablating or silencing neurons overexpressing CREB (but not a similar number of random LA neurons) before testing disrupted the expression of a previously acquired cocaine memory, suggesting that neurons overexpressing CREB become a critical hub in what is likely a larger cocaine memory engram. Consistent with theories that coordinated postencoding reactivation of neurons within an engram or cell assembly is crucial for memory consolidation (Marr, 1971; Buzsáki, 1989; Wilson and McNaughton, 1994; McClelland et al., 1995; Girardeau et al., 2009; Dupret et al., 2010; Carr et al., 2011), we also found that post-training suppression, or nondiscriminate activation, of CREB overexpressing neurons impaired consolidation of the cocaine memory. These findings reveal mechanisms underlying how and where drug memories are encoded and stored in the brain and may also inform the development of treatments for drug addiction. 10.1523/JNEUROSCI.3327-14.2014
The hippocampus, time, and memory across scales. Howard Marc W,Eichenbaum Howard Journal of experimental psychology. General A wealth of experimental studies with animals have offered insights about how neural networks within the hippocampus support the temporal organization of memories. These studies have revealed the existence of "time cells" that encode moments in time, much as the well-known "place cells" map locations in space. Another line of work inspired by human behavioral studies suggests that episodic memories are mediated by a state of temporal context that changes gradually over long time scales, up to at least a few thousand seconds. In this view, the "mental time travel" hypothesized to support the experience of episodic memory corresponds to a "jump back in time" in which a previous state of temporal context is recovered. We suggest that these 2 sets of findings could be different facets of a representation of temporal history that maintains a record at the last few thousand seconds of experience. The ability to represent long time scales comes at the cost of discarding precise information about when a stimulus was experienced--this uncertainty becomes greater for events further in the past. We review recent computational work that describes a mechanism that could construct such a scale-invariant representation. Taken as a whole, this suggests the hippocampus plays its role in multiple aspects of cognition by representing events embedded in a general spatiotemporal context. The representation of internal time can be useful across nonhippocampal memory systems. 10.1037/a0033621
Inhibitory Plasticity: Balance, Control, and Codependence. Hennequin Guillaume,Agnes Everton J,Vogels Tim P Annual review of neuroscience Inhibitory neurons, although relatively few in number, exert powerful control over brain circuits. They stabilize network activity in the face of strong feedback excitation and actively engage in computations. Recent studies reveal the importance of a precise balance of excitation and inhibition in neural circuits, which often requires exquisite fine-tuning of inhibitory connections. We review inhibitory synaptic plasticity and its roles in shaping both feedforward and feedback control. We discuss the necessity of complex, codependent plasticity mechanisms to build nontrivial, functioning networks, and we end by summarizing experimental evidence of such interactions. 10.1146/annurev-neuro-072116-031005
Selective erasure of a fear memory. Han Jin-Hee,Kushner Steven A,Yiu Adelaide P,Hsiang Hwa-Lin Liz,Buch Thorsten,Waisman Ari,Bontempi Bruno,Neve Rachael L,Frankland Paul W,Josselyn Sheena A Science (New York, N.Y.) Memories are thought to be encoded by sparsely distributed groups of neurons. However, identifying the precise neurons supporting a given memory (the memory trace) has been a long-standing challenge. We have shown previously that lateral amygdala (LA) neurons with increased cyclic adenosine monophosphate response element-binding protein (CREB) are preferentially activated by fear memory expression, which suggests that they are selectively recruited into the memory trace. We used an inducible diphtheria-toxin strategy to specifically ablate these neurons. Selectively deleting neurons overexpressing CREB (but not a similar portion of random LA neurons) after learning blocked expression of that fear memory. The resulting memory loss was robust and persistent, which suggests that the memory was permanently erased. These results establish a causal link between a specific neuronal subpopulation and memory expression, thereby identifying critical neurons within the memory trace. 10.1126/science.1164139
Neuronal competition and selection during memory formation. Han Jin-Hee,Kushner Steven A,Yiu Adelaide P,Cole Christy J,Matynia Anna,Brown Robert A,Neve Rachael L,Guzowski John F,Silva Alcino J,Josselyn Sheena A Science (New York, N.Y.) Competition between neurons is necessary for refining neural circuits during development and may be important for selecting the neurons that participate in encoding memories in the adult brain. To examine neuronal competition during memory formation, we conducted experiments with mice in which we manipulated the function of CREB (adenosine 3',5'-monophosphate response element-binding protein) in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Our results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in amemorytrace as a function of their relative CREB activity at the time of learning. 10.1126/science.1139438
Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Guzowski J F,McNaughton B L,Barnes C A,Worley P F Nature neuroscience We used fluorescent in-situ hybridization and confocal microscopy to monitor the subcellular distribution of the immediate-early gene Arc. Arc RNA appeared in discrete intranuclear foci within minutes of neuronal activation and subsequently disappeared from the nucleus and accumulated in the cytoplasm by 30 minutes. The time course of nuclear versus cytoplasmic Arc RNA accumulation was distinct, and could therefore be used to infer the activity history of individual neurons at two times. Following sequential exposure of rats to two different environments or to the same environment twice, the proportion of CA1 neurons with cytoplasmic, nuclear or overlapping Arc expression profiles matched predictions derived from ensemble neurophysiological recordings of hippocampal neuronal ensembles. Arc gene induction is thus specifically linked to neural encoding processes. 10.1038/16046
Arc expression identifies the lateral amygdala fear memory trace. Gouty-Colomer L A,Hosseini B,Marcelo I M,Schreiber J,Slump D E,Yamaguchi S,Houweling A R,Jaarsma D,Elgersma Y,Kushner S A Molecular psychiatry Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc-expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc-expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity. 10.1038/mp.2015.18
Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats. Goosens K A,Maren S Learning & memory (Cold Spring Harbor, N.Y.) A large body of literature implicates the amygdala in Pavlovian fear conditioning. In this study, we examined the contribution of individual amygdaloid nuclei to contextual and auditory fear conditioning in rats. Prior to fear conditioning, rats received a large electrolytic lesion of the amygdala in one hemisphere, and a nucleus-specific neurotoxic lesion in the contralateral hemisphere. Neurotoxic lesions targeted either the lateral nucleus (LA), basolateral and basomedial nuclei (basal nuclei), or central nucleus (CE) of the amygdala. LA and CE lesions attenuated freezing to both contextual and auditory conditional stimuli (CSs). Lesions of the basal nuclei produced deficits in contextual and auditory fear conditioning only when the damage extended into the anterior divisions of the basal nuclei; damage limited to the posterior divisions of the basal nuclei did not significantly impair conditioning to either auditory or contextual CS. These effects were typically not lateralized, although neurotoxic lesions of the posterior divisions of the basal nuclei had greater effects on contextual fear conditioning when the contralateral electrolytic lesion was placed in the right hemisphere. These results indicate that there is significant overlap within the amygdala in the neural pathways mediating fear conditioning to contextual and acoustic CS, and that these forms of learning are not anatomically dissociable at the level of amygdaloid nuclei. 10.1101/lm.37601
Neurobiology of Schemas and Schema-Mediated Memory. Gilboa Asaf,Marlatte Hannah Trends in cognitive sciences Schemas are superordinate knowledge structures that reflect abstracted commonalities across multiple experiences, exerting powerful influences over how events are perceived, interpreted, and remembered. Activated schema templates modulate early perceptual processing, as they get populated with specific informational instances (schema instantiation). Instantiated schemas, in turn, can enhance or distort mnemonic processing from the outset (at encoding), impact offline memory transformation and accelerate neocortical integration. Recent studies demonstrate distinctive neurobiological processes underlying schema-related learning. Interactions between the ventromedial prefrontal cortex (vmPFC), hippocampus, angular gyrus (AG), and unimodal associative cortices support context-relevant schema instantiation and schema mnemonic effects. The vmPFC and hippocampus may compete (as suggested by some models) or synchronize (as suggested by others) to optimize schema-related learning depending on the specific operationalization of schema memory. This highlights the need for more precise definitions of memory schemas. 10.1016/j.tics.2017.04.013
Memory for spatial location: role of the hippocampus in mediating spatial pattern separation. Gilbert P E,Kesner R P,DeCoteau W E The Journal of neuroscience : the official journal of the Society for Neuroscience A paradigm based on measuring short-term memory for spatial location information as a function of spatial similarity between distal cues was developed to examine the role of pattern separation in the modulation of short-term memory for spatial information. A delayed-match-to-sample for spatial location task using a dryland version of the Morris water maze was used to assess spatial pattern separation in male Long-Evans rats. In the sample phase, animals were trained to displace an object that covered a baited food well in one of 15 spatial locations along a row of food wells perpendicular to a start box. In the ensuing choice phase, the animal was allowed to choose between two objects identical to the sample phase object. One covered the same baited food well as did the object in the study phase (correct choice), and another foil object (incorrect choice) covered a different unbaited food well along the row of wells. Five spatial separations were randomly used to separate the correct object from the foil object. After reaching a criterion before the operation, animals were given either hippocampal or cortical control lesions. In trials after the operation, control animals matched their performance before the operation across all spatial separations. In contrast, hippocampal-lesioned animals displayed impairments across all spatial separations with the exception of the longest (105 cm) spatial separation. The results suggest that the hippocampus may serve to separate incoming spatial information by temporarily storing one place separate from another. It is proposed that hippocampal lesions decrease efficiency in pattern separation, resulting in impairments in trials with increased spatial similarity among working-memory representations.
Generation of a synthetic memory trace. Science (New York, N.Y.) We investigated the effect of activating a competing, artificially generated, neural representation on encoding of contextual fear memory in mice. We used a c-fos-based transgenic approach to introduce the hM(3)D(q) DREADD receptor (designer receptor exclusively activated by designer drug) into neurons naturally activated by sensory experience. Neural activity could then be specifically and inducibly increased in the hM(3)D(q)-expressing neurons by an exogenous ligand. When an ensemble of neurons for one context (ctxA) was artificially activated during conditioning in a distinct second context (ctxB), mice formed a hybrid memory representation. Reactivation of the artificially stimulated network within the conditioning context was required for retrieval of the memory, and the memory was specific for the spatial pattern of neurons artificially activated during learning. Similar stimulation impaired recall when not part of the initial conditioning. 10.1126/science.1214985
Memory allocation. Frankland Paul W,Josselyn Sheena A Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 10.1038/npp.2014.234
Mechanisms underlying the formation of the amygdalar fear memory trace: A computational perspective. Feng F,Samarth P,Paré D,Nair S S Neuroscience Recent experimental and modeling studies on the lateral amygdala (LA) have implicated intrinsic excitability and competitive synaptic interactions among principal neurons (PNs) in the formation of auditory fear memories. The present modeling studies, conducted over an expanded range of intrinsic excitability in the network, revealed that only excitable PNs that received tone inputs participate in the competition. Strikingly, the number of model PNs integrated into the fear memory trace remained constant despite the much larger range considered, and model runs highlighted several conditioning-induced tone responsive characteristics of the various PN populations. Furthermore, these studies showed that although excitation was important, disynaptic inhibition among PNs is the dominant mechanism that keeps the number of plastic PNs stable despite large variations in the network's excitability. Finally, we found that the overall level of inhibition in the model network determines the number of projection cells integrated into the fear memory trace. 10.1016/j.neuroscience.2016.02.059
The amygdala, fear, and memory. Fanselow Michael S,Gale Greg D Annals of the New York Academy of Sciences Lesions of the frontotemporal region of the amygdala, which includes lateral and basal nuclei, cause a loss of conditional fear responses, such as freezing, even when the lesions are made over a year and a half from the original training. These amygdala-damaged animals are not hyperactive and show normal reactivity to strong stimuli such as bright lights. After receiving tone-mild shock pairings rats normally display an appropriately weak response when exposed to the tone. Rats' fear of the tone can be inflated by giving them exposure to strong shocks in the absence of the tone between training and testing. This inflation of fear memory is abolished if the frontotemporal amygdala is inactivated by muscimol only during the inflation treatment with strong shocks. Based on such findings we suggest that the frontotemporal amygdala permanently encodes a memory for the hedonic value of the aversive stimulus used to condition fear. 10.1111/j.1749-6632.2003.tb07077.x
Statistical theory of distributional phenomena in learning. ESTES W K Psychological review
Intracellular determinants of hippocampal CA1 place and silent cell activity in a novel environment. Neuron For each environment a rodent has explored, its hippocampus contains a map consisting of a unique subset of neurons, called place cells, that have spatially tuned spiking there, with the remaining neurons being essentially silent. Using whole-cell recording in freely moving rats exploring a novel maze, we observed differences in intrinsic cellular properties and input-based subthreshold membrane potential levels underlying this division into place and silent cells. Compared to silent cells, place cells had lower spike thresholds and peaked versus flat subthreshold membrane potentials as a function of animal location. Both differences were evident from the beginning of exploration. Additionally, future place cells exhibited higher burst propensity before exploration. Thus, internal settings appear to predetermine which cells will represent the next novel environment encountered. Furthermore, place cells fired spatially tuned bursts with large, putatively calcium-mediated depolarizations that could trigger plasticity and stabilize the new map for long-term storage. Our results provide new insight into hippocampal memory formation. 10.1016/j.neuron.2011.03.006
Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia. Enwright John F,Sanapala Sowmya,Foglio Aaron,Berry Raissa,Fish Kenneth N,Lewis David A Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Alterations in cortical parvalbumin (PV)-containing neurons, including a reduced density of detectable neurons and lower PV levels, have frequently been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects. Most PV neurons are surrounded by perineuronal nets (PNNs) and the density of PNNs, as detected by Wisteria floribunda agglutinin (WFA) labeling, has been reported to be lower in schizophrenia. However, the nature of these PNN alterations, and their relationship to disease-related changes in PV neurons, has not been assessed. Using confocal microscopy, we quantified the densities and fluorescence intensities of PV neurons and PNNs labeled with WFA or immunoreactive for the major PNN protein, aggrecan, in the DLPFC from schizophrenia and matched comparison subjects. In schizophrenia, the densities of PV cells and of PNNs were not altered; however, the fluorescence intensities of PV immunoreactivity in cell bodies and of WFA labeling and aggrecan immunoreactivity in individual PNNs around PV cells were lower. These findings indicate that the normal complements of PV cells and PNNs are preserved in schizophrenia, but the levels of PV protein and of individual PNN components, especially the carbohydrate moieties on proteoglycans to which WFA binds, are lower. Given the roles of PV neurons in regulating DLPFC microcircuits and of PNNs in regulating PV cellular physiology, the identified alterations in PV neurons and their PNNs could contribute to DLPFC dysfunction in schizophrenia. 10.1038/npp.2016.24
Hippocampus: mapping or memory? Eichenbaum H Current biology : CB The identification of 'place cells' in the hippocampus has suggested a special role for this brain structure in spatial mapping, but other studies have indicated a more general role in memory. New findings on place cells point the way towards a reconciliation of the mapping and memory views.
Following the crowd: brain substrates of long-term memory conformity. Science (New York, N.Y.) Human memory is strikingly susceptible to social influences, yet we know little about the underlying mechanisms. We examined how socially induced memory errors are generated in the brain by studying the memory of individuals exposed to recollections of others. Participants exhibited a strong tendency to conform to erroneous recollections of the group, producing both long-lasting and temporary errors, even when their initial memory was strong and accurate. Functional brain imaging revealed that social influence modified the neuronal representation of memory. Specifically, a particular brain signature of enhanced amygdala activity and enhanced amygdala-hippocampus connectivity predicted long-lasting but not temporary memory alterations. Our findings reveal how social manipulation can alter memory and extend the known functions of the amygdala to encompass socially mediated memory distortions. 10.1126/science.1203557
Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons. Hippocampus Robust incorporation of new principal cells into pre-existing circuitry in the adult mammalian brain is unique to the hippocampal dentate gyrus (DG). We asked if adult-born granule cells (GCs) might act to regulate processing within the DG by modulating the substantially more abundant mature GCs. Optogenetic stimulation of a cohort of young adult-born GCs (0 to 7 weeks post-mitosis) revealed that these cells activate local GABAergic interneurons to evoke strong inhibitory input to mature GCs. Natural manipulation of neurogenesis by aging-to decrease it-and housing in an enriched environment-to increase it-strongly affected the levels of inhibition. We also demonstrated that elevating activity in adult-born GCs in awake behaving animals reduced the overall number of mature GCs activated by exploration. These data suggest that inhibitory modulation of mature GCs may be an important function of adult-born hippocampal neurons. © 2015 Wiley Periodicals, Inc. 10.1002/hipo.22557
CREB modulates excitability of nucleus accumbens neurons. Dong Yan,Green Thomas,Saal Daniel,Marie Helene,Neve Rachael,Nestler Eric J,Malenka Robert C Nature neuroscience Drugs of abuse cause activation of the cyclic AMP response element binding protein (CREB) in the nucleus accumbens (NAc). Expression of active CREB in rat NAc medium spiny neurons (MSNs) increased their excitability, whereas dominant-negative CREB had the opposite effect. Decreasing excitability of NAc MSNs in vivo by overexpression of potassium channels enhanced locomotor responses to cocaine, suggesting that the increased NAc MSN excitability caused by CREB helped to limit behavioral sensitivity to cocaine. 10.1038/nn1661
Conditioning-specific membrane changes of rabbit hippocampal neurons measured in vitro. Disterhoft J F,Coulter D A,Alkon D L Proceedings of the National Academy of Sciences of the United States of America Intracellular recordings were made from hippocampal CA1 pyramidal neurons within brain slices of nictitating membrane conditioned, pseudoconditioned, and naive adult male albino rabbits. All neurons included (26 conditioned, 26 pseudoconditioned, and 28 naive) had stable penetration and at least 60 mV action potential amplitudes. Mean input resistances were approximately equal to 60 mu omega for the three groups. A marked reduction in the afterhyperpolarization (AHP) following an impulse was apparent for conditioned (x = -0.98 mV) as compared to the pseudoconditioned (x = -1.7 mV) and naive (x = -2.0 mV) neurons. The AHP has been attributed previously to activation of a Ca2+-dependent outward K+ current. The distribution of AHP amplitudes for the conditioned group included a new lower range of values for which there was little overlap with the other groups. The conditioning-specific reduction of AHP may be due to reduction of ICa2+-K+ as shown previously for conditioned Hermissenda neurons. This conditioning-induced biophysical alteration of the CA1 pyramidal cell must be stored by mechanisms intrinsic to the hippocampal slice and cannot be explained as a consequence of changes of presynaptic input arising elsewhere in the brain. Our experiments demonstrate the feasibility of analyzing cellular mechanisms of associative learning in mammalian brain with the in vitro brain slice technique. 10.1073/pnas.83.8.2733
The role of the amygdala in fear and anxiety. Davis M Annual review of neuroscience 10.1146/annurev.ne.15.030192.002033
Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Denny Christine A,Kheirbek Mazen A,Alba Eva L,Tanaka Kenji F,Brachman Rebecca A,Laughman Kimberly B,Tomm Nicole K,Turi Gergely F,Losonczy Attila,Hen René Neuron Memory traces are believed to be ensembles of cells used to store memories. To visualize memory traces, we created a transgenic line that allows for the comparison between cells activated during encoding and expression of a memory. Mice re-exposed to a fear-inducing context froze more and had a greater percentage of reactivated cells in the dentate gyrus (DG) and CA3 than mice exposed to a novel context. Over time, these differences disappeared, in keeping with the observation that memories become generalized. Optogenetically silencing DG or CA3 cells that were recruited during encoding of a fear-inducing context prevented expression of the corresponding memory. Mice with reduced neurogenesis displayed less contextual memory and less reactivation in CA3 but, surprisingly, normal reactivation in the DG. These studies suggest that distinct memory traces are located in the DG and in CA3 but that the strength of the memory is related to reactivation in CA3. 10.1016/j.neuron.2014.05.018
Direct reactivation of a coherent neocortical memory of context. Cowansage Kiriana K,Shuman Tristan,Dillingham Blythe C,Chang Allene,Golshani Peyman,Mayford Mark Neuron Declarative memories are thought to be stored within anatomically distributed neuronal networks requiring the hippocampus; however, it is unclear how neocortical areas participate in memory at the time of encoding. Here, we use a c-fos-based genetic tagging system to selectively express the channelrhodopsin variant, ChEF, and optogenetically reactivate a specific neural ensemble in retrosplenial cortex (RSC) engaged by context fear conditioning. Artificial stimulation of RSC was sufficient to produce both context-specific behavior and downstream cellular activity commensurate with natural experience. Moreover, optogenetically but not contextually elicited responses were insensitive to hippocampal inactivation, suggesting that although the hippocampus is needed to coordinate activation by sensory cues, a higher-order cortical framework can independently subserve learned behavior, even shortly after learning. 10.1016/j.neuron.2014.09.022
Experience-dependent shaping of hippocampal CA1 intracellular activity in novel and familiar environments. Cohen Jeremy D,Bolstad Mark,Lee Albert K eLife The hippocampus is critical for producing stable representations of familiar spaces. How these representations arise is poorly understood, largely because changes to hippocampal inputs have not been measured during spatial learning. Here, using intracellular recording, we monitored inputs and plasticity-inducing complex spikes (CSs) in CA1 neurons while mice explored novel and familiar virtual environments. Inputs driving place field spiking increased in amplitude - often suddenly - during novel environment exploration. However, these increases were not sustained in familiar environments. Rather, the spatial tuning of inputs became increasingly similar across repeated traversals of the environment with experience - both within fields and throughout the whole environment. In novel environments, CSs were not necessary for place field formation. Our findings support a model in which initial inhomogeneities in inputs are amplified to produce robust place field activity, then plasticity refines this representation into one with less strongly modulated, but more stable, inputs for long-term storage. 10.7554/eLife.23040
Driving opposing behaviors with ensembles of piriform neurons. Cell Anatomic and physiologic studies have suggested a model in which neurons of the piriform cortex receive convergent input from random collections of glomeruli. In this model, odor representations can only be afforded behavioral significance upon experience. We have devised an experimental strategy that permits us to ask whether the activation of an arbitrarily chosen subpopulation of neurons in piriform cortex can elicit different behavioral responses dependent upon learning. Activation of a small subpopulation of piriform neurons expressing channelrhodopsin at multiple loci in the piriform cortex, when paired with reward or shock, elicits either appetitive or aversive behavior. Moreover, we demonstrate that different subpopulations of piriform neurons expressing ChR2 can be discriminated and independently entrained to elicit distinct behaviors. These observations demonstrate that the piriform cortex is sufficient to elicit learned behavioral outputs in the absence of sensory input. These data imply that the piriform does not use spatial order to map odorant identity or behavioral output. 10.1016/j.cell.2011.07.041
Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience. Chawla M K,Guzowski J F,Ramirez-Amaya V,Lipa P,Hoffman K L,Marriott L K,Worley P F,McNaughton B L,Barnes C A Hippocampus After a spatial behavioral experience, hippocampal CA1 pyramidal cells express the activity-regulated, immediate early gene Arc in an environment-specific manner, and in similar proportions ( 40%) to cells exhibiting electrophysiologically recorded place fields under similar conditions. Theoretical accounts of the function of the fascia dentata suggest that it plays a role in pattern separation during encoding. The hypothesis that the dentate gyrus (DG) uses a sparse, and thus more orthogonal, coding scheme has been supported by the observation that, while granule cells do exhibit place fields, most are silent in a given environment. To quantify the degree of sparsity of DG coding and its corresponding ability to generate distinct environmental representations, behaviorally induced Arc expression was assessed using in situ hybridization coupled with confocal microscopy. The proportion of Arc(+) cells in the "upper blade" of the fascia dentata (i.e., the portion that abuts CA1) increased in an environment-specific fashion, approximately 4-fold above cage-control activity, after behavioral exploration. Surprisingly, cells in the lower blade of the fascia dentata, which are capable of expressing Arc following electrical stimulation, exhibited virtually no behaviorally-induced Arc expression. This difference was confirmed using "line scan" analyses, which also revealed no patterns or gradients of activity along the upper blade of the DG. The expression of Arc in the upper blade was quantitatively similar after exploring familiar or novel environments. When animals explored two different environments, separated by 20 min, a new group of cells responded to the second environment, whereas two separated experiences in the same environment did not activate a new set of granular cells. Thus, granule cells generate distinct codes for different environments. These findings suggest differential contribution of upper and lower blade neurons to plastic networks and confirm the hypothesis that the DG uses sparse coding that may facilitate orthogonalization of information. 10.1002/hipo.20091
The molecular basis of neuronal excitability. Catterall W A Science (New York, N.Y.) Neurons process and transmit information in the form of electrical signals. Their electrical excitability is due to the presence of voltage-sensitive ion channels in the neuronal plasma membrane. In recent years, the voltage-sensitive sodium channel of mammalian brain has become the first of these important neuronal components to be studied at the molecular level. This article describes the distribution of sodium channels among the functional compartments of the neuron and reviews work leading to the identification, purification, and characterization of this membrane glycoprotein. 10.1126/science.6320365
Adult-born hippocampal neurons promote cognitive flexibility in mice. Burghardt Nesha S,Park Eun Hye,Hen René,Fenton André A Hippocampus The hippocampus is involved in segregating memories, an ability that utilizes the neural process of pattern separation and allows for cognitive flexibility. We evaluated a proposed role for adult hippocampal neurogenesis in cognitive flexibility using variants of the active place avoidance task and two independent methods of ablating adult-born neurons, focal X-irradiation of the hippocampus, and genetic ablation of glial fibrillary acidic protein positive neural progenitor cells, in mice. We found that ablation of adult neurogenesis did not impair the ability to learn the initial location of a shock zone. However, when conflict was introduced by switching the location of the shock zone to the opposite side of the room, irradiated and transgenic mice entered the new shock zone location significantly more than their respective controls. This impairment was associated with increased upregulation of the immediate early gene Arc in the dorsal dentate gyrus, suggesting a role for adult neurogenesis in modulating network excitability and/or synaptic plasticity. Additional experiments revealed that irradiated mice were also impaired in learning to avoid a rotating shock zone when it was added to an initially learned stationary shock zone, but were unimpaired in learning the identical simultaneous task variant if it was their initial experience with place avoidance. Impaired avoidance could not be attributed to a deficit in extinction or an inability to learn a new shock zone location in a different environment. Together these results demonstrate that adult neurogenesis contributes to cognitive flexibility when it requires changing a learned response to a stimulus-evoked memory. 10.1002/hipo.22013
Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Bossert Jennifer M,Stern Anna L,Theberge Florence R M,Cifani Carlo,Koya Eisuke,Hope Bruce T,Shaham Yavin Nature neuroscience In a rat model of context-induced relapse to heroin, we identified sparsely distributed ventral medial prefrontal cortex (mPFC) neurons that were activated by the heroin-associated context. Selective pharmacogenetic inactivation of these neurons inhibited context-induced drug relapse. A small subset of ventral mPFC neurons formed neuronal ensembles that encode the learned associations between heroin reward and heroin-associated contexts; re-activation of these neuronal ensembles by drug-associated contexts during abstinence provoked drug relapse. 10.1038/nn.2758
Divergent Routing of Positive and Negative Information from the Amygdala during Memory Retrieval. Beyeler Anna,Namburi Praneeth,Glober Gordon F,Simonnet Clémence,Calhoon Gwendolyn G,Conyers Garrett F,Luck Robert,Wildes Craig P,Tye Kay M Neuron Although the basolateral amygdala (BLA) is known to play a critical role in the formation of memories of both positive and negative valence, the coding and routing of valence-related information is poorly understood. Here, we recorded BLA neurons during the retrieval of associative memories and used optogenetic-mediated phototagging to identify populations of neurons that synapse in the nucleus accumbens (NAc), the central amygdala (CeA), or ventral hippocampus (vHPC). We found that despite heterogeneous neural responses within each population, the proportions of BLA-NAc neurons excited by reward predictive cues and of BLA-CeA neurons excited by aversion predictive cues were higher than within the entire BLA. Although the BLA-vHPC projection is known to drive behaviors of innate negative valence, these neurons did not preferentially code for learned negative valence. Together, these findings suggest that valence encoding in the BLA is at least partially mediated via divergent activity of anatomically defined neural populations. 10.1016/j.neuron.2016.03.004
An organization of visual and auditory fear conditioning in the lateral amygdala. Bergstrom Hadley C,Johnson Luke R Neurobiology of learning and memory Pavlovian fear conditioning is an evolutionary conserved and extensively studied form of associative learning and memory. In mammals, the lateral amygdala (LA) is an essential locus for Pavlovian fear learning and memory. Despite significant progress unraveling the cellular mechanisms responsible for fear conditioning, very little is known about the anatomical organization of neurons encoding fear conditioning in the LA. One key question is how fear conditioning to different sensory stimuli is organized in LA neuronal ensembles. Here we show that Pavlovian fear conditioning, formed through either the auditory or visual sensory modality, activates a similar density of LA neurons expressing a learning-induced phosphorylated extracellular signal-regulated kinase (p-ERK1/2). While the size of the neuron population specific to either memory was similar, the anatomical distribution differed. Several discrete sites in the LA contained a small but significant number of p-ERK1/2-expressing neurons specific to either sensory modality. The sites were anatomically localized to different levels of the longitudinal plane and were independent of both memory strength and the relative size of the activated neuronal population, suggesting some portion of the memory trace for auditory and visually cued fear conditioning is allocated differently in the LA. Presenting the visual stimulus by itself did not activate the same p-ERK1/2 neuron density or pattern, confirming the novelty of light alone cannot account for the specific pattern of activated neurons after visual fear conditioning. Together, these findings reveal an anatomical distribution of visual and auditory fear conditioning at the level of neuronal ensembles in the LA. 10.1016/j.nlm.2014.07.008
CREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models. Benito Eva,Barco Angel Trends in neurosciences The activation of cAMP-response element binding protein (CREB)-dependent gene expression seems a crucial step in the molecular cascade that mediates the formation of long-lasting memories. This view is based both on correlative evidence and on functional assays that demonstrate, through loss- and gain-of-function experiments, the impact of CREB manipulation on memory performance. Mechanistically, CREB's role in memory is thought to be a consequence of its participation in long-term forms of synaptic plasticity. Recent studies demonstrate that CREB, in addition to synaptic plasticity, also modulates the intrinsic excitability of the neuron. This discovery reveals new intriguing connections between intrinsic and synaptic plasticity and is likely to have a significant impact on our understanding of the role of CREB in memory formation. 10.1016/j.tins.2010.02.001
Unmasking Latent Inhibitory Connections in Human Cortex to Reveal Dormant Cortical Memories. Barron H C,Vogels T P,Emir U E,Makin T R,O'Shea J,Clare S,Jbabdi S,Dolan R J,Behrens T E J Neuron Balance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans. Using fMRI repetition suppression we measure newly formed cortical associations in the human brain. We show that expression of these associations reduces over time despite persistence in behavior, consistent with inhibitory rebalancing. To test this, we modulated excitation/inhibition balance with transcranial direct current stimulation (tDCS). Using ultra-high-field (7T) MRI and spectroscopy, we show that reducing GABA allows cortical associations to be re-expressed. This suggests that in humans associative memories are stored in balanced excitatory-inhibitory ensembles that lie dormant unless latent inhibitory connections are unmasked. 10.1016/j.neuron.2016.02.031
Inhibitory engrams in perception and memory. Barron Helen C,Vogels Tim P,Behrens Timothy E,Ramaswami Mani Proceedings of the National Academy of Sciences of the United States of America Nervous systems use excitatory cell assemblies to encode and represent sensory percepts. Similarly, synaptically connected cell assemblies or "engrams" are thought to represent memories of past experience. Multiple lines of recent evidence indicate that brain systems create and use inhibitory replicas of excitatory representations for important cognitive functions. Such matched "inhibitory engrams" can form through homeostatic potentiation of inhibition onto postsynaptic cells that show increased levels of excitation. Inhibitory engrams can reduce behavioral responses to familiar stimuli, thereby resulting in behavioral habituation. In addition, by preventing inappropriate activation of excitatory memory engrams, inhibitory engrams can make memories quiescent, stored in a latent form that is available for context-relevant activation. In neural networks with balanced excitatory and inhibitory engrams, the release of innate responses and recall of associative memories can occur through focused disinhibition. Understanding mechanisms that regulate the formation and expression of inhibitory engrams in vivo may help not only to explain key features of cognition but also to provide insight into transdiagnostic traits associated with psychiatric conditions such as autism, schizophrenia, and posttraumatic stress disorder. 10.1073/pnas.1701812114
Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Barco Angel,Alarcon Juan M,Kandel Eric R Cell Restricted and regulated expression in mice of VP16-CREB, a constitutively active form of CREB, in hippocampal CA1 neurons lowers the threshold for eliciting a persistent late phase of long-term potentiation (L-LTP) in the Schaffer collateral pathway. This L-LTP has unusual properties in that its induction is not dependent on transcription. Pharmacological and two-pathway experiments suggest a model in which VP16-CREB activates the transcription of CRE-driven genes and leads to a cell-wide distribution of proteins that prime the synapses for subsequent synapse-specific capture of L-LTP by a weak stimulus. Our analysis indicates that synaptic capture of CRE-driven gene products may be sufficient for consolidation of LTP and provides insight into the molecular mechanisms of synaptic tagging and synapse-specific potentiation. 10.1016/s0092-8674(02)00657-8
Impaired associative inference in patients with schizophrenia. Armstrong Kristan,Kose Samet,Williams Lisa,Woolard Austin,Heckers Stephan Schizophrenia bulletin The ability to learn, store, and retrieve information about relationships is impaired in schizophrenia. Here, we tested 38 control and 61 schizophrenia subjects for their ability to identify the novel pairing of stimuli, based on associations learned during training. Subjects were trained on 3 sets of paired associates: 30 face-house pairs (H-F1), 30 face-house pairs (H-F2, same house with new face), and 30 face-face pairs (F3-F4). After training, participants were tested on the 3 explicitly trained pair types, as well as 30 new face-face pairs (F1-F2), which could only be linked together via the same house during the H-F1/H-F2 training blocks. Of 99 subjects tested, 37 patients with schizophrenia and 36 age-matched healthy control subjects learned the premise pairs and performed the relational memory test. Healthy control subjects were significantly more accurate in identifying the inferential (F1-F2) pairs than the noninferential (F3-F4) pairs. In contrast, schizophrenia patients were equally accurate on inferential and noninferential pairs, providing evidence for a relational memory deficit in schizophrenia. However, the current version of the associative inference paradigm, suggested by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia initiative, has limited feasibility, calling into question the generalizability of the findings for the larger schizophrenia population. 10.1093/schbul/sbq145
Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Armbruster Blaine N,Li Xiang,Pausch Mark H,Herlitze Stefan,Roth Bryan L Proceedings of the National Academy of Sciences of the United States of America We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide). Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies. We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor. We also expressed a G(i)-coupled designer receptor in hippocampal neurons (hM(4)D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing. We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities. Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo. 10.1073/pnas.0700293104
Reduction of two voltage-dependent K+ currents mediates retention of a learned association. Alkon D L,Sakakibara M,Forman R,Harrigan J,Lederhendler I,Farley J Behavioral and neural biology A single identified neuron, the medial type B photoreceptor, was isolated by axotomy from the nervous systems of nudibranch molluscs (Hermissenda) which had been exposed to three different training experiences. Paired animals had been trained with repeated paired presentations of light and rotation and random animals with randomized light and rotation; naive animals had no training. A two-microelectrode voltage clamp of axotomized type B somata (separated from all synaptic interactions and impulse activity) was used to measure, with a blind procedure, three distinct ionic currents at least 24 h after the training experience. An early K+ current, IA, and a Ca2+-dependent K+ current, ICa2+-K+, but not a light-induced inward Na+ current, were significantly reduced for the paired as compared to the random and naive animals. The magnitude of ICa2+-K+ reduction was related (again measured blindly) to the degree of training-induced suppression of phototaxis (a measure of the learned behavior) for the paired animals. These data are consistent with previous observations indicating that changes of intrinsic type B membrane properties are an important means for encoding the acquisition and retention of Hermissenda associative learning.
Primary changes of membrane currents during retention of associative learning. Alkon D L,Lederhendler I,Shoukimas J J Science (New York, N.Y.) A single identified neuron was repeatedly isolated by axotomy from the central nervous system of the nudibranch mollusk Hermissenda crassicornis. An early voltage-dependent outward K+ current of this neuron was reduced and more rapidly inactivated for animals previously trained with paired but not randomized light and rotation. Since this current change can affect interneuron and motorneuron output via known synaptic pathways, it helps explain a long-lasting behavioral change that shows the defining features of vertebrate associative learning. 10.1126/science.7058334
Changes of membrane currents during learning. Alkon D L The Journal of experimental biology The integrated response of a population of neurones during conditioning results in long-term (days) changes of specific membrane currents within identified neurones. Prolonged elevation of intracellular calcium during conditioning causes a persistent increase of excitability by reducing K+ currents (IA and probably ICa2+-K+) in the membranes of identified somata. This Ca2+-mediated reduction of K+ currents, which encodes a learned stimulus association is thought to involve changes of Ca2+-calmodulin-dependent phosphorylation of distinct membrane proteins. These changes are contrasted with the short-term regulation of currents by neurohormones during altered behavioural states such as arousal. 10.1242/jeb.112.1.95
Calcium-mediated reduction of ionic currents: a biophysical memory trace. Alkon D L Science (New York, N.Y.) Learning behavior similar to vertebrate classical conditioning was demonstrated for the mollusc Hermissenda crassicornis. Postsynaptic membrane changes within well-defined neural systems that mediate the learning play a casual role in recording the learned association for later recall. Specific ionic currents in neural tissue undergo transformations lasting days after associative training with physiologic stimuli. During acquisition the intracellular calcium increases; this increase is accompanied by specific potassium current reduction that lasts for days after conditioning. The increase of calcium enhances calmodulin-dependent phosphorylation of proteins that either regulate or are part of ion channels. These currents and the conditions that precede their transformation occur in many types of vertebrate neurons, and hence this biophysical basis of Hermissenda learning could have relevance for species other than the gastropod studied. 10.1126/science.6093258
Associative training of Hermissenda. Alkon D L The Journal of general physiology Reflex behavior of Hermissenda in response to visual and rotational stimuli is described. It is shown that repeated association of light with rotation modifies the subsequent responses of the animals to light. This modification does not occur after the same period of light or rotation alone. The effect of the associative training is strongly dependent on the amount of daily light with which the animals are maintained. 10.1085/jgp.64.1.70
Metaplasticity: the plasticity of synaptic plasticity. Abraham W C,Bear M F Trends in neurosciences In this paper, we review experimental evidence for a novel form of persistent synaptic plasticity we call metaplasticity. Metaplasticity is induced by synaptic or cellular activity, but it is not necessarily expressed as a change in the efficacy of normal synaptic transmission. Instead, it is manifest as a change in the ability to induce subsequent synaptic plasticity, such as long-term potentiation or depression. Thus, metaplasticity is a higher-order form of synaptic plasticity. Metaplasticity might involve alterations in NMDA-receptor function in some cases, but there are many other candidate mechanisms. The induction of metaplasticity complicates the interpretation of many commonly studied aspects of synaptic plasticity, such as saturation and biochemical correlates.
[Interlevel relations in neural memory: extrasynaptic reception of mediators, potentiation, and spontaneous activity]. Radchenko A N Uspekhi fiziologicheskikh nauk The firing of "spontaneous" spikes is regarded as a result of mediator propagation to extrasynaptic receptors. Receptor-receptor interaction unites them in dimer and dimer clusters, which accept three conformational states under agonist action. There are two cooperative and potential dependent transitions between the states, where cluster accumulates or releases energy. The released energy can trigger a mechanism of endogenous (spontaneous) neuron firing in potentiation condition. These accumulating and triggering properties are absent in third (passive) conformational state, where gating charges immobilization reduces conformational mobility. The features of ionotropic, metabotropic and combined mediator action are discussed for different level of slow potential. Conformational effect depends on conformity of pattern space-temporal structure to geometric and functional features of metabotropic mediator sources in cluster environment. Each cluster appears to be adjusted for recognizing a certain vast set of afferent patterns. Number, structure and dimensionality of the recognized patterns are given by: 1) threshold of conformational transition, 2) allocation of synaptic and extrasynaptic mediator ejecting points in gap-hole environment of the receptive cluster 3) combinatorial connections of presynaptic cells with inhibit and excite synapses and 4) signal delays in presynaptic ways and neuropil. Numerous receptive clusters of soma-dendrite membrane are capable to write down information, to keep and accumulate it and to recover. Engram stored as passive/active conformational receptive cluster states is recovered in inversion by "spontaneous" neuronal activity. The original information may be recovered by reading via inhibit synapses.
Molecular and cellular mechanisms of memory allocation in neuronetworks. Won Jaejoon,Silva Alcino J Neurobiology of learning and memory Determining how neuronal networks encode memories is a key goal of neuroscience. Although neuronal circuit processes involved in encoding, storing and retrieving memory have attracted a great deal of attention, the processes that allocate individual memories to specific neurons within a network have remained elusive. Recent findings unraveled the first insights into the processes that modulate memory allocation in neuronetworks. They showed that neurons in the lateral amygdala compete to take part in auditory fear conditioned memory traces and that the levels of the transcription factor CREB (cAMP-response element binding protein) can affect the probability of a neuron to be recruited into a given memory representation. CREB-mediated transcriptional regulation involves several signaling pathways, known to mediate nuclear responses to diverse behavioral stimuli, along with coordinated interactions with multiple other transcription activators, coactivators and repressors. Moreover, activation of CREB triggers an autoinhibitory feedback loop, a metaplastic process that could be used to allocate memories away from cells that have been recently involved in memory. Beyond CREB, there may be a host of other processes that dynamically modulate memory allocation in neuronetworks by shaping cooperation and competition among neurons. 10.1016/j.nlm.2007.08.017
Molecular and cellular approaches to memory allocation in neural circuits. Science (New York, N.Y.) Although memory allocation is a subject of active research in computer science, little is known about how the brain allocates information within neural circuits. There is an extensive literature on how specific types of memory engage different parts of the brain, and how neurons in these regions process and store information. Until recently, however, the mechanisms that determine how specific cells and synapses within a neural circuit (and not their neighbors) are recruited during learning have received little attention. Recent findings suggest that memory allocation is not random, but rather specific mechanisms regulate where information is stored within a neural circuit. New methods that allow tagging, imaging, activation, and inactivation of neurons in behaving animals promise to revolutionize studies of brain circuits, including memory allocation. Results from these studies are likely to have a considerable impact on computer science, as well as on the understanding of memory and its disorders. 10.1126/science.1174519
The structure of Pavlovian fear conditioning in the amygdala. Bergstrom Hadley C,McDonald Craig G,Dey Smita,Tang Haying,Selwyn Reed G,Johnson Luke R Brain structure & function Do different brains forming a specific memory allocate the same groups of neurons to encode it? One way to test this question is to map neurons encoding the same memory and quantitatively compare their locations across individual brains. In a previous study, we used this strategy to uncover a common topography of neurons in the dorsolateral amygdala (LAd) that expressed a learning-induced and plasticity-related kinase (p42/44 mitogen-activated protein kinase; pMAPK), following auditory Pavlovian fear conditioning. In this series of experiments, we extend our initial findings to ask to what extent this functional topography depends upon intrinsic neuronal structure. We first showed that the majority (87 %) of pMAPK expression in the lateral amygdala was restricted to principal-type neurons. Next, we verified a neuroanatomical reference point for amygdala alignment using in vivo magnetic resonance imaging and in vitro morphometrics. We then determined that the topography of neurons encoding auditory fear conditioning was not exclusively governed by principal neuron cytoarchitecture. These data suggest that functional patterning of neurons undergoing plasticity in the amygdala following Pavlovian fear conditioning is specific to memory formation itself. Further, the spatial allocation of activated neurons in the LAd was specific to cued (auditory), but not contextual, fear conditioning. Spatial analyses conducted at another coronal plane revealed another spatial map unique to fear conditioning, providing additional evidence that the functional topography of fear memory storing cells in the LAd is non-random and stable. Overall, these data provide evidence for a spatial organizing principle governing the functional allocation of fear memory in the amygdala. 10.1007/s00429-012-0478-2
Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory. Nonaka Mio,Kim Ryang,Fukushima Hotaka,Sasaki Kazuki,Suzuki Kanzo,Okamura Michiko,Ishii Yuichiro,Kawashima Takashi,Kamijo Satoshi,Takemoto-Kimura Sayaka,Okuno Hiroyuki,Kida Satoshi,Bito Haruhiko Neuron CREB is a pivotal mediator of activity-regulated gene transcription that underlies memory formation and allocation. The contribution of a key CREB cofactor, CREB-regulated transcription coactivator 1 (CRTC1), has, however, remained elusive. Here we show that several constitutive kinase pathways and an activity-regulated phosphatase, calcineurin, converge to determine the nucleocytoplasmic shuttling of CRTC1. This, in turn, triggered an activity-dependent association of CRTC1 with CREB-dependent regulatory elements found on IEG promoters. Forced expression of nuclear CRTC1 in hippocampal neurons activated CREB-dependent transcription, and was sufficient to enhance contextual fear memory. Surprisingly, during contextual fear conditioning, we found evidence of nuclear recruitment of endogenous CRTC1 only in the basolateral amygdala, and not in the hippocampus. Consistently, CRTC1 knockdown in the amygdala, but not in the hippocampus, significantly attenuated fear memory. Thus, CRTC1 has a wide impact on CREB-dependent memory processes, but fine-tunes CREB output in a region-specific manner. 10.1016/j.neuron.2014.08.049
CREB regulates memory allocation in the insular cortex. Current biology : CB The molecular and cellular mechanisms of memory storage have attracted a great deal of attention. By comparison, little is known about memory allocation, the process that determines which specific neurons in a neural network will store a given memory. Previous studies demonstrated that memory allocation is not random in the amygdala; these studies showed that amygdala neurons with higher levels of the cyclic-AMP-response-element-binding protein (CREB) are more likely to be recruited into encoding and storing fear memory. To determine whether specific mechanisms also regulate memory allocation in other brain regions and whether CREB also has a role in this process, we studied insular cortical memory representations for conditioned taste aversion (CTA). In this task, an animal learns to associate a taste (conditioned stimulus [CS]) with the experience of malaise (such as that induced by LiCl; unconditioned stimulus [US]). The insular cortex is required for CTA memory formation and retrieval. CTA learning activates a subpopulation of neurons in this structure, and the insular cortex and the basolateral amygdala (BLA) interact during CTA formation. Here, we used a combination of approaches, including viral vector transfections of insular cortex, arc fluorescence in situ hybridization (FISH), and designer receptors exclusively activated by designer drugs (DREADD) system, to show that CREB levels determine which insular cortical neurons go on to encode a given conditioned taste memory. 10.1016/j.cub.2014.10.018
Emotional modulation of synapses, circuits and memory. Ploski Jonathan E,McIntyre Christa K Frontiers in behavioral neuroscience 10.3389/fnbeh.2015.00035
Irreplaceability of Neuronal Ensembles after Memory Allocation. Matsuo Naoki Cell reports Lesion studies suggest that an alternative system can compensate for damage to the primary region employed when animals acquire a memory. However, it is unclear whether functional compensation occurs at the cellular ensemble level. Here, we inhibited the activities of a specific subset of neurons activated during initial learning by utilizing a transgenic mouse that expresses tetanus toxin (TeNT) under the control of the c-fos promoter. Notably, suppression interfered with relearning while sparing the ability to acquire and express fear memory for a distinct context. These results suggest that the activity of the initial ensemble is preferentially dedicated to the same learning and that it is not replaceable once it is allocated. Our results provide substantial insights into the machinery underlying how the brain allocates individual memories to discrete neuronal ensembles and how it ensures that repetitive learning strengthens memory by reactivating the same neuronal ensembles. 10.1016/j.celrep.2015.03.042
Structural, Synaptic, and Epigenetic Dynamics of Enduring Memories. Khalaf Ossama,Gräff Johannes Neural plasticity Our memories are the records of the experiences we gain in our everyday life. Over time, they slowly transform from an initially unstable state into a long-lasting form. Many studies have been investigating from different aspects how a memory could persist for sometimes up to decades. In this review, we highlight three of the greatly addressed mechanisms that play a central role for a given memory to endure: the allocation of the memory to a given neuronal population and what brain areas are recruited for its storage; the structural changes that underlie memory persistence; and finally the epigenetic control of gene expression that might regulate and support memory perseverance. Examining such key properties of a memory is essential towards a finer understanding of its capacity to last. 10.1155/2016/3425908
Which Neurons Will Be the Engram - Activated Neurons and/or More Excitable Neurons? Kim Ji-Il,Cho Hye-Yeon,Han Jin-Hee,Kaang Bong-Kiun Experimental neurobiology During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression. 10.5607/en.2016.25.2.55
Competition between engrams influences fear memory formation and recall. Rashid Asim J,Yan Chen,Mercaldo Valentina,Hsiang Hwa-Lin Liz,Park Sungmo,Cole Christina J,De Cristofaro Antonietta,Yu Julia,Ramakrishnan Charu,Lee Soo Yeun,Deisseroth Karl,Frankland Paul W,Josselyn Sheena A Science (New York, N.Y.) Collections of cells called engrams are thought to represent memories. Although there has been progress in identifying and manipulating single engrams, little is known about how multiple engrams interact to influence memory. In lateral amygdala (LA), neurons with increased excitability during training outcompete their neighbors for allocation to an engram. We examined whether competition based on neuronal excitability also governs the interaction between engrams. Mice received two distinct fear conditioning events separated by different intervals. LA neuron excitability was optogenetically manipulated and revealed a transient competitive process that integrates memories for events occurring closely in time (coallocating overlapping populations of neurons to both engrams) and separates memories for events occurring at distal times (disallocating nonoverlapping populations to each engram). 10.1126/science.aaf0594
Linking Memories across Time via Neuronal and Dendritic Overlaps in Model Neurons with Active Dendrites. Cell reports Memories are believed to be stored in distributed neuronal assemblies through activity-induced changes in synaptic and intrinsic properties. However, the specific mechanisms by which different memories become associated or linked remain a mystery. Here, we develop a simplified, biophysically inspired network model that incorporates multiple plasticity processes and explains linking of information at three different levels: (1) learning of a single associative memory, (2) rescuing of a weak memory when paired with a strong one, and (3) linking of multiple memories across time. By dissecting synaptic from intrinsic plasticity and neuron-wide from dendritically restricted protein capture, the model reveals a simple, unifying principle: linked memories share synaptic clusters within the dendrites of overlapping populations of neurons. The model generates numerous experimentally testable predictions regarding the cellular and sub-cellular properties of memory engrams as well as their spatiotemporal interactions. 10.1016/j.celrep.2016.10.015
Behavioral and neural mechanisms by which prior experience impacts subsequent learning. Parsons Ryan G Neurobiology of learning and memory Memory is often thought about in terms of its ability to recollect and store information about the past, but its function likely rests with the fact that it permits adaptation to ongoing and future experience. Thus, the brain circuitry that encodes memory must act as if stored information is likely to be modified by subsequent experience. Considerable progress has been made in identifying the behavioral and neural mechanisms supporting the acquisition and consolidation of memories, but this knowledge comes largely from studies in laboratory animals in which the training experience is presented in isolation from prior experimentally-controlled events. Given that memories are unlikely to be formed upon a clean slate, there is a clear need to understand how learning occurs upon the background of prior experience. This article reviews recent studies from an emerging body of work on metaplasticity, memory allocation, and synaptic tagging and capture, all of which demonstrate that prior experience can have a profound effect on subsequent learning. Special attention will be given to discussion of the neural mechanisms that allow past experience to affect future learning and to the time course by which past learning events can alter subsequent learning. Finally, consideration will be given to the possible significance of a non-synaptic component of the memory trace, which in some cases is likely responsible for the priming of subsequent learning and may be involved in the recovery from amnestic treatments in which the synaptic mechanisms of memory have been impaired. 10.1016/j.nlm.2017.11.008
Activity-dependent expression of Channelrhodopsin at neuronal synapses. Gobbo Francesco,Marchetti Laura,Jacob Ajesh,Pinto Bruno,Binini Noemi,Pecoraro Bisogni Federico,Alia Claudia,Luin Stefano,Caleo Matteo,Fellin Tommaso,Cancedda Laura,Cattaneo Antonino Nature communications Increasing evidence points to the importance of dendritic spines in the formation and allocation of memories, and alterations of spine number and physiology are associated to memory and cognitive disorders. Modifications of the activity of subsets of synapses are believed to be crucial for memory establishment. However, the development of a method to directly test this hypothesis, by selectively controlling the activity of potentiated spines, is currently lagging. Here we introduce a hybrid RNA/protein approach to regulate the expression of a light-sensitive membrane channel at activated synapses, enabling selective tagging of potentiated spines following the encoding of a novel context in the hippocampus. This approach can be used to map potentiated synapses in the brain and will make it possible to re-activate the neuron only at previously activated synapses, extending current neuron-tagging technologies in the investigation of memory processes. 10.1038/s41467-017-01699-7
Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nature neuroscience The modification of synaptic strength produced by long-term potentiation (LTP) is widely thought to underlie memory storage. Indeed, given that hippocampal pyramidal neurons have >10,000 independently modifiable synapses, the potential for information storage by synaptic modification is enormous. However, recent work suggests that CREB-mediated global changes in neuronal excitability also play a critical role in memory formation. Because these global changes have a modest capacity for information storage compared with that of synaptic plasticity, their importance for memory function has been unclear. Here we review the newly emerging evidence for CREB-dependent control of excitability and discuss two possible mechanisms. First, the CREB-dependent transient change in neuronal excitability performs a memory-allocation function ensuring that memory is stored in ways that facilitate effective linking of events with temporal proximity (hours). Second, these changes may promote cell-assembly formation during the memory-consolidation phase. It has been unclear whether such global excitability changes and local synaptic mechanisms are complementary. Here we argue that the two mechanisms can work together to promote useful memory function. 10.1038/s41593-018-0076-6
Memory Allocation: Mechanisms and Function. Annual review of neuroscience Memories for events are thought to be represented in sparse, distributed neuronal ensembles (or engrams). In this article, we review how neurons are chosen to become part of a particular engram, via a process of neuronal allocation. Experiments in rodents indicate that eligible neurons compete for allocation to a given engram, with more excitable neurons winning this competition. Moreover, fluctuations in neuronal excitability determine how engrams interact, promoting either memory integration (via coallocation to overlapping engrams) or separation (via disallocation to nonoverlapping engrams). In parallel with rodent studies, recent findings in humans verify the importance of this memory integration process for linking memories that occur close in time or share related content. A deeper understanding of allocation promises to provide insights into the logic underlying how knowledge is normally organized in the brain and the disorders in which this process has gone awry. 10.1146/annurev-neuro-080317-061956
Tune it in: mechanisms and computational significance of neuron-autonomous plasticity. Reuveni Iris,Barkai Edi Journal of neurophysiology The activity of a neural network is a result of synaptic signals that convey the communication between neurons and neuron-based intrinsic currents that determine the neuron's input-output transfer function. Ample studies have demonstrated that cell-based excitability, and in particular intrinsic excitability, is modulated by learning and that these modifications play a key role in learning-related behavioral changes. The field of cell-based plasticity is largely growing, and it entails numerous experimental findings that demonstrate a large diversity of currents that are affected by learning. The diverse effect of learning on the neuron's excitability emphasizes the need for a framework under which cell-based plasticity can be categorized to enable the assessment of the computational roles of the intrinsic modifications. We divide the domain of cell-based plasticity into three main categories, where the first category entails the currents that mediate the passive properties and single-spike generation, the second category entails the currents that mediate spike frequency adaptation, and the third category entails a novel learning-induced mechanism where all excitatory and inhibitory synapses double their strength. Curiously, this elementary division enables a natural categorization of the computational roles of these learning-induced plasticities. The computational roles are diverse and include modification of the neuronal mode of action, such as bursting, prolonged, and fast responsive; attention-like effect where the signal detection is improved; transfer of the network into an active state; biasing the competition for memory allocation; and transforming an environmental cue into a dominant cue and enabling a quicker formation of new memories. 10.1152/jn.00102.2018
How the Hippocampus Represents Memories: Making Sense of Memory Allocation Studies. França Thiago F A,Monserrat José M BioEssays : news and reviews in molecular, cellular and developmental biology In recent years there has been a wealth of studies investigating how memories are allocated in the hippocampus. Some of those studies showed that it is possible to manipulate the identity of neurons recruited to represent a given memory without affecting the memory's behavioral expression. Those findings raised questions about how the hippocampus represents memories, with some researchers arguing that hippocampal neurons do not represent fixed stimuli. Herein, an alternative hypothesis is argued. Neurons in high-order brain regions can be tuned to multiple dimensions, forming complex, abstract representations. It is argued that such complex receptive fields allow those neurons to show some flexibility in their responses while still representing relatively fixed sets of stimuli. Moreover, it is pointed out that changes induced by artificial manipulation of cell assemblies are not completely redundant-the observed behavioral redundancy does not imply cognitive redundancy, as different, but similar, memories may induce the same behavior. 10.1002/bies.201800068
A time-dependent role for the transcription factor CREB in neuronal allocation to an engram underlying a fear memory revealed using a novel in vivo optogenetic tool to modulate CREB function. Park Albert,Jacob Alexander D,Walters Brandon J,Park Sungmo,Rashid Asim J,Jung Jung Hoon,Lau Jocelyn,Woolley G Andrew,Frankland Paul W,Josselyn Sheena A Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology The internal representation of an experience is thought to be encoded by long-lasting physical changes to the brain ("engrams") . Previously, we and others showed within the lateral amygdala (LA), a region critical for auditory conditioned fear, eligible neurons compete against one other for allocation to an engram. Neurons with relatively higher function of the transcription factor CREB were more likely to be allocated to the engram. In these studies, though, CREB function was artificially increased for several days before training. Precisely when increased CREB function is important for allocation remains an unanswered question. Here, we took advantage of a novel optogenetic tool (opto-DN-CREB) to gain spatial and temporal control of CREB function in freely behaving mice. We found increasing CREB function in a small, random population of LA principal neurons in the minutes, but not 24 h, before training was sufficient to enhance memory, likely because these neurons were preferentially allocated to the underlying engram. However, similarly increasing CREB activity in a small population of random LA neurons immediately after training disrupted subsequent memory retrieval, likely by disrupting the precise spatial and temporal patterns of offline post-training neuronal activity and/or function required for consolidation. These findings reveal the importance of the timing of CREB activity in regulating allocation and subsequent memory retrieval, and further, highlight the potential of optogenetic approaches to control protein function with temporal specificity in behaving animals. 10.1038/s41386-019-0588-0
Synaptic Clustering and Memory Formation. Frontiers in molecular neuroscience In the study of memory engrams, synaptic memory allocation is a newly emerged theme that focuses on how specific synapses are engaged in the storage of a given memory. Cumulating evidence from imaging and molecular experiments indicates that the recruitment of synapses that participate in the encoding and expression of memory is neither random nor uniform. A hallmark observation is the emergence of groups of synapses that share similar response properties and/or similar input properties and are located within a stretch of a dendritic branch. This grouping of synapses has been termed "synapse clustering" and has been shown to emerge in many different memory-related paradigms, as well as in studies. The clustering of synapses may emerge from synapses receiving similar input, or many processes which allow for cross-talk between nearby synapses within a dendritic branch, leading to cooperative plasticity. Clustered synapses can act in concert to maximally exploit the nonlinear integration potential of the dendritic branches in which they reside. Their main contribution is to facilitate the induction of dendritic spikes and dendritic plateau potentials, which provide advanced computational and memory-related capabilities to dendrites and single neurons. This review focuses on recent evidence which investigates the role of synapse clustering in dendritic integration, sensory perception, learning, and memory as well as brain dysfunction. We also discuss recent theoretical work which explores the computational advantages provided by synapse clustering, leading to novel and revised theories of memory. As an eminent phenomenon during memory allocation, synapse clustering both shapes memory engrams and is also shaped by the parallel plasticity mechanisms upon which it relies. 10.3389/fnmol.2019.00300
Neuronal ensemble-specific DNA methylation strengthens engram stability. Gulmez Karaca Kubra,Kupke Janina,Brito David V C,Zeuch Benjamin,Thome Christian,Weichenhan Dieter,Lutsik Pavlo,Plass Christoph,Oliveira Ana M M Nature communications Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular mechanisms that drive engram stabilization during consolidation and consequently ensure its reactivation by memory recall are not fully understood. In this study we manipulate, during memory consolidation, the levels of the de novo DNA methyltransferase 3a2 (Dnmt3a2) selectively within dentate gyrus neurons activated by fear conditioning. We found that Dnmt3a2 upregulation enhances memory performance in mice and improves the fidelity of reconstitution of the original neuronal ensemble upon memory retrieval. Moreover, similar manipulation in a sparse, non-engram subset of neurons does not bias engram allocation or modulate memory strength. We further show that neuronal Dnmt3a2 overexpression changes the DNA methylation profile of synaptic plasticity-related genes. Our data implicates DNA methylation selectively within neuronal ensembles as a mechanism of stabilizing engrams during consolidation that supports successful memory retrieval. 10.1038/s41467-020-14498-4
The role of intrinsic excitability in the evolution of memory: Significance in memory allocation, consolidation, and updating. Neurobiology of learning and memory Memory is a dynamic process that is continuously regulated by both synaptic and intrinsic neural mechanisms. While numerous studies have shown that synaptic plasticity is important in various types and phases of learning and memory, neuronal intrinsic excitability has received relatively less attention, especially regarding the dynamic nature of memory. In this review, we present evidence demonstrating the importance of intrinsic excitability in memory allocation, consolidation, and updating. We also consider the intricate interaction between intrinsic excitability and synaptic plasticity in shaping memory, supporting both memory stability and flexibility. 10.1016/j.nlm.2020.107266
The role of neuronal excitability, allocation to an engram and memory linking in the behavioral generation of a false memory in mice. Lau Jocelyn M H,Rashid Asim J,Jacob Alexander D,Frankland Paul W,Schacter Daniel L,Josselyn Sheena A Neurobiology of learning and memory Memory is a constructive, not reproductive, process that is prone to errors. Errors in memory, though, may originate from normally adaptive memory processes. At the extreme of memory distortion is falsely "remembering" an event that did not occur. False memories are well-studied in cognitive psychology, but have received relatively less attention in neuroscience. Here, we took advantage of mechanistic insights into how neurons are allocated or recruited into an engram (memory trace) to generate a false memory in mice using only behavioral manipulations. At the time of an event, neurons compete for allocation to an engram supporting the memory for this event; neurons with higher excitability win this competition (Han et al., 2007). Even after the event, these allocated "engram neurons" remain temporarily (~6 h) more excitable than neighboring neurons. Should a similar event occur in this 6 h period of heightened engram neuron excitability, an overlapping population of neurons will be co-allocated to this second engram, which serves to functionally link the two memories (Rashid et al., 2016). Here, we applied this principle of co-allocation and found that mice develop a false fear memory to a neutral stimulus if exposed to this stimulus shortly (3 h), but not a longer time (24 h), after cued fear conditioning. Similar to co-allocation, the generation of this false memory depended on the post-training excitability of engram neurons such that these neurons remained more excitable during exposure to the neutral stimulus at 3 h but not 24 h. Optogenetically silencing engram neurons 3 h after cued fear conditioning impaired formation of a false fear memory to the neutral stimulus, while optogenetically activating engram neurons 24 h after cued fear conditioning created a false fear memory. These results suggest that some false memories may originate from normally adaptive mnemonic processes such as neuronal excitability-dependent allocation and memory linking. 10.1016/j.nlm.2020.107284
The Interplay of Synaptic Plasticity and Scaling Enables Self-Organized Formation and Allocation of Multiple Memory Representations. Frontiers in neural circuits It is commonly assumed that memories about experienced stimuli are represented by groups of highly interconnected neurons called cell assemblies. This requires allocating and storing information in the neural circuitry, which happens through synaptic weight adaptations at different types of synapses. In general, memory allocation is associated with synaptic changes at feed-forward synapses while memory storage is linked with adaptation of recurrent connections. It remains, however, largely unknown how memory allocation and storage can be achieved and the adaption of the different synapses involved be coordinated to allow for a faithful representation of memories without disruptive interference between them. In this theoretical study, by using network simulations and phase space analyses, we show that the interplay between long-term synaptic plasticity and homeostatic synaptic scaling organizes simultaneously the adaptations of feed-forward and recurrent synapses such that a new stimulus forms a new memory and where different stimuli are assigned to distinct cell assemblies. The resulting dynamics can reproduce experimental data, focusing on how diverse factors, such as neuronal excitability and network connectivity, influence memory formation. Thus, the here presented model suggests that a few fundamental synaptic mechanisms may suffice to implement memory allocation and storage in neural circuitry. 10.3389/fncir.2020.541728
Local memory allocation recruits memory ensembles across brain regions. Neuron Memories are thought to be stored in ensembles of neurons across multiple brain regions. However, whether and how these ensembles are coordinated at the time of learning remains largely unknown. Here, we combined CREB-mediated memory allocation with transsynaptic retrograde tracing to demonstrate that the allocation of aversive memories to a group of neurons in one brain region directly affects the allocation of interconnected neurons in upstream brain regions in a behavioral- and brain region-specific manner in mice. Our analysis suggests that this cross-regional recruitment of presynaptic neurons is initiated by downstream memory neurons through a retrograde mechanism. Together with statistical modeling, our results indicate that in addition to the anterograde flow of information between brain regions, the establishment of interconnected, brain-wide memory traces relies on a retrograde mechanism that coordinates memory ensembles at the time of learning. 10.1016/j.neuron.2022.11.018
Generalized extinction of fear memory depends on co-allocation of synaptic plasticity in dendrites. Nature communications Memories can be modified by new experience in a specific or generalized manner. Changes in synaptic connections are crucial for memory storage, but it remains unknown how synaptic changes associated with different memories are distributed within neuronal circuits and how such distributions affect specific or generalized modification by novel experience. Here we show that fear conditioning with two different auditory stimuli (CS) and footshocks (US) induces dendritic spine elimination mainly on different dendritic branches of layer 5 pyramidal neurons in the mouse motor cortex. Subsequent fear extinction causes CS-specific spine formation and extinction of freezing behavior. In contrast, spine elimination induced by fear conditioning with >2 different CS-USs often co-exists on the same dendritic branches. Fear extinction induces CS-nonspecific spine formation and generalized fear extinction. Moreover, activation of somatostatin-expressing interneurons increases the occurrence of spine elimination induced by different CS-USs on the same dendritic branches and facilitates the generalization of fear extinction. These findings suggest that specific or generalized modification of existing memories by new experience depends on whether synaptic changes induced by previous experiences are segregated or co-exist at the level of individual dendritic branches. 10.1038/s41467-023-35805-9
Defective engram allocation contributes to impaired fear memory performance in Down syndrome. bioRxiv : the preprint server for biology Down syndrome (DS) is the most common genetic form of intellectual disability (ID). The cellular and molecular mechanisms contributing to ID in DS are not completely understood. Recent evidence indicates that a given memory is encoded by sparsely distributed neurons, highly activated during learning, the engram cells. Intriguingly, mechanisms that are of paramount importance for engram formation are impaired in DS. Here we explored engram formation in a DS mouse model, the Ts65Dn and we found a reduced number of engram cells in the dentate gyrus (DG), suggesting reduced neuronal allocation to engrams. We also show that trisomic engram cells present reduced number of mature spines than WT engram cells and their excitability is not enhanced during memory recall. In fact, activation of engram cells using a chemogenetic approach does not recover memory deficits in Ts65Dn. Altogether, our findings suggest that perturbations in engram neurons may play a significant role in memory alterations in DS. 10.1101/2023.01.11.523460
Memory travels through cells backward. Neuron Can memory ensembles recruit neurons in connected brain regions? In this issue of Neuron, Lavi et al. drove the allocation of memory to selected cells in one area, causing their presynaptic partners to become part of a cross-regional ensemble. 10.1016/j.neuron.2023.01.024
A shift in the mechanisms controlling hippocampal engram formation during brain maturation. Science (New York, N.Y.) The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 through assembly of extracellular perineuronal nets, which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision. 10.1126/science.ade6530
Consolidated and labile odor memory are separately encoded within the Drosophila brain. Scheunemann Lisa,Jost Eva,Richlitzki Antje,Day Jonathan P,Sebastian Sujith,Thum Andreas S,Efetova Marina,Davies Shireen-A,Schwärzel Martin The Journal of neuroscience : the official journal of the Society for Neuroscience Memories are classified as consolidated (stable) or labile according to whether they withstand amnestic treatment, or not. In contrast to the general prevalence of this classification, its neuronal and molecular basis is poorly understood. Here, we focused on consolidated and labile memories induced after a single cycle training in the Drosophila aversive olfactory conditioning paradigm and we used mutants to define the impact of cAMP signals. At the biochemical level we report that cAMP signals misrelated in either rutabaga (rut) or dunce (dnc) mutants separate between consolidated anesthesia-resistant memory (ARM) and labile anesthesia-sensitive memory (ASM). Those functionally distinct cAMP signals act within different neuronal populations: while rut-dependent cAMP signals act within Kenyon cells (KCs) of the mushroom bodies to support ASM, dnc-sensitive cAMP signals support ARM within antennal lobe local neurons (LNs) and KCs. Collectively, different key positions along the olfactory circuitry seem to get modified during storage of ARM or ASM independently. A precise separation between those functionally distinct cAMP signals seems mandatory to allocate how they support appropriate memories. 10.1523/JNEUROSCI.3286-12.2012
A shared neural ensemble links distinct contextual memories encoded close in time. Nature Recent studies suggest that a shared neural ensemble may link distinct memories encoded close in time. According to the memory allocation hypothesis, learning triggers a temporary increase in neuronal excitability that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that recall of one memory increases the likelihood of recalling the other memory. Here we show in mice that the overlap between the hippocampal CA1 ensembles activated by two distinct contexts acquired within a day is higher than when they are separated by a week. Several findings indicate that this overlap of neuronal ensembles links two contextual memories. First, fear paired with one context is transferred to a neutral context when the two contexts are acquired within a day but not across a week. Second, the first memory strengthens the second memory within a day but not across a week. Older mice, known to have lower CA1 excitability, do not show the overlap between ensembles, the transfer of fear between contexts, or the strengthening of the second memory. Finally, in aged mice, increasing cellular excitability and activating a common ensemble of CA1 neurons during two distinct context exposures rescued the deficit in linking memories. Taken together, these findings demonstrate that contextual memories encoded close in time are linked by directing storage into overlapping ensembles. Alteration of these processes by ageing could affect the temporal structure of memories, thus impairing efficient recall of related information. 10.1038/nature17955
Evoked brain potentials and memory: more positivity in response to forgotten items. Jordan J S,Kotchoubey B,Grözinger B,Westphal K P Neuroreport Brain evoked potentials (EPs) were recorded in human subjects participating in a free recall memory task involving retroactive interference. A learning list was presented five times. The fifth repetition was followed by an interference list. Both lists were composed of either words or abstract figures, and each subject experienced each of four possible combinations. Analysis of items recalled during the learning phase revealed larger N400 and P600 amplitudes for those items that were later forgotten vs remembered following the interference. This contradicts the usual finding that more positivity is associated with better memory. However, both the present as well as the extant findings can be explained in terms of cognitive resource allocation. Specifically, items receiving greater allocations are more likely to be immediately recalled. However, as the number of items in working memory increases, the allocation required to add new items also increases. Thus, items learned on later trials would receive larger allocations (i.e., larger positivities) than items learned earlier, yet would be more likely forgotten following the interference because their presence in memory would not be reinforced during later trials, as is the case with items learned earlier. 10.1097/00001756-199510020-00022
From contextual fear to a dynamic view of memory systems. Fanselow Michael S Trends in cognitive sciences The brain does not learn and remember in a unitary fashion. Rather, different circuits specialize in certain classes of problems and encode different types of information. Damage to one of these systems typically results in amnesia only for the form of memory that is the specialty of the affected region. However, the question of how the brain allocates a specific category of memory to a particular circuit has received little attention. The currently dominant view (multiple memory systems theory) assumes that such abilities are hard wired. Using fear conditioning as a paradigmatic case, I propose an alternative model in which mnemonic processing is allocated to specific circuits through a dynamic process. Potential circuits compete to form memories, with the most efficient circuits emerging as winners. However, alternate circuits compensate when these 'primary' circuits are compromised. 10.1016/j.tics.2009.10.008
Formation and fate of an engram in the lateral amygdala supporting a rewarding memory in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Memories allow past experiences to guide future decision making and behavior. Sparse ensembles of neurons, known as engrams, are thought to store memories in the brain. Most previous research has focused on engrams supporting threatening or fearful memories where results show that neurons involved in a particular engram ("engram neurons") are both necessary and sufficient for memory expression. Far less is understood about engrams supporting appetitive or rewarding memories. As circumstances and environments are dynamic, the fate of a previously acquired engram with changing circumstances is unknown. Here we examined how engrams supporting a rewarding cue-cocaine memory are formed and whether this original engram is important in reinstatement of memory-guided behavior following extinction. Using a variety of techniques, we show that neurons in the lateral amygdala are allocated to an engram based on relative neuronal excitability at training. Furthermore, once allocated, these neurons become both necessary and sufficient for behavior consistent with recall of that rewarding memory. Allocated neurons are also critical for cocaine-primed reinstatement of memory-guided behavior following extinction. Moreover, artificial reactivation of initially allocated neurons supports reinstatement-like behavior following extinction even in the absence of cocaine-priming. Together, these findings suggest that cocaine priming after extinction reactivates the original engram, and that memory-guided reinstatement behavior does not occur in the absence of this reactivation. Although we focused on neurons in one brain region only, our findings that manipulations of lateral amygdala engram neurons alone were sufficient to impact memory-guided behavior indicate that the lateral amygdala is a critical hub region in what may be a larger brain-wide engram. 10.1038/s41386-022-01472-5
Localization of Contextual and Context Removed Auditory Fear Memory within the Basolateral Amygdala Complex. Chaaya N,Jacques A,Belmer A,Richard D J,Bartlett S E,Battle A R,Johnson L R Neuroscience Debilitating and persistent fear memories can rapidly form in humans following exposure to traumatic events. Fear memories can also be generated and studied in animals via Pavlovian fear conditioning. The current study was designed to evaluate basolateral amygdala complex (BLC) involvement following the formation of different fear memories (two contextual fear memories and one adjusted auditory fear memory). Fear memories were created in the same context with five 1.0 mA (0.50 s) foot-shocks and, where necessary, five auditory tones (5 kHz, 75 dB, 20 s). The adjusted auditory fear conditioning protocol was employed to remove background contextual fear and produce isolated auditory fear memories. Immunofluorescent labeling was utilized to identify neurons expressing immediate early genes (IEGs). We found the two contextual fear conditioning (CFC) procedures to produce similar levels of fear-related freezing to context. Contextual fear memories produced increases in BLC IEG expression with distinct and separate patterns of expression. These data suggest contextual fear memories created in slightly altered contexts, can produce unique patterns of amygdala activation. The adjusted auditory fear conditioning procedure produced memories to a tone, but not to a context. This group, where no contextual fear was present, had a significant reduction in BLC IEG expression. These data suggest background contextual fear memories, created in standard auditory fear conditioning protocols, contribute significantly to increases in amygdala activation. 10.1016/j.neuroscience.2018.12.004
The hippocampus as a stable memory allocator for cortex. Valiant Leslie G Neural computation It is suggested here that mammalian hippocampus serves as an allocator of neurons in cortex for memorizing new items. A construction of a shallow feedforward network with biologically plausible parameters is given that possesses the characteristics needed for such an allocator. In particular, the construction is stabilizing in that for inputs within a range of activity levels spanning more than an order of magnitude, the output will have activity levels differing as little as 1%. It is also noise tolerant in that pairs of input patterns that differ little will generate output patterns that differ little. Further, pairs of inputs that differ by much will be mapped to outputs that also differ sufficiently that they can be treated by cortex as distinct. 10.1162/NECO_a_00357
Artificially Enhancing and Suppressing Hippocampus-Mediated Memories. Chen Briana K,Murawski Nathen J,Cincotta Christine,McKissick Olivia,Finkelstein Abby,Hamidi Anahita B,Merfeld Emily,Doucette Emily,Grella Stephanie L,Shpokayte Monika,Zaki Yosif,Fortin Amanda,Ramirez Steve Current biology : CB Emerging evidence indicates that distinct hippocampal domains differentially drive cognition and emotion [1, 2]; dorsal regions encode spatial, temporal, and contextual information [3-5], whereas ventral regions regulate stress responses [6], anxiety-related behaviors [7, 8], and emotional states [8-10]. Although previous studies demonstrate that optically manipulating cells in the dorsal hippocampus can drive the behavioral expression of positive and negative memories, it is unknown whether changes in cellular activity in the ventral hippocampus can drive such behaviors [11-14]. Investigating the extent to which distinct hippocampal memories across the longitudinal axis modulate behavior could aid in the understanding of stress-related psychiatric disorders known to affect emotion, memory, and cognition [15]. Here, we asked whether tagging and stimulating cells along the dorsoventral axis of the hippocampus could acutely, chronically, and differentially promote context-specific behaviors. Acute reactivation of both dorsal and ventral hippocampus cells that were previously active during memory formation drove freezing behavior, place avoidance, and place preference. Moreover, chronic stimulation of dorsal or ventral hippocampal fear memories produced a context-specific reduction or enhancement of fear responses, respectively, thus demonstrating bi-directional and context-specific modulation of memories along the longitudinal axis of the hippocampus. Fear memory suppression was associated with a reduction in hippocampal cells active during retrieval, while fear memory enhancement was associated with an increase in basolateral amygdala activity. Together, our data demonstrate that discrete sets of cells throughout the hippocampus provide key nodes sufficient to bi-directionally reprogram both the neural and behavioral expression of memory. 10.1016/j.cub.2019.04.065
Can sleep protect memories from catastrophic forgetting? eLife Continual learning remains an unsolved problem in artificial neural networks. The brain has evolved mechanisms to prevent catastrophic forgetting of old knowledge during new training. Building upon data suggesting the importance of sleep in learning and memory, we tested a hypothesis that sleep protects old memories from being forgotten after new learning. In the thalamocortical model, training a new memory interfered with previously learned old memories leading to degradation and forgetting of the old memory traces. Simulating sleep after new learning reversed the damage and enhanced old and new memories. We found that when a new memory competed for previously allocated neuronal/synaptic resources, sleep replay changed the synaptic footprint of the old memory to allow overlapping neuronal populations to store multiple memories. Our study predicts that memory storage is dynamic, and sleep enables continual learning by combining consolidation of new memory traces with reconsolidation of old memory traces to minimize interference. 10.7554/eLife.51005
Molecular and Cellular Mechanisms for Trapping and Activating Emotional Memories. PloS one Recent findings suggest that memory allocation to specific neurons (i.e., neuronal allocation) in the amygdala is not random, but rather the transcription factor cAMP-response element binding protein (CREB) modulates this process, perhaps by regulating the transcription of channels that control neuronal excitability. Here, optogenetic studies in the mouse lateral amygdala (LA) were used to demonstrate that CREB and neuronal excitability regulate which neurons encode an emotional memory. To test the role of CREB in memory allocation, we overexpressed CREB in the lateral amygdala to recruit the encoding of an auditory-fear conditioning (AFC) memory to a subset of neurons. Then, post-training activation of these neurons with Channelrhodopsin-2 was sufficient to trigger recall of the memory for AFC, suggesting that CREB regulates memory allocation. To test the role of neuronal excitability in memory allocation, we used a step function opsin (SFO) to transiently increase neuronal excitability in a subset of LA neurons during AFC. Post-training activation of these neurons with Volvox Channelrhodopsin-1 was able to trigger recall of that memory. Importantly, our studies show that activation of the SFO did not affect AFC by either increasing anxiety or by strengthening the unconditioned stimulus. Our findings strongly support the hypothesis that CREB regulates memory allocation by modulating neuronal excitability. 10.1371/journal.pone.0161655
Corticosterone and propranolol's role on taste recognition memory. Ruetti E,Justel N,Mustaca A,Boccia M Pharmacology, biochemistry, and behavior Taste recognition is a robust procedure to study learning and memory processes, as well as the different stages involved in them, i.e. encoding, storage and recall. Considerable evidence indicates that adrenal hormones and the noradrenergic system play an important role in aversive and appetitive memory formation in rats and humans. The present experiments were designed to characterize the effects of immediate post training corticosterone (Experiment 1) and propranolol administration (Experiment 2 and 3) on taste recognition memory. Administration of a high dose of corticosterone (5mg/kg, sc) impairs consolidation of taste memory, but the low and moderate doses (1 and 3mg/kg, sc) didn't affect it. On the other hand, immediate post-training administration of propranolol (1 and 2mg/kg, ip) impaired taste recognition memory. These effects were time-dependent since no effects were seen when drug administration was delayed 3h after training. These findings support the importance of stress hormones and noradrenergic system on the modulation of taste memory consolidation. 10.1016/j.pbb.2014.09.013
The Roles of Cortical Slow Waves in Synaptic Plasticity and Memory Consolidation. Miyamoto Daisuke,Hirai Daichi,Murayama Masanori Frontiers in neural circuits Sleep plays important roles in sensory and motor memory consolidation. Sleep oscillations, reflecting neural population activity, involve the reactivation of learning-related neurons and regulate synaptic strength and, thereby affect memory consolidation. Among sleep oscillations, slow waves (0.5-4 Hz) are closely associated with memory consolidation. For example, slow-wave power is regulated in an experience-dependent manner and correlates with acquired memory. Furthermore, manipulating slow waves can enhance or impair memory consolidation. During slow wave sleep, inter-areal interactions between the cortex and hippocampus (HC) have been proposed to consolidate declarative memory; however, interactions for non-declarative (HC-independent) memory remain largely uninvestigated. We recently showed that the directional influence in a slow-wave range through a top-down cortical long-range circuit is involved in the consolidation of non-declarative memory. At the synaptic level, the average cortical synaptic strength is known to be potentiated during wakefulness and depressed during sleep. Moreover, learning causes plasticity in a subset of synapses, allocating memory to them. Sleep may help to differentiate synaptic strength between allocated and non-allocated synapses (i.e., improving the signal-to-noise ratio, which may facilitate memory consolidation). Herein, we offer perspectives on inter-areal interactions and synaptic plasticity for memory consolidation during sleep. 10.3389/fncir.2017.00092
Convergent Coding of Recent and Remote Fear Memory in the Basolateral Amygdala. Biological psychiatry BACKGROUND:In both rodents and humans, the basolateral amygdala (BLA) is essential for encoding and retrieving conditioned fear memories. Although the BLA is a putative storage site for these memories, recent evidence suggests that they become independent of the BLA with the passage of time. METHODS:We systematically examined the role for the BLA in the retrieval of recent (1 day) and remote (2 weeks) fear memory using optogenetic, electrophysiological, and calcium imaging methods in male and female Long-Evans rats. Critically, we used a behavioral design that permits within-subjects comparison of recent and remote memory at the same time point; freezing behavior served as the index of learned fear. RESULTS:We found that BLA c-Fos expression was similar after the retrieval of recent or remote fear memories. Extracellular single-unit recordings in awake, behaving animals revealed that single BLA neurons exhibit robust increases in spike firing to both recent and remote conditioned stimuli. Fiber photometry recordings revealed that these patterns of activity emerge from principal neurons. Consistent with these results, optogenetic inhibition of BLA principal neurons impaired conditioned freezing to both recent and remote conditioned stimuli. There were no sex differences in any of the measures or manipulations. CONCLUSIONS:These data reveal that BLA neurons encode both recent and remote fear memories, suggesting substantial overlap in the allocation of temporally distinct events. This may underlie the broad generalization of fear memories across both space and time. Ultimately, these results provide evidence that the BLA is a long-term storage site for emotional memories. 10.1016/j.biopsych.2021.12.018
Neurons are recruited to a memory trace based on relative neuronal excitability immediately before training. Yiu Adelaide P,Mercaldo Valentina,Yan Chen,Richards Blake,Rashid Asim J,Hsiang Hwa-Lin Liz,Pressey Jessica,Mahadevan Vivek,Tran Matthew M,Kushner Steven A,Woodin Melanie A,Frankland Paul W,Josselyn Sheena A Neuron Memories are thought to be sparsely encoded in neuronal networks, but little is known about why a given neuron is recruited or allocated to a particular memory trace. Previous research shows that in the lateral amygdala (LA), neurons with increased CREB are selectively recruited to a fear memory trace. CREB is a ubiquitous transcription factor implicated in many cellular processes. Which process mediates neuronal memory allocation? One hypothesis is that CREB increases neuronal excitability to bias neuronal recruitment, although this has not been shown experimentally. Here we use several methods to increase neuronal excitability and show this both biases recruitment into the memory trace and enhances memory formation. Moreover, artificial activation of these neurons alone is a sufficient retrieval cue for fear memory expression, showing that these neurons are critical components of the memory trace. These results indicate that neuronal memory allocation is based on relative neuronal excitability immediately before training. 10.1016/j.neuron.2014.07.017
Neurons activated during fear memory consolidation and reconsolidation are mapped to a common and new topography in the lateral amygdala. Bergstrom Hadley C,McDonald Craig G,Dey Smita,Fernandez Gina M,Johnson Luke R Brain topography A key question in neuroscience is how memory is selectively allocated to neural networks in the brain. This question remains a significant research challenge, in both rodent models and humans alike, because of the inherent difficulty in tracking and deciphering large, highly dimensional neuronal ensembles that support memory (i.e., the engram). In a previous study we showed that consolidation of a new fear memory is allocated to a common topography of amygdala neurons. When a consolidated memory is retrieved, it may enter a labile state, requiring reconsolidation for it to persist. What is not known is whether the original spatial allocation of a consolidated memory changes during reconsolidation. Knowledge about the spatial allocation of a memory, during consolidation and reconsolidation, provides fundamental insight into its core physical structure (i.e., the engram). Using design-based stereology, we operationally define reconsolidation by showing a nearly identical quantity of neurons in the dorsolateral amygdala (LAd) that expressed a plasticity-related protein, phosphorylated mitogen-activated protein kinase, following both memory acquisition and retrieval. Next, we confirm that Pavlovian fear conditioning recruits a stable, topographically organized population of activated neurons in the LAd. When the stored fear memory was briefly reactivated in the presence of the relevant conditioned stimulus, a similar topography of activated neurons was uncovered. In addition, we found evidence for activated neurons allocated to new regions of the LAd. These findings provide the first insight into the spatial allocation of a fear engram in the LAd, during its consolidation and reconsolidation phase. 10.1007/s10548-012-0266-6