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    Relocation of an Extrasynaptic GABA Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory. Davenport Christopher M,Rajappa Rajit,Katchan Ljudmila,Taylor Charlotte R,Tsai Ming-Chi,Smith Caleb M,de Jong Johannes W,Arnold Don B,Lammel Stephan,Kramer Richard H Neuron The excitatory synapse between hippocampal CA3 and CA1 pyramidal neurons exhibits long-term potentiation (LTP), a positive feedback process implicated in learning and memory in which postsynaptic depolarization strengthens synapses, promoting further depolarization. Without mechanisms for interrupting positive feedback, excitatory synapses could strengthen inexorably, corrupting memory storage. Here, we reveal a hidden form of inhibitory synaptic plasticity that prevents accumulation of excitatory LTP. We developed a knockin mouse that allows optical control of endogenous α5-subunit-containing γ-aminobutyric acid (GABA) receptors (α5-GABARs). Induction of excitatory LTP relocates α5-GABARs, which are ordinarily extrasynaptic, to inhibitory synapses, quashing further NMDA receptor activation necessary for inducing more excitatory LTP. Blockade of α5-GABARs accelerates reversal learning, a behavioral test for cognitive flexibility dependent on repeated LTP. Hence, inhibitory synaptic plasticity occurs in parallel with excitatory synaptic plasticity, with the ensuing interruption of the positive feedback cycle of LTP serving as a possible critical early step in preserving memory. 10.1016/j.neuron.2020.09.037
    Rpd3/CoRest-mediated activity-dependent transcription regulates the flexibility in memory updating in Drosophila. Takakura Mai,Nakagawa Reiko,Ota Takeshi,Kimura Yoko,Ng Man Yung,Alia Abdalla G,Okuno Hiroyuki,Hirano Yukinori Nature communications Consolidated memory can be preserved or updated depending on the environmental change. Although such conflicting regulation may happen during memory updating, the flexibility of memory updating may have already been determined in the initial memory consolidation process. Here, we explored the gating mechanism for activity-dependent transcription in memory consolidation, which is unexpectedly linked to the later memory updating in Drosophila. Through proteomic analysis, we discovered that the compositional change in the transcriptional repressor, which contains the histone deacetylase Rpd3 and CoRest, acts as the gating mechanism that opens and closes the time window for activity-dependent transcription. Opening the gate through the compositional change in Rpd3/CoRest is required for memory consolidation, but closing the gate through Rpd3/CoRest is significant to limit future memory updating. Our data indicate that the flexibility of memory updating is determined through the initial activity-dependent transcription, providing a mechanism involved in defining memory state. 10.1038/s41467-021-20898-x
    Synaptic plasticity-dependent competition rule influences memory formation. Jeong Yire,Cho Hye-Yeon,Kim Mujun,Oh Jung-Pyo,Kang Min Soo,Yoo Miran,Lee Han-Sol,Han Jin-Hee Nature communications Memory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation. 10.1038/s41467-021-24269-4
    The role of anxiety in the integrative memory model. Nephew Benjamin C,Chumachenko Serhiy,Forester Brent P The Behavioral and brain sciences We suggest that the inclusion of anxiety, as one relevant mood factor, could enhance the implementation of the integrative memory model in research and the clinic. The role of anxiety in Alzheimer's disease neuroanatomy, symptomology, and progression is used as an example. Customization of the integrative memory model can establish strong foundations for pathology-specific models of memory deficits, enhancing the development of precision medicine applications. 10.1017/S0140525X19001900
    Impairments to Consolidation, Reconsolidation, and Long-Term Memory Maintenance Lead to Memory Erasure. Haubrich Josué,Bernabo Matteo,Baker Andrew G,Nader Karim Annual review of neuroscience An enduring problem in neuroscience is determining whether cases of amnesia result from eradication of the memory trace (storage impairment) or if the trace is present but inaccessible (retrieval impairment). The most direct approach to resolving this question is to quantify changes in the brain mechanisms of long-term memory (BM-LTM). This approach argues that if the amnesia is due to a retrieval failure, BM-LTM should remain at levels comparable to trained, unimpaired animals. Conversely, if memories are erased, BM-LTM should be reduced to resemble untrained levels. Here we review the use of BM-LTM in a number of studies that induced amnesia by targeting memory maintenance or reconsolidation. The literature strongly suggests that such amnesia is due to storage rather than retrieval impairments. We also describe the shortcomings of the purely behavioral protocol that purports to show recovery from amnesia as a method of understanding the nature of amnesia. 10.1146/annurev-neuro-091319-024636
    Is Activity Silent Working Memory Simply Episodic Memory? Beukers Andre O,Buschman Timothy J,Cohen Jonathan D,Norman Kenneth A Trends in cognitive sciences Working memory (WM) maintains task-relevant information in a state ready for processing. While traditional theories assume that sustained neuronal activity is responsible for WM, the Activity Silent WM (ASWM) account proposes that maintenance can also be supported by short-term synaptic weight changes. Here, we argue that the evidence for ASWM can be explained more parsimoniously by the involvement of episodic memory (EM) in WM tasks. Like ASWM, EM relies on rapid synaptic modification that is also activity silent; however, while ASWM posits transient synaptic modifications, EM traces persist over longer time periods. We discuss how, despite this difference, well-established EM mechanisms can account for the key findings attributed to ASWM, and describe predictions of this account. 10.1016/j.tics.2021.01.003
    Synaptic correlates of associative fear memory in the lateral amygdala. Choi Dong Il,Kim Jooyoung,Lee Hoonwon,Kim Ji-Il,Sung Yongmin,Choi Ja Eun,Venkat S Jayakumar,Park Pojeong,Jung Hyunsu,Kaang Bong-Kiun Neuron Successful adaptation to the environment requires an accurate response to external threats by recalling specific memories. Memory formation and recall require engram cell activity and synaptic strengthening among activated neuronal ensembles. However, elucidation of the underlying neural substrates of associative fear memory has remained limited without a direct interrogation of extinction-induced changes of specific synapses that encode a specific auditory fear memory. Using dual-eGRASP (enhanced green fluorescent protein reconstitution across synaptic partners), we found that synapses among activated neuronal ensembles or activated synaptic ensembles showed a significantly larger spine morphology at auditory cortex (AC)-to-lateral amygdala (LA) projections after auditory fear conditioning in mice. Fear extinction reversed these enhanced synaptic ensemble spines, whereas re-conditioning with the same tone and shock restored the spine size of the synaptic ensemble. We suggest that synaptic ensembles encode and represent different fear memory states. 10.1016/j.neuron.2021.07.003
    Precisely timed theta oscillations are selectively required during the encoding phase of memory. Quirk Clare R,Zutshi Ipshita,Srikanth Sunandha,Fu Maylin L,Devico Marciano Naomie,Wright Morgan K,Parsey Darian F,Liu Stanley,Siretskiy Rachel E,Huynh Tiffany L,Leutgeb Jill K,Leutgeb Stefan Nature neuroscience Brain oscillations have been hypothesized to support cognitive function by coordinating spike timing within and across brain regions, yet it is often not known when timing is either critical for neural computations or an epiphenomenon. The entorhinal cortex and hippocampus are necessary for learning and memory and exhibit prominent theta oscillations (6-9 Hz), which are controlled by pacemaker cells in the medial septal area. Here we show that entorhinal and hippocampal neuronal activity patterns were strongly entrained by rhythmic optical stimulation of parvalbumin-positive medial septal area neurons in mice. Despite strong entrainment, memory impairments in a spatial working memory task were not observed with pacing frequencies at or below the endogenous theta frequency and only emerged at frequencies ≥10 Hz, and specifically when pacing was targeted to maze segments where encoding occurs. Neural computations during the encoding phase were therefore selectively disrupted by perturbations of the timing of neuronal firing patterns. 10.1038/s41593-021-00919-0
    The impact of Semaphorin 4C/Plexin-B2 signaling on fear memory via remodeling of neuronal and synaptic morphology. Simonetti Manuela,Paldy Eszter,Njoo Christian,Bali Kiran Kumar,Worzfeld Thomas,Pitzer Claudia,Kuner Thomas,Offermanns Stefan,Mauceri Daniela,Kuner Rohini Molecular psychiatry Aberrant fear is a cornerstone of several psychiatric disorders. Consequently, there is large interest in elucidation of signaling mechanisms that link extracellular cues to changes in neuronal function and structure in brain pathways that are important in the generation and maintenance of fear memory and its behavioral expression. Members of the Plexin-B family of receptors for class 4 semaphorins play important roles in developmental plasticity of neurons, and their expression persists in some areas of the adult nervous system. Here, we aimed to elucidate the role of Semaphorin 4C (Sema4C) and its cognate receptor, Plexin-B2, in the expression of contextual and cued fear memory, setting a mechanistic focus on structural plasticity and exploration of contributing signaling pathways. We observed that Plexin-B2 and Sema4C are expressed in forebrain areas related to fear memory, such as the anterior cingulate cortex, amygdala and the hippocampus, and their expression is regulated by aversive stimuli that induce fear memory. By generating forebrain-specific Plexin-B2 knockout mice and analyzing fear-related behaviors, we demonstrate that Sema4C-PlexinB2 signaling plays a crucial functional role in the recent and remote recall of fear memory. Detailed neuronal morphological analyses revealed that Sema4C-PlexinB2 signaling largely mediates fear-induced structural plasticity by enhancing dendritic ramifications and modulating synaptic density in the adult hippocampus. Analyses on signaling-related mutant mice showed that these functions are mediated by PlexinB2-dependent RhoA activation. These results deliver important insights into the mechanistic understanding of maladaptive plasticity in fear circuits and have implications for novel therapeutic strategies against fear-related disorders. 10.1038/s41380-019-0491-4
    Hippocampal Lnx1-NMDAR multiprotein complex mediates initial social memory. Liu Xian-Dong,Ai Peng-Hui,Zhu Xiao-Na,Pan Yuan-Bo,Halford Michael M,Henkemeyer Mark,Feng Dong-Fu,Xu Tian-Le,Sun Suya,Xu Nan-Jie Molecular psychiatry Social interaction and communication are evolutionary conserved behaviours that are developed in mammals to establish partner cognition. Deficit in sociability has been represented in human patients and animal models of neurodevelopmental disorders, which are connected with genetic variants of synaptic glutamate receptors and associated PDZ-binding proteins. However, it remains elusive how these key proteins are specialized in the cellular level for the initial social behaviour during postnatal developmental stage. Here we identify a hippocampal CA3 specifically expressed PDZ scaffold protein Lnx1 required for initial social behaviour. Through gene targeting we find that Lnx1 deficiency led to a hippocampal subregional disorder in neuronal activity and social memory impairments for partner discrimination observed in juvenile mice which also show cognitive defects in adult stage. We further demonstrate that Lnx1 deletion causes NMDA receptor (NMDAR) hypofunction and this is attributable to decreased GluN2B expression in PSD compartment and disruption of the Lnx1-NMDAR-EphB2 complex. Specific restoration of Lnx1 or EphB2 protein in the CA3 area of Lnx1 mice rescues the defective synaptic function and social memory. These findings thus reveal crucial roles of postsynaptic NMDAR multiprotein complex that regulates the formation of initial social memory during the adolescent period. 10.1038/s41380-019-0606-y
    SorCS2 is required for social memory and trafficking of the NMDA receptor. Yang Jianmin,Ma Qian,Dincheva Iva,Giza Joanna,Jing Deqiang,Marinic Tina,Milner Teresa A,Rajadhyaksha Anjali,Lee Francis S,Hempstead Barbara L Molecular psychiatry Social memory processing requires functional CA2 neurons, however the specific mechanisms that regulate their activity are poorly understood. Here, we document that SorCS2, a member of the family of the Vps10 family of sorting receptors, is highly expressed in pyramidal neurons of CA2, as well as ventral CA1, a circuit implicated in social memory. SorCS2 specifically localizes to the postsynaptic density and endosomes within dendritic spines of CA2 neurons. We have discovered that SorCS2 is a selective regulator of NMDA receptor surface trafficking in hippocampal neurons, without altering AMPA receptor trafficking. In addition, SorCS2 regulates dendritic spine density in CA2 neurons where SorCS2 expression is enriched, but not in dorsal CA1 neurons, which normally express very low levels of this protein. To specifically test the role of SorCS2 in behavior, we generated a novel SorCS2-deficient mouse, and identify a significant social memory deficit, with no change in sociability, olfaction, anxiety, or several hippocampal-dependent behaviors. Mutations in sorCS2 have been associated with bipolar disease, schizophrenia, and attention deficient-hyperactivity disorder, and abnormalities in social memory are core components of these neuropsychiatric conditions. Thus, our findings provide a new mechanism for social memory formation, through regulating synaptic receptor trafficking in pyramidal neurons by SorCS2. 10.1038/s41380-020-0650-7
    Functionally Distinct Neuronal Ensembles within the Memory Engram. Sun Xiaochen,Bernstein Max J,Meng Meizhen,Rao Siyuan,Sørensen Andreas T,Yao Li,Zhang Xiaohui,Anikeeva Polina O,Lin Yingxi Cell Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual memory engrams, i.e., if separate neuronal subpopulations encode distinct aspects of the memory and drive memory expression differently. Here, we show that contextual fear memory engrams in the mouse dentate gyrus contain functionally distinct neuronal ensembles, genetically defined by the Fos- or Npas4-dependent transcriptional pathways. The Fos-dependent ensemble promotes memory generalization and receives enhanced excitatory synaptic inputs from the medial entorhinal cortex, which we find itself also mediates generalization. The Npas4-dependent ensemble promotes memory discrimination and receives enhanced inhibitory drive from local cholecystokinin-expressing interneurons, the activity of which is required for discrimination. Our study provides causal evidence for functional heterogeneity within the memory engram and reveals synaptic and circuit mechanisms used by each ensemble to regulate the memory discrimination-generalization balance. 10.1016/j.cell.2020.02.055
    Reward Prediction Error and Declarative Memory. Ergo Kate,De Loof Esther,Verguts Tom Trends in cognitive sciences Learning based on reward prediction error (RPE) was originally proposed in the context of nondeclarative memory. We postulate that RPE may support declarative memory as well. Indeed, recent years have witnessed a number of independent empirical studies reporting effects of RPE on declarative memory. We provide a brief overview of these studies, identify emerging patterns, and discuss open issues such as the role of signed versus unsigned RPEs in declarative learning. 10.1016/j.tics.2020.02.009
    Active Forgetting: Adaptation of Memory by Prefrontal Control. Anderson Michael C,Hulbert Justin C Annual review of psychology Over the past century, psychologists have discussed whether forgetting might arise from active mechanisms that promote memory loss to achieve various functions, such as minimizing errors, facilitating learning, or regulating one's emotional state. The past decade has witnessed a great expansion in knowledge about the brain mechanisms underlying active forgetting in its varying forms. A core discovery concerns the role of the prefrontal cortex in exerting top-down control over mnemonic activity in the hippocampus and other brain structures, often via inhibitory control. New findings reveal that such processes not only induce forgetting of specific memories but also can suppress the operation of mnemonic processes more broadly, triggering windows of anterograde and retrograde amnesia in healthy people. Recent work extends active forgetting to nonhuman animals, presaging the development of a multilevel mechanistic account that spans the cognitive, systems, network, and even cellular levels. This work reveals how organisms adapt their memories to their cognitive and emotional goals and has implications for understanding vulnerability to psychiatric disorders. 10.1146/annurev-psych-072720-094140
    Memory and Sleep: How Sleep Cognition Can Change the Waking Mind for the Better. Paller Ken A,Creery Jessica D,Schechtman Eitan Annual review of psychology The memories that we retain can serve many functions. They guide our future actions, form a scaffold for constructing the self, and continue to shape both the self and the way we perceive the world. Although most memories we acquire each day are forgotten, those integrated within the structure of multiple prior memories tend to endure. A rapidly growing body of research is steadily elucidating how the consolidation of memories depends on their reactivation during sleep. Processing memories during sleep not only helps counteract their weakening but also supports problem solving, creativity, and emotional regulation. Yet, sleep-based processing might become maladaptive, such as when worries are excessively revisited. Advances in research on memory and sleep can thus shed light on how this processing influences our waking life, which can further inspire the development of novel strategies for decreasing detrimental rumination-like activity during sleep and for promoting beneficial sleep cognition. 10.1146/annurev-psych-010419-050815
    Mapping the epigenomic and transcriptomic interplay during memory formation and recall in the hippocampal engram ensemble. Marco Asaf,Meharena Hiruy S,Dileep Vishnu,Raju Ravikiran M,Davila-Velderrain Jose,Zhang Amy Letao,Adaikkan Chinnakkaruppan,Young Jennie Z,Gao Fan,Kellis Manolis,Tsai Li-Huei Nature neuroscience The epigenome and three-dimensional (3D) genomic architecture are emerging as key factors in the dynamic regulation of different transcriptional programs required for neuronal functions. In this study, we used an activity-dependent tagging system in mice to determine the epigenetic state, 3D genome architecture and transcriptional landscape of engram cells over the lifespan of memory formation and recall. Our findings reveal that memory encoding leads to an epigenetic priming event, marked by increased accessibility of enhancers without the corresponding transcriptional changes. Memory consolidation subsequently results in spatial reorganization of large chromatin segments and promoter-enhancer interactions. Finally, with reactivation, engram neurons use a subset of de novo long-range interactions, where primed enhancers are brought in contact with their respective promoters to upregulate genes involved in local protein translation in synaptic compartments. Collectively, our work elucidates the comprehensive transcriptional and epigenomic landscape across the lifespan of memory formation and recall in the hippocampal engram ensemble. 10.1038/s41593-020-00717-0
    Aperiodic sleep networks promote memory consolidation. Helfrich Randolph F,Lendner Janna D,Knight Robert T Trends in cognitive sciences Hierarchical synchronization of sleep oscillations establishes communication pathways to support memory reactivation, transfer, and consolidation. From an information-theoretical perspective, oscillations constitute highly structured network states that provide limited information-coding capacity. Recent findings indicate that sleep oscillations occur in transient bursts that are interleaved with aperiodic network states, which were previously considered to be random noise. We argue that aperiodic activity exhibits unique and variable spatiotemporal patterns, providing an ideal information-rich neurophysiological substrate for imprinting new mnemonic patterns onto existing circuits. We discuss novel avenues in conceptualizing and quantifying aperiodic network states during sleep to further understand their relevance and interplay with sleep oscillations in support of memory consolidation. 10.1016/j.tics.2021.04.009
    Successful Memory Aging. Nyberg Lars,Pudas Sara Annual review of psychology For more than 50 years, psychologists, gerontologists, and, more recently, neuroscientists have considered the possibility of successful aging. How to define successful aging remains debated, but well-preserved age-sensitive cognitive functions, like episodic memory, is an often-suggested criterion. Evidence for successful memory aging comes from cross-sectional and longitudinal studies showing that some older individuals display high and stable levels of performance. Successful memory aging may be accomplished via multiple paths. One path is through brain maintenance, or relative lack of age-related brain pathology. Through another path, successful memory aging can be accomplished despite brain pathology by means of efficient compensatory and strategic processes. Genetic, epigenetic, and lifestyle factors influence memory aging via both paths. Some of these factors can be promoted throughout the life course, which, at the individual as well as the societal level, can positively impact successful memory aging. 10.1146/annurev-psych-010418-103052
    Modulating Human Memory via Entrainment of Brain Oscillations. Hanslmayr Simon,Axmacher Nikolai,Inman Cory S Trends in neurosciences In the human brain, oscillations occur during neural processes that are relevant for memory. This has been demonstrated by a plethora of studies relating memory processes to specific oscillatory signatures. Several recent studies have gone beyond such correlative approaches and provided evidence supporting the idea that modulating oscillations via frequency-specific entrainment can alter memory functions. Such causal evidence is important because it allows distinguishing mechanisms directly related to memory from mere epiphenomenal oscillatory signatures of memory. This review provides an overview of stimulation studies using different approaches to entrain brain oscillations for modulating human memory. We argue that these studies demonstrate a causal link between brain oscillations and memory, speaking against an epiphenomenal perspective of brain oscillations. 10.1016/j.tins.2019.04.004
    A Dynamic Memory Systems Framework for Sex Differences in Fear Memory. Tronson Natalie C,Keiser Ashley A Trends in neurosciences Emerging research demonstrates that a pattern of overlapping but distinct molecular and circuit mechanisms are engaged by males and females during memory tasks. Importantly, sex differences in neural mechanisms and behavioral strategies are evident even when performance on a memory task is similar between females and males. We propose that sex differences in memory may be best understood within a dynamic memory systems framework. Specifically, sex differences in hormonal influences and neural circuit development result in biases in the circuits engaged and the information preferentially stored or retrieved in males and females. By using animal models to understand the neural networks and molecular mechanisms required for memory in both sexes, we can gain crucial insights into sex and gender biases in disorders including post-traumatic stress disorder (PTSD) in humans. 10.1016/j.tins.2019.07.009
    Computational Models of Memory Search. Kahana Michael J Annual review of psychology The capacity to search memory for events learned in a particular context stands as one of the most remarkable feats of the human brain. How is memory search accomplished? First, I review the central ideas investigated by theorists developing models of memory. Then, I review select benchmark findings concerning memory search and analyze two influential computational approaches to modeling memory search: dual-store theory and retrieved context theory. Finally, I discuss the key theoretical ideas that have emerged from these modeling studies and the open questions that need to be answered by future research. 10.1146/annurev-psych-010418-103358
    An update on memory formation and retrieval: An engram-centric approach. Bostancıklıoğlu Mehmet Alzheimer's & dementia : the journal of the Alzheimer's Association OBJECTIVE:We explore here that memory loss observed in the early stage of Alzheimer's disease (AD) is a disorder of memory retrieval, instead of a storage impairment. This engram-centric explanation aims to enlarge the conceptual frame of memory as an emergent behavior of the brain and to propose a new treatment strategy for memory retrieval in dementia-AD. BACKGROUND:The conventional memory hypothesis suggests that memory is stored as multiple traces in hippocampal neurons but recent evidence indicates that there are specialized memory engrams responsible for the storage and the retrieval of different memory types. UPDATED MEMORY HYPOTHESIS:There are specialized memory engram neurons for each memory type and when information will be stored as a memory arrives in the hippocampus through afferent neurons finds its neuron according to the excitability states of engram neurons. The excitability level in engram neurons seems like a code canalizing the interactions between engrams and information. Therefore, to enhance the excitability of memory engram neurons improves memory loss observed in AD. In addition, we suggest that the hippocampus creates an index for information stored in memory engram cells in specialized regions for different types of memory, instead of storing all information; and different anatomic locations of engram cells and their roles in memory retrieval point out that memory could be an emergent behavior of the brain, and the interaction between serotonin fluctuation and engram neurons could be neural underpinnings of terminal lucidity. MAJOR CHALLENGES FOR THE MODEL:The major challenge for this engram-centric memory retrieval model is the translation from bench to patient, specifically the delivery of optogenetic tools in patients. Engram neurons can be specifically activated by optogenetic tools, but optogenetics is an invasive technique which requires optic fiber implantation into the brain. In addition, light can overheat the tissue and thus induce damage in tissue. Furthermore, light is a foreign object and its direct implantation into the brain may cause neuroinflammation, the main trigger of neurodegenerative diseases. Therefore, to test the engram hypothesis in human, new tools to allow specific engram activation should be discovered. 10.1002/alz.12071
    Oestradiol as a neuromodulator of learning and memory. Taxier Lisa R,Gross Kellie S,Frick Karyn M Nature reviews. Neuroscience Although hormones such as glucocorticoids have been broadly accepted in recent decades as general neuromodulators of memory processes, sex steroid hormones such as the potent oestrogen 17β-oestradiol have been less well recognized by the scientific community in this capacity. The predominance of females in studies of oestradiol and memory and the general (but erroneous) perception that oestrogens are 'female' hormones have probably prevented oestradiol from being more widely considered as a key memory modulator in both sexes. Indeed, although considerable evidence supports a crucial role for oestradiol in regulating learning and memory in females, a growing body of literature indicates a similar role in males. This Review discusses the mechanisms of oestradiol signalling and provides an overview of the effects of oestradiol on spatial, object recognition, social and fear memories. Although the primary focus is on data collected in females, effects of oestradiol on memory in males will be discussed, as will sex differences in the molecular mechanisms that regulate oestrogenic modulation of memory, which may have important implications for the development of future cognitive therapeutics. 10.1038/s41583-020-0362-7
    Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease. Germann Jürgen,Elias Gavin J B,Boutet Alexandre,Narang Keshav,Neudorfer Clemens,Horn Andreas,Loh Aaron,Deeb Wissam,Salvato Bryan,Almeida Leonardo,Foote Kelly D,Rosenberg Paul B,Tang-Wai David F,Wolk David A,Burke Anna D,Salloway Stephen,Sabbagh Marwan N,Chakravarty M Mallar,Smith Gwenn S,Lyketsos Constantine G,Okun Michael S,Lozano Andres M Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Fornix deep brain stimulation (fx-DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation. METHODS:Thirty-nine patients with mild AD who took part in a prior fx-DBS trial (NCT01608061) were studied. After localizing patients' implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel-wise VTA mapping to identify flashback-associated zones; (2) machine learning-based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback-associated brain-wide networks. RESULTS:A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback-inducing stimulation exhibited greater functional connectivity to a network of memory-evoking and autobiographical memory-related sites. DISCUSSION:These results clarify the neuroanatomical substrates of stimulation-evoked flashbacks. 10.1002/alz.12238
    Test a Witness's Memory of a Suspect Only Once. Wixted John T,Wells Gary L,Loftus Elizabeth F,Garrett Brandon L Psychological science in the public interest : a journal of the American Psychological Society Eyewitness misidentifications are almost always made with high confidence in the courtroom. The courtroom is where eyewitnesses make their identification of defendants suspected of (and charged with) committing a crime. But what did those same eyewitnesses do on the identification test, conducted early in a police investigation? Despite testifying with high confidence in court, many eyewitnesses also testified that they had initially identified the suspect with low confidence or failed to identify the suspect at all. Presenting a lineup leaves the eyewitness with a memory trace of the faces in the lineup, including that of the suspect. As a result, the memory signal generated by the face of that suspect will be stronger on a later test involving the same witness, even if the suspect is innocent. In that sense, testing memory contaminates memory. These considerations underscore the importance of a newly proposed recommendation for conducting eyewitness identifications: . This recommendation applies not only to additional tests conducted by police investigators but also to the final test conducted in the courtroom, in front of the judge and jury. 10.1177/15291006211026259
    Clinical outcomes in transient epileptic amnesia: A 10-year follow-up cohort study of 47 cases. Epilepsia OBJECTIVE:Transient epileptic amnesia (TEA) is a form of adult-onset epilepsy where presenting features are well described, but little is known regarding prognosis. This study aimed to elucidate the long-term prognosis of TEA regarding seizure control, memory, medical comorbidities, and life expectancy. METHODS:Up-to-date clinical information was collected for 47 people diagnosed with TEA who had joined the The Impairment of Memory in Epilepsy (TIME) study 10 years earlier. At entry to the study, information about comorbid conditions was systematically collected. Details regarding subsequent diagnoses, seizure activity, changes to treatment, or reports of cognitive impairment were obtained through the family doctor. The variables of interest were compared with UK population data. RESULTS:Mortality in the cohort was 21 of 47 (45%), with an average age at death of 82.5 years. Seizures remained well controlled for the majority but medications required adjustments in dose and type for some (28%). A small number (three cases) remained seizure-free without medication. History of cardiovascular disorders was frequent (78.7%), typically involving hypertension (55.3%). Autoimmune disorders (25.5%), cancer (23.4%), and depression (21.3%) were also commonly reported. Although persisting memory problems were often noted, dementia was diagnosed in seven cases (14.9%). Life expectancy and comorbidities in TEA did not differ from available population norms. SIGNIFICANCE:Results suggest that life expectancy is not reduced in TEA. Although TEA does not appear to be a self-limiting form of epilepsy, seizures are typically well controlled via medication. Because adjustments to medication may be required, even after long periods of stability, ongoing medical monitoring is recommended. Comorbid vascular disorders are frequent but appear similar to general population estimates. Monitoring mood may be important, given that people with chronic conditions are often vulnerable to depression. Because of persisting memory difficulties, the development of effective memory interventions for people with TEA is warranted. 10.1111/epi.17214
    Serum neurofilament light levels are correlated to long-term neurocognitive outcome measures after cardiac arrest. Brain injury OBJECTIVE:To explore associations between four methods assessing long-term neurocognitive outcome after out-of-hospital cardiac arrest and early hypoxic-ischemic neuronal brain injury assessed by the biomarker serum neurofilament light (NFL), and to compare the agreement for the outcome methods. METHODS:An explorative post-hoc study was conducted on survivor data from the international Target Temperature Management after Out-of-hospital Cardiac Arrest trial, investigating serum NFL sampled 48/72-hours post-arrest and neurocognitive outcome 6 months post-arrest. RESULTS:Among the long-term surviving participants ( = 457), serum NFL ( = 384) was associated to all outcome instruments, also when controlling for demographic and cardiovascular risk factors. Associations between NFL and the patient-reported Two Simple Questions (TSQ) were however attenuated when adjusting for vitality and mental health. NFL predicted results on the outcome instruments to varying degrees, with an excellent area under the curve for the clinician-report Cerebral Performance Category (CPC 1-2: 0.90). Most participants were classified as CPC 1 (79%). Outcome instrument correlations ranged from small (Mini-Mental State Examination [MMSE]-TSQ) to strong (CPC-MMSE). CONCLUSIONS:The clinician-reported CPC was mostly related to hypoxic-ischemic brain injury, but with a ceiling effect. These results may be useful when selecting methods and instruments for clinical follow-up models. 10.1080/02699052.2022.2048693
    Music, Mind, Mood, and Mingling in Alzheimer's Disease and Related Dementias: A Scoping Review. Journal of Alzheimer's disease : JAD BACKGROUND:Music-based interventions may help to alleviate neuropsychiatric symptoms of dementia and promote prosocial interactions between individuals living with dementia and their caregivers. However, current literature does not combine these evidence bases toward explanation of how music-based interventions may alleviate symptoms and promote prosocial interactions. OBJECTIVE:We conducted a scoping review to address the following question: what do the evidence bases suggest toward how music therapy or music-based therapeutic interventions might promote prosocial interactions between individuals living with dementia and their caregivers? METHODS:In this review we focused on: 1) quantitative and qualitative evidence of music-based therapies promoting prosocial behaviors in individuals living with dementia, and 2) potential neurobehavioral mechanisms associated with the processes involved with how music may promote prosocial interactions. Databases included PubMed, EBSCOhost's CINAHL and PsycINFO, Cochrane Library (sub-search conducted using ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group), Web of Science, clinicaltrials.gov, ProQuest's Biological Science Collection, the Journal of Music Therapy, Nordic Journal of Music Therapy, and Google Scholar. RESULTS:Sixteen original research studies were included for evidence synthesis. This scoping review reveals the need to define and clarify mechanisms of prosocial interactions between individuals living with dementia and their caregivers considering biological and social factors. These mechanisms may include dynamic interactions between preserved brain regions associated with music-evoked autobiographical memory recall and shifts from negative to positive mood states. CONCLUSION:Defining and clarifying how and to what extent music may promote prosocial behaviors using well-designed and well-controlled mixed-methods studies may positively influence the design of interventions to promote prosocial interactions with caregivers. 10.3233/JAD-215199
    Progression from Subjective Cognitive Decline to Mild Cognitive Impairment or Dementia: The Role of Baseline Cognitive Performance. Journal of Alzheimer's disease : JAD BACKGROUND:Older adults with subjective cognitive decline (SCD) are at an increased risk of progression to mild cognitive impairment (MCI) or dementia. However, few have examined the specific cognitive tests that are associated with progression. OBJECTIVE:This study examined performance on 18 neuropsychological tests among participants with SCD who later progressed to MCI or dementia. METHODS:We included 131 participants from the Czech Brain Aging Study that had SCD at baseline. They completed a comprehensive neuropsychological battery including cognitive tests from the Uniform Data Set 2.0 enriched by the verbal memory test Rey Auditory Verbal Learning Test (RAVLT) and Rey-Osterrieth Complex Figure Test (ROCFT). RESULTS:Fifty-five participants progressed: 53% to non-amnestic MCI (naMCI), 44% to amnestic MCI (aMCI), and 4% to dementia. Scoring one SD below the mean at baseline on the RAVLT 1 and RAVLT 1-5 was associated with 133% (RAVLT 1; HR: 2.33 [1.50, 3.62]) and 122% (RAVLT 1-5; HR: 2.22 [1.55, 3.16]) greater risk of progression to MCI or dementia over 3.84 years on average. Worse performance on the RAVLT 5, RAVLT 1-5, RAVLT 30, and ROCFT-Recall was associated with progression to aMCI whereas worse performance on the RAVLT 1, TMT B, and Boston Naming Test was associated with progression to naMCI. CONCLUSION:At baseline, lower verbal memory performance was most strongly associated with progression to aMCI whereas lower executive or language performance was most strongly associated with progression to naMCI. 10.3233/JAD-215291
    Improving Diagnosis of Functional Cognitive Impairment in Younger Adults in Primary Care: Validation of Cognitive Screening Tools and the 4-Item Geriatric Depression Scale. Journal of Alzheimer's disease : JAD BACKGROUND:Cognitive decline is classically attributed to organic causes such as dementia; however, depression can play a role in cognitive decline. OBJECTIVE:To evaluate cognitive screening tools and the 4-item Geriatric Depression Scale (GDS-4) for use in primary care to distinguish cognitive decline secondary to depression. METHOD:Clinical data collected over 2.5 years for assessed patients in a secondary clinical service for younger adults. Cognitive screening tools (General Practitioner Assessment of Cognition, Addenbrooke's Cognitive Examination-III, Rowland Universal Dementia Assessment Scale, Salzburg Dementia Test Prediction) and GDS-4 were analyzed for their accuracy to differentiate patients with cognitive decline due to depression from those with subjective cognitive complaints. RESULTS:180 young adults seen in a memory clinic setting (< 65 years) were included. These individuals either had a diagnosis of depression (n = 46) or no cognitive impairment on assessment (n = 134) despite having subjective cognitive complaints. All used cognitive tools had poor accuracy in differentiating cognitive decline secondary to depression from subjective cognitive complaints. The GDS-4 alone, however, was able to differentiate with high accuracy (AUC = 0.818) individuals who had cognitive problems secondary to depression. CONCLUSION:Cognitive screening tools used alone are ineffective in discriminating cognitive decline secondary to depression. Incorporating the GDS-4 into the screening process by primary practitioners could facilitate early identification and treatment of depression in younger people, avoiding unnecessary referrals memory services. 10.3233/JAD-215552
    Modulation of the Ubiquitin-Proteasome System Restores Plasticity in Hippocampal Pyramidal Neurons of the APP/PS1 Alzheimer's Disease-Like Mice. Journal of Alzheimer's disease : JAD Alzheimer's disease (AD) is characterized by memory and cognitive deficits that in part are related to a diminished ability to activity-dependent synaptic plasticity. In AD, an attenuated long-term potentiation has been correlated with a deficit of synaptic plasticity-relevant proteins and protein turnover. The ubiquitin-proteasome system (UPS) critically regulates the protein turnover and contributes to dynamic changes of the protein milieu within synapses. In AD, UPS aberration has been implicated in inadequate proteostasis and synaptic malfunction. However, here we show that the inhibition of proteasome-mediated protein degradation by MG132 or lactacystin restored an impaired activity-dependent synaptic plasticity in an AD-like mouse model. In this whole-cell voltage-clamp study, we provided evidence that an amelioration of long-term plasticity by modulating UPS activity in pyramidal neurons. 10.3233/JAD-215718
    FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model. The Journal of experimental medicine Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3A385E/+) of this syndrome. Surprisingly, Fgfr3A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis. 10.1084/jem.20201879
    Somatic Depolarization Enhances Hippocampal CA1 Dendritic Spike Propagation and Distal Input-Driven Synaptic Plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience Synaptic inputs that target distal regions of neuronal dendrites can often generate local dendritic spikes that can amplify synaptic depolarization, induce synaptic plasticity, and enhance neuronal output. However, distal dendritic spikes are subject to significant attenuation by dendritic cable properties, and often produce only a weak subthreshold depolarization of the soma. Nonetheless, such spikes have been implicated in memory storage, sensory perception and place field formation. How can such a weak somatic response produce such powerful behavioral effects? Here, we use dual dendritic and somatic recordings in acute hippocampal slices of male mice to reveal that dendritic spike propagation, but not spike initiation, is strongly enhanced when the somatic resting potential is depolarized, likely as a result of increased inactivation of A-type K channels. Somatic depolarization also facilitates the induction of a form of dendritic spike driven heterosynaptic plasticity that enhances memory specificity. Thus, the effect of somatic membrane depolarization to enhance dendritic spike propagation and long-term synaptic plasticity is likely to play an important role in hippocampal-dependent spatial representations as well as learning and memory. Neurons receive synaptic input along their dendrites but produce action potential (AP) output at their soma. Signals arriving at the distal dendrites of pyramidal neurons (PNs) have little impact on the soma unless they combine to initiate a dendritic spike, which needs to propagate to the soma to trigger an AP. This study shows that small subthreshold depolarization of the soma powerfully enhances the propagation of dendritic spikes, through inactivation of dendritic A-type potassium channels. Enhanced dendritic spike propagation also markedly facilitates the induction of a form of plasticity driven by the distal synaptic inputs. Thus, small changes in somatic membrane potential, similar to those observed , act as a powerful gate of neuronal information transfer. 10.1523/JNEUROSCI.0780-21.2022
    Behavioral phenotyping of a rat model of the BDNF Val66Met polymorphism reveals selective impairment of fear memory. Jaehne Emily J,Kent Jessica N,Antolasic Emily J,Wright Bradley J,Spiers Jereme G,Creutzberg Kerstin C,De Rosa Federico,Riva Marco A,Sortwell Caryl E,Collier Timothy J,van den Buuse Maarten Translational psychiatry The common brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety disorders and PTSD. Here we behaviorally phenotyped a novel Val66Met rat model with an equivalent valine to methionine substitution in the rat Bdnf gene (Val68Met). In a three-day fear conditioning protocol of fear learning and extinction, adult rats with the Met/Met genotype demonstrated impaired fear memory compared to Val/Met rats and Val/Val controls, with no genotype differences in fear learning or extinction. This deficit in fear memory occurred irrespective of the sex of the animals and was not seen in adolescence (4 weeks of age). There were no changes in open-field locomotor activity or anxiety measured in the elevated plus maze (EPM) nor in other types of memory measured using the novel-object recognition test or Y-maze. BDNF exon VI expression in the dorsal hippocampus was higher and BDNF protein level in the ventral hippocampus was lower in female Val/Met rats than female Val/Val rats, with no other genotype differences, including in total BDNF, BDNF long, or BDNF IV mRNA. These data suggest a specific role for the BDNF Met/Met genotype in fear memory in rats. Further studies are required to investigate gene-environment interactions in this novel animal model. 10.1038/s41398-022-01858-5
    L-DOPA-Induced Neurogenesis in the Hippocampus Is Mediated Through GPR143, a Distinct Mechanism of Dopamine. Stem cells (Dayton, Ohio) Neurogenesis occurs in the hippocampus throughout life and is implicated in various physiological brain functions such as memory encoding and mood regulation. L-3,4-dihydroxyphenylalanine (L-DOPA) has long been believed to be an inert precursor of dopamine. Here, we show that L-DOPA and its receptor, GPR143, the gene product of ocular albinism 1, regulate neurogenesis in the dentate gyrus (DG) in a dopamine-independent manner. L-DOPA at concentrations far lower than that of dopamine promoted proliferation of neural stem and progenitor cells in wild-type mice under the inhibition of its conversion to dopamine; this effect was abolished in GPR143 gene-deficient (Gpr143-/y) mice. Hippocampal neurogenesis decreased during development and adulthood, and exacerbated depression-like behavior was observed in adult Gpr143-/y mice. Replenishment of GPR143 in the DG attenuated the impaired neurogenesis and depression-like behavior. Our findings suggest that L-DOPA through GPR143 modulates hippocampal neurogenesis, thereby playing a role in mood regulation in the hippocampus. 10.1093/stmcls/sxab013
    Acute stress reactivity and intrusive memory development: a randomized trial using an adjusted trauma film paradigm. Psychoneuroendocrinology Understanding the neurobiological and cognitive processes underlying the development of posttraumatic stress disorder (PTSD) and its specific symptoms may facilitate preventive intervention development. Severe traumatic stress and resulting biological stress system activations can alter contextual memory processes. This may provide a neurobiological explanation for the occurrence of intrusive memories following trauma. Investigating the associations between temporal aspects and individual variation in peri- and post-traumatic hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS) stress reactivity and memory processing may increase our understanding of intrusive symptom development. The experimental trauma film paradigm is commonly used for this purpose but lacks robust SNS and HPA axis activation. Here, we performed an RCT to investigate the effect of an adjusted trauma film paradigm containing an added brief psychosocial stressor on HPA and SNS stress reactivity throughout the experiment and intrusive memory frequency in the following week in healthy males (N = 63, mean age = 22.3). Secondary, we investigated effects on film-related declarative memory accuracy and intrusion-related characteristics, and associations between acute HPA and SNS stress reactivity, film-related memory, glucocorticoid receptor functioning and intrusion frequency and characteristics. Participants were randomized to the socially-evaluated cold pressor test (seCPT n = 29) or control condition (warm water n = 34) immediately prior to a trauma film. Linear Mixed Models revealed increased acute SNS and cortisol reactivity, lower recognition memory accuracy and more intrusions that were more vivid and distressing during the following week in the seCPT compared to control condition. Linear regression models revealed initial associations between cortisol and alpha amylase reactivity during the experimental assessment and subsequent intrusions, but these effects did not survive multiple comparison corrections. Thus, with this adjustment, we increased the translational value of the trauma film paradigm as it appears to elicit a stronger stress response that is likely more comparable to real-life trauma. The adapted paradigm may be useful to investigate individual variation in biological and cognitive processes underlying early post-trauma PTSD symptoms and could advance potential preventive interventions. 10.1016/j.psyneuen.2022.105686
    The evidence for and against reactivation-induced memory updating in humans and nonhuman animals. Neuroscience and biobehavioral reviews Systematic investigation of reactivation-induced memory updating began in the 1960s, and a wave of research in this area followed the seminal articulation of "reconsolidation" theory in the early 2000s. Myriad studies indicate that memory reactivation can cause previously consolidated memories to become labile and sensitive to weakening, strengthening, or other forms of modification. However, from its nascent period to the present, the field has been beset by inconsistencies in researchers' abilities to replicate seemingly established effects. Here we review these many studies, synthesizing the human and nonhuman animal literature, and suggest that these failures-to-replicate reflect a highly complex and delicately balanced memory modification system, the substrates of which must be finely tuned to enable adaptive memory updating while limiting maladaptive, inaccurate modifications. A systematic approach to the entire body of evidence, integrating positive and null findings, will yield a comprehensive understanding of the complex and dynamic nature of long-term memory storage and the potential for harnessing modification processes to treat mental disorders driven by pervasive maladaptive memories. 10.1016/j.neubiorev.2022.104598
    The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms. Scientific reports Soluble guanylate cyclase (sGC) requires a heme-group bound in order to produce cGMP, a second messenger involved in memory formation, while heme-free sGC is inactive. Two compound classes can increase sGC activity: sGC stimulators acting on heme-bound sGC, and sGC activators acting on heme-free sGC. In this rodent study, we investigated the potential of the novel brain-penetrant sGC stimulator BAY-747 and sGC activator runcaciguat to enhance long-term memory and attenuate short-term memory deficits induced by the NOS-inhibitor L-NAME. Furthermore, hippocampal plasticity mechanisms were investigated. In vivo, oral administration of BAY-747 and runcaciguat to male Wistar rats enhanced memory acquisition in the object location task (OLT), while only BAY-747 reversed L-NAME induced memory impairments in the OLT. Ex vivo, both BAY-747 and runcaciguat enhanced hippocampal GluA1-containing AMPA receptor (AMPAR) trafficking in a chemical LTP model for memory acquisition using acute mouse hippocampal slices. In vivo only runcaciguat acted on the glutamatergic AMPAR system in hippocampal memory acquisition processes, while for BAY-747 the effects on the neurotrophic system were more pronounced as measured in male mice using western blot. Altogether this study shows that sGC stimulators and activators have potential as cognition enhancers, while the underlying plasticity mechanisms may determine disease-specific effectiveness. 10.1038/s41598-022-07391-1
    The hippocampus supports high-precision binding in visual working memory. Borders Alyssa A,Ranganath Charan,Yonelinas Andrew P Hippocampus It is well established that the hippocampus is critical for long-term episodic memory, but a growing body of research suggests that it also plays a critical role in supporting memory over very brief delays as measured in tests of working memory (WM). However, the circumstances under which the hippocampus is necessary for WM and the specific processes that it supports remain controversial. We propose that the hippocampus supports WM by binding together high-precision properties of an event, and we test this claim by examining the precision of color-location bindings in a visual WM task in which participants report the precise color of studied items using a continuous color wheel. Amnestic patients with hippocampal damage were significantly impaired at retrieving these colors after a 1-s delay, and these impairments reflected a reduction in the precision of those memories rather than increases in total memory failures or binding errors. Moreover, a parallel fMRI study in healthy subjects revealed that neural activity in the head and body of the hippocampus was directly related to the precision of visual WM decisions. Together, these results indicate that the hippocampus is critical in complex high-precision binding that supports memory over brief delays. 10.1002/hipo.23401
    Modulation of threat extinction by working memory load: An event-related potential study. Behaviour research and therapy Distraction is typically discouraged during exposure therapy for anxiety, because it is thought to interfere with extinction learning by diverting attention away from anxiety-provoking stimuli. Working memory load is one form of distraction that might interfere with extinction learning. Alternatively, working memory load might reduce threat responding and benefit extinction learning by engaging prefrontal brain regions that have a reciprocal relationship with brain circuits involved in threat detection and processing. Prior work examining the effect of working memory load on threat extinction has been limited and has found mixed results. Here, we used the late positive potential (LPP), an event-related potential that is larger for threatening compared to non-threatening stimuli to assess the effect of working memory load on threat extinction. After acquisition, 38 participants performed three blocks of an extinction task interspersed with low and high working memory load trials. Results showed that overall, the LPP was reduced under high compared to low working memory load, and that working memory load slowed extinction learning. Results provide empirical evidence in support of limiting distraction during exposure therapy in order to optimize extinction learning efficiency. 10.1016/j.brat.2022.104031
    Working memory guidance of visual attention to threat in offenders. Satmarean Tamara S,Milne Elizabeth,Rowe Richard PloS one Aggression and trait anger have been linked to attentional biases toward angry faces and attribution of hostile intent in ambiguous social situations. Memory and emotion play a crucial role in social-cognitive models of aggression but their mechanisms of influence are not fully understood. Combining a memory task and a visual search task, this study investigated the guidance of attention allocation toward naturalistic face targets during visual search by visual working memory (WM) templates in 113 participants who self-reported having served a custodial sentence. Searches were faster when angry faces were held in working memory regardless of the emotional valence of the visual search target. Higher aggression and trait anger predicted increased working memory modulated attentional bias. These results are consistent with the Social-Information Processing model, demonstrating that internal representations bias attention allocation to threat and that the bias is linked to aggression and trait anger. 10.1371/journal.pone.0261882
    Differential associations of regional cerebellar volume with gait speed and working memory. Won Junyeon,Callow Daniel D,Purcell Jeremy J,Smith J Carson Scientific reports The relationship between gait speed and working memory is well-understood in older adults. However, it remains to be determined whether this relationship also exists in younger adults; and there is little known regarding the possible neural mechanism underlying the association between gait speed and working memory. The aims of this study are to determine if there is: (1) an association between gait speed and working memory performance; and (2) a mediating role of cerebellar subregion volume in the correlation between gait speed and working memory in healthy younger adults. 1054 younger adults (28.7 ± 3.6 years) from the Human Connectome Project were included in the analyses. A four-meter gait test was used to assess gait speed. The 2-back task was used to measure working memory performance [accuracy and response time (RT)]. T1-weighted structural MRI data (obtained using Siemens 3 T MRI scanner) was used to assess cerebellar subregion volumes. Linear regression and mediation analysis were used to examine the relationships between the variables after controlling for age, sex, and education. There was no association between gait speed and 2-back working memory performance in younger adults. Greater Crus I and whole cerebellar volumes were associated with better 2-back working memory accuracy. Greater VIIIa volume was associated with faster gait speed. Greater Crus 1 and VIIIa volumes were also associated with higher fluid cognition. The present study suggests that specific subregions of the cerebellar volumes are distinctively associated with gait speed and working memory performance in healthy younger adults. 10.1038/s41598-022-06180-0
    Directed forgetting in associative memory: Dissociating item and associative impairment. Whitlock Jonathon,Chiu Judy Yi-Chieh,Sahakyan Lili Journal of experimental psychology. Learning, memory, and cognition We report three item-method directed forgetting (DF) studies to evaluate whether DF impairs primarily item memory, or whether it also impairs associative memory. The current studies used a modified associative recognition paradigm that allowed disentangling item impairment from associative impairment in DF. Participants studied scene-object pairings, followed by DF cues (item-method), and at test were presented with a previously studied scene along with three objects, one of which was studied with that scene (target), whereas the remaining two objects were studied with different scenes (lures). Experiment 1 used an associative encoding orienting task, and DF impairment was observed only when the forget targets were paired with forget lures within the test display; however, DF was eliminated when the forget targets were paired with remember lures, possibly due to a recall-to-reject strategy. Experiment 2 used an object-focused orienting task that downplayed the encoding of associative information. The results revealed the opposite of Experiment 1, with significant DF when the forget targets were paired with remember lures, and no DF when the lures and the target came from the same memory instruction. Experiment 3 used the same orienting task as Experiment 1, but testing used a sequential procedure, where item recognition was assessed first, followed by associative recognition test. Conditionalizing associative recognition on item recognition outcomes confirmed that DF impairment of associative memory can be obtained despite retained memory for forget-cued objects. Overall, the results provide strong support for the impairment of associative memory by DF. (PsycInfo Database Record (c) 2022 APA, all rights reserved). 10.1037/xlm0001027
    Out of Rhythm: Compromised Precision of Theta-Gamma Coupling Impairs Associative Memory in Old Age. Karlsson Anna E,Lindenberger Ulman,Sander Myriam C The Journal of neuroscience : the official journal of the Society for Neuroscience Episodic memory declines with advancing adult age. This decline is particularly pronounced when associations between items and their contexts need to be formed. According to theories of neural communication, the precise coupling of gamma power to the phase of the theta rhythm supports associative memory formation. To investigate whether age differences in associative memory are related to compromised theta-gamma coupling, we took EEG recordings during the encoding phase of an item-context association task. Fifty-eight younger (33 females) and 55 older (24 females) adults studied pictures of objects superimposed on background scenes. In a recognition test, objects were presented on old or new backgrounds, and participants responded if they had seen (1) the object and (2) the object/scene pair. Theta-gamma coupling supported pair memory formation in both age groups. Whereas pair memory was associated with coupling closer to the peak of the theta rhythm, item-only memory was associated with a deviation in phase angle relative to pair memory. Furthermore, a stable relation between coupling phase and pair memory performance demonstrated that coupling closer to the peak is beneficial for associative memory. Critically, older adults' lower pair memory was accompanied by a shift in coupling phase relative to that of younger adults. In concert, the present results are consistent with the hypothesis that decrements in the temporal precision with which gamma power is coupled to a specific theta phase underlie the decline of associative memory in normal cognitive aging. According to prominent theories of neural communication, the precise coordination of oscillatory activity enables the formation of associative memories. We propose that normal cognitive aging impairs associative memory formation by compromising the temporal precision of neural communication. We show that the coupling of high-frequency gamma power to low-frequency theta phase supports associative memory formation in both younger and older adults, with coupling closer to the theta peak benefitting memory performance. However, compared with younger adults, the coupling phase angle is shifted in time and is more variable in the older adults. We conclude that alterations in the precise timing of theta-gamma coupling contribute to adult age differences in associative memory. 10.1523/JNEUROSCI.1678-21.2021
    Guidance of attention by working memory is a matter of representational fidelity. Williams Jamal R,Brady Timothy F,Störmer Viola S Journal of experimental psychology. Human perception and performance Items that are held in visual working memory can guide attention toward matching features in the environment. Predominant theories propose that to guide attention, a memory item must be internally prioritized and given a special template status, which builds on the assumption that there are qualitatively distinct states in working memory. Here, we propose that no distinct states in working memory are necessary to explain why some items guide attention and others do not. Instead, we propose variations in attentional guidance arise because individual memories naturally vary in their representational fidelity, and only highly accurate memories automatically guide attention. Across a series of experiments and a simulation we show that (a) items in working memory vary naturally in representational fidelity; (b) attention is guided by all well-represented items, though frequently only one item is represented well enough to guide; and (c) no special working memory state for prioritized items is necessary to explain guidance. These findings challenge current models of attentional guidance and working memory and instead support a simpler account for how working memory and attention interact: Only the representational fidelity of memories, which varies naturally between items, determines whether and how strongly a memory representation guides attention. (PsycInfo Database Record (c) 2022 APA, all rights reserved). 10.1037/xhp0000985
    Hebbian plasticity in parallel synaptic pathways: A circuit mechanism for systems memory consolidation. Remme Michiel W H,Bergmann Urs,Alevi Denis,Schreiber Susanne,Sprekeler Henning,Kempter Richard PLoS computational biology Systems memory consolidation involves the transfer of memories across brain regions and the transformation of memory content. For example, declarative memories that transiently depend on the hippocampal formation are transformed into long-term memory traces in neocortical networks, and procedural memories are transformed within cortico-striatal networks. These consolidation processes are thought to rely on replay and repetition of recently acquired memories, but the cellular and network mechanisms that mediate the changes of memories are poorly understood. Here, we suggest that systems memory consolidation could arise from Hebbian plasticity in networks with parallel synaptic pathways-two ubiquitous features of neural circuits in the brain. We explore this hypothesis in the context of hippocampus-dependent memories. Using computational models and mathematical analyses, we illustrate how memories are transferred across circuits and discuss why their representations could change. The analyses suggest that Hebbian plasticity mediates consolidation by transferring a linear approximation of a previously acquired memory into a parallel pathway. Our modelling results are further in quantitative agreement with lesion studies in rodents. Moreover, a hierarchical iteration of the mechanism yields power-law forgetting-as observed in psychophysical studies in humans. The predicted circuit mechanism thus bridges spatial scales from single cells to cortical areas and time scales from milliseconds to years. 10.1371/journal.pcbi.1009681
    The microglial P2Y receptor mediates neuronal loss and memory deficits in neurodegeneration. Puigdellívol Mar,Milde Stefan,Vilalta Anna,Cockram Tom O J,Allendorf David H,Lee Jeffrey Y,Dundee Jacob M,Pampuščenko Katryna,Borutaite Vilmante,Nuthall Hugh N,Brelstaff Jack H,Spillantini Maria Grazia,Brown Guy C Cell reports Microglia are implicated in neurodegeneration, potentially by phagocytosing neurons, but it is unclear how to block the detrimental effects of microglia while preserving their beneficial roles. The microglial P2Y receptor (P2YR) - activated by extracellular UDP released by stressed neurons - is required for microglial phagocytosis of neurons. We show here that injection of amyloid beta (Aβ) into mouse brain induces microglial phagocytosis of neurons, followed by neuronal and memory loss, and this is all prevented by knockout of P2YR. In a chronic tau model of neurodegeneration (P301S TAU mice), P2YR knockout prevented TAU-induced neuronal and memory loss. In vitro, P2YR knockout blocked microglial phagocytosis of live but not dead targets and reduced tau-, Aβ-, and UDP-induced neuronal loss in glial-neuronal cultures. Thus, the P2Y receptor appears to mediate Aβ- and tau-induced neuronal and memory loss via microglial phagocytosis of neurons, suggesting that blocking this receptor may be beneficial in the treatment of neurodegenerative diseases. 10.1016/j.celrep.2021.110148
    Induced negative arousal modulates the speed of visual working memory consolidation. Emotion (Washington, D.C.) This study examines how induced negative arousal influences the consolidation of fragile sensory inputs into durable working memory (WM) representations. Participants performed a visual WM change detection task with different amounts of encoding time manipulated by random pattern masks inserted at different levels of memory-and-mask Stimulus Onset Asynchrony (SOA). Prior to the WM task, negative or neutral emotion was induced using audio clips from the International Affective Digital Sounds (IADS). Pupillometry was simultaneously recorded to provide an objective measure of induced arousal. Self-report measures of early-life stress (i.e., adverse childhood experiences) and current mood states (i.e., depressed mood and anxious feeling) were also collected as covariates. We find that participants initially remember a comparable number of WM items under a short memory-and-mask SOA of 100 ms across emotion conditions, but then encode more items into WM at a longer memory-and-mask SOA of 333 ms under induced negative arousal. These findings suggest that induced negative arousal speeds up WM consolidation. Yet, induced negative arousal does not seem to significantly affect participants' WM storage capacity estimated from a separate no mask condition. Furthermore, this emotional effect on WM consolidation speed is moderated by key affect-related individual differences. Participants who have greater pupil responses to negative IADS sounds or have more early-life stress show faster WM consolidation under induced negative arousal. Collectively, our findings reveal a critical role of phasic adrenergic responses in the rapid consolidation of visual WM content and identify potential moderators of this association. (PsycInfo Database Record (c) 2022 APA, all rights reserved). 10.1037/emo0001059
    A Putative Role for Ubiquitin-Proteasome Signaling in Estrogenic Memory Regulation. Beamish Sarah B,Frick Karyn M Frontiers in behavioral neuroscience Sex steroid hormones such as 17β-estradiol (E) are critical neuromodulators of hippocampal synaptic plasticity and hippocampus-dependent memory in both males and females. However, the mechanisms through which E regulates memory formation in both sexes remain unclear. Research to date suggests that E regulates hippocampus-dependent memory by activating numerous cell-signaling cascades to promote the synthesis of proteins that support structural changes at hippocampal synapses. However, this work has largely overlooked the equally important contributions of protein degradation mediated by the ubiquitin proteasome system (UPS) in remodeling the synapse. Despite being critically implicated in synaptic plasticity and successful formation of long-term memories, it remains unclear whether protein degradation mediated by the UPS is necessary for E to exert its beneficial effects on hippocampal plasticity and memory formation. The present article provides an overview of the receptor and signaling mechanisms so far identified as critical for regulating hippocampal E and UPS function in males and females, with a particular emphasis on the ways in which these mechanisms overlap to support structural integrity and protein composition of hippocampal synapses. We argue that the high degree of correspondence between E and UPS activity warrants additional study to examine the contributions of ubiquitin-mediated protein degradation in regulating the effects of sex steroid hormones on cognition. 10.3389/fnbeh.2021.807215
    Barriers to Effective Memory Assessments for Alzheimer's Disease. Parra Mario A Journal of Alzheimer's disease : JAD Recently, Alzheimer's Disease International (ADI) stressed that around 75% of people living with dementia globally are still not receiving a diagnosis. In this commentary, I reflect on how efforts towards better cognitive assessments, particularly of memory, can be aligned and harmonized to contribute to such needs. I highlight some barriers that ongoing collaborations and trials are facing and their potential drivers. I suggest some strategies that can help overcome them and in so doing, integrate research agendas. We need to ignite the debate towards strategies that can help level the playfield to tackle Alzheimer's disease with true global solutions. 10.3233/JAD-215445
    Sensitivity of the hippocampus to objective but not subjective episodic memory judgments. Cognitive neuroscience We assessed whether neural activity in the hippocampus dissociates according to whether memory test items elicit a subjective sense of recollection or accurate retrieval of contextual information. We reanalyzed a previously acquired dataset from a study in which participants made both objective (source memory for spatial context) and subjective (Remember-Know) judgments for each test item. Results indicated that the hippocampus was exclusively sensitive to the amount of contextual information retrieved, such that accurate source memory judgments were associated with greater activity than inaccurate judgments, regardless of Remember/Know status. The findings add to the evidence that the hippocampus is insensitive to the subjective experience of recollection, but supports retrieval of contextual information. 10.1080/17588928.2022.2033713
    Sex Differences in the Role of CNIH3 on Spatial Memory and Synaptic Plasticity. Frye Hannah E,Izumi Yukitoshi,Harris Alexis N,Williams Sidney B,Trousdale Christopher R,Sun Min-Yu,Sauerbeck Andrew D,Kummer Terrance T,Mennerick Steven,Zorumski Charles F,Nelson Elliot C,Dougherty Joseph D,Morón Jose A Biological psychiatry BACKGROUND:CNIH3 is an AMPA receptor (AMPAR) auxiliary protein prominently expressed in the dorsal hippocampus (dHPC), a region that plays a critical role in spatial memory and synaptic plasticity. However, the effects of CNIH3 on AMPAR-dependent synaptic function and behavior have not been investigated. METHODS:We assessed a gain-of-function model of Cnih3 overexpression in the dHPC and generated and characterized a line of Cnih3 C57BL/6 mice. We assessed spatial memory through behavioral assays, protein levels of AMPAR subunits and synaptic proteins by immunoblotting, and long-term potentiation in electrophysiological recordings. We also utilized a super-resolution imaging workflow, SEQUIN (Synaptic Evaluation and Quantification by Imaging of Nanostructure), for analysis of nanoscale synaptic connectivity in the dHPC. RESULTS:Overexpression of Cnih3 in the dHPC improved short-term spatial memory in female mice but not in male mice. Cnih3 female mice exhibited weakened short-term spatial memory, reduced dHPC synapse density, enhanced expression of calcium-impermeable AMPAR (GluA2-containing) subunits in synaptosomes, and attenuated long-term potentiation maintenance compared with Cnih3 control mice; Cnih3 males were unaffected. Further investigation revealed that deficiencies in spatial memory and changes in AMPAR composition and synaptic plasticity were most pronounced during the metestrus phase of the estrous cycle in female Cnih3 mice. CONCLUSIONS:This study identified a novel effect of sex and estrous on CNIH3's role in spatial memory and synaptic plasticity. Manipulation of CNIH3 unmasked sexually dimorphic effects on spatial memory, synaptic function, AMPAR composition, and hippocampal plasticity. These findings reinforce the importance of considering sex as a biological variable in studies of memory and hippocampal synaptic function. 10.1016/j.biopsych.2021.07.014
    Superior Verbal Memory Outcome After Stereotactic Laser Amygdalohippocampotomy. Drane Daniel L,Willie Jon T,Pedersen Nigel P,Qiu Deqiang,Voets Natalie L,Millis Scott R,Soares Bruno P,Saindane Amit M,Hu Ranliang,Kim Michelle S,Hewitt Kelsey C,Hakimian Shahin,Grabowski Thomas,Ojemann Jeffrey G,Loring David W,Meador Kimford J,Faught Edward,Miller John W,Gross Robert E Frontiers in neurology To evaluate declarative memory outcomes in medically refractory epilepsy patients who underwent either a highly selective laser ablation of the amygdalohippocampal complex or a conventional open temporal lobe resection. Post-operative change scores were examined for verbal memory outcome in epilepsy patients who underwent stereotactic laser amygdalohippocampotomy (SLAH: = 40) or open resection procedures ( = 40) using both reliable change index (RCI) scores and a 1-SD change metric. Using RCI scores, patients undergoing open resection (12/40, 30.0%) were more likely to decline on verbal memory than those undergoing SLAH (2/40 [5.0%], = 0.0064, Fisher's exact test). Patients with language dominant procedures were much more likely to experience a significant verbal memory decline following open resection (9/19 [47.4%]) compared to laser ablation (2/19 [10.5%], = 0.0293, Fisher's exact test). 1 SD verbal memory decline frequently occurred in the open resection sample of language dominant temporal lobe patients with mesial temporal sclerosis (8/10 [80.0%]), although it rarely occurred in such patients after SLAH (2/14, 14.3%) ( = 0.0027, Fisher's exact test). Memory improvement occurred significantly more frequently following SLAH than after open resection. These findings suggest that while verbal memory function can decline after laser ablation of the amygdalohippocampal complex, it is better preserved when compared to open temporal lobe resection. Our findings also highlight that the dominant hippocampus is not uniquely responsible for verbal memory. While this is at odds with our simple and common heuristic of the hippocampus in memory, it supports the findings of non-human primate studies showing that memory depends on broader medial and lateral TL regions. 10.3389/fneur.2021.779495
    Language is activated by visual input regardless of memory demands or capacity. Cognition In the present study, we provide compelling evidence that viewing objects automatically activates linguistic labels and that this activation is not due to task-specific memory demands. In two experiments, eye-movements of English speakers were tracked while they identified a visual target among an array of four images, including a phonological competitor (e.g., flower-flag). Experiment 1 manipulated the capacity to subvocally rehearse the target label by imposing linguistic, spatial, or no working memory load. Experiment 2 manipulated the need to encode target objects by presenting target images either before or concurrently with the search display. While the timing and magnitude of competitor activation varied across conditions, we observed consistent evidence of language activation regardless of the capacity or need to maintain object labels in memory. We propose that language activation is automatic and not contingent upon working memory capacity or demands, and conclude that objects' labels influence visual search. 10.1016/j.cognition.2021.104994
    Working memory development: A 50-year assessment of research and underlying theories. Cognition The author has thought about working memory, not always by that name, since 1969 and has conducted research on its infant and child development since the same year that the seminal work of Baddeley and Hitch (1974) was published. The present article assesses how the field of working memory development has been influenced since those years by major theoretical perspectives: empiricism (along with behaviorism), nativism (along with modularity), cognitivism (along with constructivism), and dynamic systems theory. The field has not fully discussed the point that these theoretical perspectives have helped to shape different kinds of proposed working memory systems, which in turn have deeply influenced what is researched and how it is researched. Here I discuss that mapping of theoretical viewpoints onto assumptions about working memory and trace the influence of this mapping on the field of working memory development. I illustrate where these influences have led in my own developmental research program over the years. 10.1016/j.cognition.2022.105075
    The Impacts of Early-life Adversity on Striatal and Hippocampal Memory Functions. Neuroscience The impacts of early-life adversity (ELA) on cognitive functions including striatal-dependent habit memory and hippocampal-dependent spatial memory were investigated in male mice. The ELA mouse model was generated via an altered cage environment with limited nesting and bedding materials during postnatal days 2-9 (P2-9). The altered cage environment affected the nesting behaviors of dams, creating a stressful condition for their offspring. The ELA mice had biased decision making and poor spatial memory when they grew into young adults (4-month-old). To explore the underlying synaptic basis of these effects, excitatory synapses represented by postsynaptic density protein-95 (PSD-95) were immunolabelled on a series of brain sections and stereologically quantified in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), as well as in area CA1 of the dorsal hippocampus. Increased PSD-95-immunoreactive synapses were observed in DLS but not DMS, whereas selective loss of PSD-95 synapses was detected in the stratum radiatum of area CA1. The spine data supported the selective effects of ELA on PSD-95 synapses. Specifically, both thin and mushroom-type spines were increased in DLS, while loss of thin spines was apparent in CA1 radiatum in ELA mice versus controls. The correlation between PSD-95 synapses and memory performances was further analyzed, and the data suggested that increased small (<0.20 μm) and large (>0.40 μm) synapses in DLS might drive ELA mice to make decisions largely relying on habit memory, while loss of small synapses in hippocampal CA1 damage the spatial memory of ELA mice. 10.1016/j.neuroscience.2022.02.029
    Episodic Memory Precision and Reality Monitoring Following Stimulation of Angular Gyrus. Kwon Simon,Richter Franziska R,Siena Michael J,Simons Jon S Journal of cognitive neuroscience The qualities of remembered experiences are often used to inform "reality monitoring" judgments, our ability to distinguish real and imagined events. Previous experiments have tended to investigate only whether reality monitoring decisions are accurate or not, providing little insight into the extent to which reality monitoring may be affected by qualities of the underlying mnemonic representations. We used a continuous-response memory precision task to measure the quality of remembered experiences that underlie two different types of reality monitoring decisions: self/experimenter decisions that distinguish actions performed by participants and the experimenter and imagined/perceived decisions that distinguish imagined and perceived experiences. The data revealed memory precision to be associated with higher accuracy in both self/experimenter and imagined/perceived reality monitoring decisions, with lower precision linked with a tendency to misattribute self-generated experiences to external sources. We then sought to investigate the possible neurocognitive basis of these observed associations by applying brain stimulation to a region that has been implicated in precise recollection of personal events, the left angular gyrus. Stimulation of angular gyrus selectively reduced the association between memory precision and self-referential reality monitoring decisions, relative to control site stimulation. The angular gyrus may, therefore, be important for the mnemonic processes involved in representing remembered experiences that give rise to a sense of self-agency, a key component of "autonoetic consciousness" that characterizes episodic memory. 10.1162/jocn_a_01814
    Effects of sleep on positive, negative and neutral valenced story and image memory. Reid Alex,Bloxham Anthony,Carr Michelle,van Rijn Elaine,Basoudan Nasreen,Tulip Chloe,Blagrove Mark British journal of psychology (London, England : 1953) During sleep, emotional memories are preferentially strengthened. However, most studies on sleep and emotional memory focus on comparing negative valence with neutral valence stimuli. This study compared the sleep-dependent memory effects for stories and images, each comprising negative, neutral, and positive stimuli. It was hypothesized that a sleep effect would be seen for negatively and positively valenced stimuli. A novel story memory task (comprising three stories), and photographs from the Nencki Affective Picture database were presented for learning to 61 healthy adults (ages 18-25). They were tested for memory on the two tasks immediately, and then again after either a 2-hr nap (n = 31; 17 women, 14 men) or 2-hr wake period (n = 30; 13 women, 17 men). At second testing, the sleep condition had significantly better recall compared to the wake condition on both tasks. There was a relationship with valence only for the story task, with better performance for the sleep condition on the negatively and positively valenced texts, but not on the neutral text. There were no significant relationships between memory measures and sleep-stage duration and EEG power variables. The story memory findings support the hypothesis that memory consolidation prioritizes emotional memory, whether positively or negatively valenced. 10.1111/bjop.12559
    BDNF Val66Met gene polymorphism modulates brain activity following rTMS-induced memory impairment. Abellaneda-Pérez Kilian,Martin-Trias Pablo,Cassé-Perrot Catherine,Vaqué-Alcázar Lídia,Lanteaume Laura,Solana Elisabeth,Babiloni Claudio,Lizio Roberta,Junqué Carme,Bargalló Núria,Rossini Paolo Maria,Micallef Joëlle,Truillet Romain,Charles Estelle,Jouve Elisabeth,Bordet Régis,Santamaria Joan,Rossi Simone,Pascual-Leone Alvaro,Blin Olivier,Richardson Jill,Jovicich Jorge,Bartrés-Faz David Scientific reports The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions. 10.1038/s41598-021-04175-x
    A specific relationship between musical sophistication and auditory working memory. Scientific reports Previous studies have found conflicting results between individual measures related to music and fundamental aspects of auditory perception and cognition. The results have been difficult to compare because of different musical measures being used and lack of uniformity in the auditory perceptual and cognitive measures. In this study we used a general construct of musicianship, musical sophistication, that can be applied to populations with widely different backgrounds. We investigated the relationship between musical sophistication and measures of perception and working memory for sound by using a task suitable to measure both. We related scores from the Goldsmiths Musical Sophistication Index to performance on tests of perception and working memory for two acoustic features-frequency and amplitude modulation. The data show that musical sophistication scores are best related to working memory for frequency in an analysis that accounts for age and non-verbal intelligence. Musical sophistication was not significantly associated with working memory for amplitude modulation rate or with the perception of either acoustic feature. The work supports a specific association between musical sophistication and working memory for sound frequency. 10.1038/s41598-022-07568-8
    Brain connectivity-based prediction of real-life creativity is mediated by semantic memory structure. Ovando-Tellez Marcela,Kenett Yoed N,Benedek Mathias,Bernard Matthieu,Belo Joan,Beranger Benoit,Bieth Theophile,Volle Emmanuelle Science advances Associative theories of creativity argue that creative cognition involves the abilities to generate remote associations and make useful connections between unrelated concepts in one's semantic memory. Yet, whether and how real-life creative behavior relies on semantic memory structure and its neural substrates remains unclear. We acquired multi-echo functional magnetic resonance imaging data while participants underwent a semantic relatedness judgment task. These ratings were used to estimate their individual semantic memory networks, whose properties significantly predicted their real-life creativity. Using a connectome predictive modeling approach, we identified patterns of task-based functional connectivity that predicted creativity-related semantic memory network properties. Furthermore, these properties mediated the relationship between functional connectivity and real-life creativity. These results provide new insights into how brain connectivity patterns support real-life creative behavior via the structure of semantic memory. We also show how computational network science can be used to couple behavioral, cognitive, and neural levels of analysis. 10.1126/sciadv.abl4294
    Fear memory modulation by incentive down and up-shifts. Mugnaini Matías,Alfei Joaquín M,Bueno Adrian M,Ferrer Monti Roque I,Urcelay Gonzalo P Behavioural brain research Research on retrieval-induced malleability of maladaptive emotional memories has been mostly focused on the effect of drugs and extinction (i.e. post-retrieval extinction). Only a few studies addressed post-retrieval appetitive-aversive interactions. Due to the relevance that the understanding of the interactions between memory content and appetitive or aversive states under retrieval circumstances has for translational research, here we explored the relation between fear (i.e. contextual fear conditioning) and sucrose concentration down (32-4%) or up-shifts (4-32%). These have been reported as methods to induce aversive or appetitive internal states, respectively. We observed that fear expression is differentially susceptible to incentive contrast manipulations depending on the memory stage: acquisition, mere retrieval or retrieval-induced memory malleability. After fear acquisition, freezing behavior and incentive shift direction followed an inverse relation, that is: up-shift decreased fear responding and down-shift increased it. However, freezing behavior remained unaltered when incentive contrast was absent, regardless of the sucrose concentration employed (4-4% and 32-32%). When incentive shifts occurred after mere-retrieval, both negative and positive incentive shifts resulted in increased freezing behavior. Strikingly, this effect was unrelated to the nature of the incentive contrast (either positive or negative), occurring only when animals had no previous experience with the shifted solution. On the other hand, when fear retrieval led to memory malleability, up-shifts in sucrose concentration dampened freezing behavior as much as unshifted controls, whilst down-shift left freezing unaltered. Freezing facilitation was finally achieved after retrieval-induced memory malleability only after prior sampling of the down-shifted solution (i.e. 4% SUC). These results reveal a complex pattern of interactions between memory retrieval and incentive shift-induced internal states. 10.1016/j.bbr.2022.113766
    Aging-related episodic-like memory decline in dogs. Sanches Felipe Jacques,de Melo Jéssica Cardia,Ferreira Sabrina Palha,Trinca Luzia Aparecida,Arambula Omar Gurrola,Padovani Flavia Helena Pereira,Schelp Arthur Oscar,Amorim Rogério Martins Behavioural brain research Episodic memory, in humans, is the memory most affected by age-related deterioration or the constitution of neurodegenerative pathologies, such as Alzheimer's disease. However, it is unknown whether this relationship is also present in nonhuman animals. Since studies in birds, rats, primates, and dogs have been shown to have episodic-like memory, more studies aiming to improve the present understanding of this relationship in nonhuman animals are important to aid the development of new translational models for neurodegenerative disorders. Knowing that dogs (Canis familiaris) represent a promising experimental model for neurodegenerative disorders, a memory retrieval test was conducted with 90 clinically healthy domestic dogs of different ages, both sexes, and distinct breeds, for the purpose of evaluating episodic-like memory. The present study adapted a test that corroborates episodic memory requirements through incidental codification of experienced events. We performed a test with two exposure phases, with different characteristics between them, so that in the third phase it was necessary to integrate previous experiences in order to achieve success in the test. In our study, it was possible to verify the decline of episodic memory in elderly dogs, even clinically healthy, regardless of the dogs' sex and size. This episodic-like memory decline observed in elderly dogs may be related to the physiological process of aging or preclinical pathological manifestation of cognitive impairment, similar as reported in humans. More studies should be carried out evaluating episodic-like memory in dogs with suspected of canine cognitive dysfunction syndrome in order to better understand the physiological and pathological behavior of this type of memory in canine species. 10.1016/j.bbr.2022.113762
    Synaptic memory requires CaMKII. Tao Wucheng,Lee Joel,Chen Xiumin,Díaz-Alonso Javier,Zhou Jing,Pleasure Samuel,Nicoll Roger A eLife Long-term potentiation (LTP) is arguably the most compelling cellular model for learning and memory. While the mechanisms underlying the induction of LTP ('learning') are well understood, the maintenance of LTP ('memory') has remained contentious over the last 20 years. Here, we find that Ca-calmodulin-dependent kinase II (CaMKII) contributes to synaptic transmission and is required LTP maintenance. Acute inhibition of CaMKII erases LTP and transient inhibition of CaMKII enhances subsequent LTP. These findings strongly support the role of CaMKII as a molecular storage device. 10.7554/eLife.60360
    Missing links: The functional unification of language and memory (L∪M). Roger Elise,Banjac Sonja,Thiebaut de Schotten Michel,Baciu Monica Neuroscience and biobehavioral reviews The field of neurocognition is currently undergoing a significant change of perspective. Traditional neurocognitive models evolved into an integrative and dynamic vision of cognitive functioning. Dynamic integration assumes an interaction between cognitive domains traditionally considered to be distinct. Language and declarative memory are regarded as separate functions supported by different neural systems. However, they also share anatomical structures (notably, the inferior frontal gyrus, the supplementary motor area, the superior and middle temporal gyrus, and the hippocampal complex) and cognitive processes (such as semantic and working memory) that merge to endorse our quintessential daily lives. We propose a new model, "L∪M" (i.e., Language/union/Memory), that considers these two functions interactively. We fractionated language and declarative memory into three fundamental dimensions or systems ("Receiver-Transmitter", "Controller-Manager" and "Transformer-Associative" Systems), that communicate reciprocally. We formalized their interactions at the brain level with a connectivity-based approach. This new taxonomy overcomes the modular view of cognitive functioning and reconciles functional specialization with plasticity in neurological disorders. 10.1016/j.neubiorev.2021.12.012
    Memory related molecular signatures: The pivots for memory consolidation and Alzheimer's related memory decline. Ageing research reviews Age-related cognitive decline is the major cause of concern due to its 70% more incidence than dementia cases worldwide. Moreover, aging is also the major risk factor of Alzheimer's disease (AD), associated with progressive memory loss. Approx. 13 million people will have Alzheimer-related memory decline by 2050. Learning and memory is the fundamental process of brain functions. However, the mechanism for the same is still under investigation. Thus, it is critical to understand the process of memory consolidation in the brain and extrapolate its understanding to the memory decline mechanism. Research on learning and memory has identified several molecular signatures such as Protein kinase M zeta (PKMζ), Calcium/calmodulin-dependent protein kinase II (CaMKII), Brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB) and Activity-regulated cytoskeleton-associated protein (Arc) crucial for the maintenance and stabilization of long-term memory in the brain. Interestingly, memory decline in AD has also been linked to the abnormality in expressing these memory-related molecular signatures. Hence, in the present consolidated review, we explored the role of these memory-related molecular signatures in long-term memory consolidation. Additionally, the effect of amyloid-beta toxicity on these molecular signatures is discussed in detail. 10.1016/j.arr.2022.101577
    The Sounds of Memory: Extending the Age-Prospective Memory Paradox to Everyday Behavior and Conversations. The journals of gerontology. Series B, Psychological sciences and social sciences OBJECTIVES:Around the turn of the millennium, the "age-prospective memory (PM) paradox" challenged the classical assumption that older adults necessarily evidence a marked decline in PM functioning. As previous investigations highlighted ecological validity to be a potential explanation, the present study sought to extend established approaches by using novel real-world assessment technologies to examine PM unobtrusively in everyday-life conversations. METHOD:Next to laboratory PM tasks, real-life PM performance of 53 younger adults (19-32 years) and 38 older adults (60-81 years) was assessed from three sources: Over 9 days, participants completed an experimenter-given naturalistic task, a diary-based approach assessing self-assigned intentions, as well as an ambulatory assessment with the Electronically Activated Recorder (EAR), a device that unobtrusively samples ambient sounds to detect spontaneous speech production related to (lapses in) everyday PM. RESULTS:Older adults showed lower performance in laboratory PM only for the time-based task and performed either equally well as or even better than younger adults in everyday PM. With regard to PM performance as captured in real-life ambient audio data, younger adults talked more frequently about PM than older adults, but no significant difference between younger and older adults was found for speech related to PM errors. DISCUSSION:Findings confirmed older adults' preserved PM performance in everyday life across different indicators with increasing ecological validity. Furthermore, as a novel method to assess conversational PM in everyday life, the EAR opens new insights about the awareness of PM lapses and the communication of intentions in real life. 10.1093/geronb/gbac012
    Retrospective memory integration accompanies reconfiguration of neural cell assemblies. Wang Ye,Deng Yaling,Cao Lihong,Zhang Jiahong,Yang Lei Hippocampus Memory is a dynamic process that is based on and can be altered by experiences. Integrating memories of multiple experiences (memory integration) is the basis of flexible and complex decision-making. However, the mechanism of memory integration in neural networks of the brain remains poorly understood. In this study, we built a recurrent spiking network model and investigated the neural mechanism of memory integration before a decision is made (retrospective memory integration) at the neural circuit level. Our simulations suggest that retrospective memory integration accompanies reconfiguration of neural cell assemblies. Additionally, partially blocking neural network plasticity leads to failure of memory integration. These findings can potentially guide the experimental investigation of the neural mechanism of retrospective memory integration and serve as the basis for developing new artificial intelligence algorithms. 10.1002/hipo.23399
    Hippocampal subfield volumes and memory discrimination in the developing brain. Bouyeure Antoine,Patil Sandesh,Mauconduit Franck,Poiret Clément,Isai Damien,Noulhiane Marion Hippocampus The ability to keep distinct memories of similar events is underpinned by a type of neural computation called pattern separation (PS). Children typically report coarse-grained memories narratives lacking specificity and detail. This lack of memory specificity is illustrative of an immature or impaired PS. Despite its importance for the ontogeny of memory, data regarding the maturation of PS during childhood is still scarce. PS is known to rely on the hippocampus, particularly on hippocampal subfields DG and CA3. In this study, we used a memory discrimination task, a behavioral proxy for PS, and manually segmented hippocampal subfields volumes in the hippocampal body in a cohort of 26 children aged from 5 to 12 years. We examined the association between subfields volumes and memory discrimination performance. The main results were: (1) we showed age-related differences of memory discrimination suggesting a continuous increase of memory performance during early to late childhood. (2) We evidenced distinct associations between age and the volumes of hippocampal subfield, suggesting distinct developmental trajectories. (3) We showed a relationship between memory discrimination performance and the volumes of CA3 and subiculum. Our results further confirm the role of CA3 in memory discrimination, and suggest to scrutinize more closely the role of the subiculum. Overall, we showed that hippocampal subfields contribute distinctively to PS during development. 10.1002/hipo.23385
    Extended amygdala, conditioned withdrawal and memory consolidation. Baidoo Nana,Leri Francesco Progress in neuro-psychopharmacology & biological psychiatry Opioid withdrawal can be associated to environmental cues through classical conditioning. Exposure to these cues can precipitate a state of conditioned withdrawal in abstinent subjects, and there are suggestions that conditioned withdrawal can perpetuate the addiction cycle in part by promoting the storage of memories. This review discusses evidence supporting the hypothesis that conditioned withdrawal facilitates memory consolidation by activating a neurocircuitry that involves the extended amygdala. Specifically, the central amygdala, the bed nucleus of the stria terminalis, and the nucleus accumbens shell interact functionally during withdrawal, mediate expression of conditioned responses, and are implicated in memory consolidation. From this perspective, the extended amygdala could be a neural pathway by which drug-seeking behaviour performed during a state of conditioned withdrawal is more likely to become habitual and persistent. 10.1016/j.pnpbp.2021.110435
    Adaptive control of working memory. Cognition The present study investigated mechanisms of adaptive cognitive control in working memory (WM). WM is conceived as a system for short-term maintenance, updating and manipulation of representations required for goal-directed action. Adaptive control refers to the finding of flexible adjustments of control processes based on conflict. For instance, a higher frequency of incongruent stimuli, that is, stimuli evoking conflicting response tendencies, leads to a higher level of cognitive control as reflected by smaller congruency effects (i.e., the difference between congruent and incongruent items). Likewise, conflict on the previous trial leads to a higher level of cognitive control on the current trial. To investigate adaptive control in WM, we used a modified Sternberg paradigm. Participants memorized two differently colored lists of four digits (i.e., 2 5 7 1), in which corresponding positions in both lists contained the same digits (congruent items) or different digits (incongruent items). Participants were required to make a match/mismatch judgement (Experiment 1 and 2) or to recollect the correct digit at a probed position in one of the two lists (Experiment 3). In all experiments, we could replicate both hallmark effects of adaptive control, the proportion congruency effect, and the congruency sequence effect. Our results strongly support the assumption that WM representations can be dynamically adapted based on the amount of conflict, and that adaptive control of WM follows the same principles that have previously been shown for selective attention. 10.1016/j.cognition.2022.105053
    Fear learning induces α7-nicotinic acetylcholine receptor-mediated astrocytic responsiveness that is required for memory persistence. Nature neuroscience Memory persistence is a fundamental cognitive process for guiding behaviors and is considered to rely mostly on neuronal and synaptic plasticity. Whether and how astrocytes contribute to memory persistence is largely unknown. Here, by using two-photon Ca imaging in head-fixed mice and fiber photometry in freely moving mice, we show that aversive sensory stimulation activates α7-nicotinic acetylcholine receptors (nAChRs) in a subpopulation of astrocytes in the auditory cortex. We demonstrate that fear learning causes the de novo induction of sound-evoked Ca transients in these astrocytes. The astrocytic responsiveness persisted over days along with fear memory and disappeared in animals that underwent extinction of learned freezing behavior. Conditional genetic deletion of α7-nAChRs in astrocytes significantly impaired fear memory persistence. We conclude that learning-acquired, α7-nAChR-dependent astrocytic responsiveness is an integral part of the cellular substrate underlying memory persistence. 10.1038/s41593-021-00949-8
    NMDA receptor-mediated synaptic transmission in prefrontal neurons underlies social memory retrieval in female mice. Zhang Yu-Xiang,Xing Bo,Li Yan-Chun,Yan Chun-Xia,Gao Wen-Jun Neuropharmacology Social memory is the ability to discriminate familiar conspecific from the unknown ones. Prefrontal neurons are essentially required for social memory, but the mechanism associated with this regulation remains unknown. It is also unclear to what extent the neuronal representations of social memory formation and retrieval events overlap in the prefrontal cortex (PFC) and which event drives social memory strength. Here we asked these questions by using a repeated social training paradigm for social recognition in FosTRAP mice. We found that after 4 days' repeated social training, female mice developed stable social memory. Specifically, repeated social training activated more cells that were labeled with tdTomato during memory retrieval compared with the first day of memory encoding. Besides, combining TRAP with c-Fos immunostaining, we found about 30% of the FosTRAPed cells were reactivated during retrieval. Moreover, the number of retrieval-induced but not first-day encoding-induced tdTomato neurons correlates with the social recognition ratio in the prelimbic but not other subregions. The activated cells during the retrieval session also showed increased NMDA receptor-mediated synaptic transmission compared with that in non-labeled pyramidal neurons. Blocking NMDA receptors by MK-801 impaired social memory but not sociability. Therefore, our results reveal that repetitive training elevates mPFC involvement in social memory retrieval via enhancing NMDA receptor-mediated synaptic transmission, thus rendering stable social memory. 10.1016/j.neuropharm.2021.108895
    Engram reactivation during memory retrieval predicts long-term memory performance in aged mice. Gulmez Karaca Kubra,Brito David V C,Kupke Janina,Zeuch Benjamin,Oliveira Ana M M Neurobiology of aging Age-related cognitive decline preferentially targets long-lasting episodic memories that require intact hippocampal function. Memory traces (or engrams) are believed to be encoded within the neurons activated during learning (neuronal ensembles), and recalled by reactivation of the same population. However, whether engram reactivation dictates memory performance late in life is not known. Here, we labeled neuronal ensembles formed during object location recognition learning in the dentate gyrus, and analyzed the reactivation of this population during long-term memory recall in young adult, cognitively impaired- and unimpaired-aged mice. We found that reactivation of memory-encoding neuronal ensembles at long-term memory recall was disrupted in impaired but not unimpaired-aged mice. Furthermore, we showed that the memory performance in the aged population correlated with the degree of engram reactivation at long-term memory recall. Overall, our data implicates recall-induced engram reactivation as a prediction factor of memory performance in aging. Moreover, our findings suggest impairments in neuronal ensemble stabilization and/or reactivation as an underlying mechanism in age-dependent cognitive decline. 10.1016/j.neurobiolaging.2021.01.019
    Affective Episodic Memory System for Virtual Creatures: The First Step of Emotion-Oriented Memory. Martin Luis,Rosales Jonathan H,Jaime Karina,Ramos Felix Computational intelligence and neuroscience Episodic memory and emotions are considered essential functions in human cognition. Both allow us to acquire new knowledge from the environment, ranging from the objects around us to how we feel towards them. These qualities make them crucial functions for systems trying to create human-like behaviour. In the field of cognitive architectures (CAs), there are multiple studies covering memory and emotions. However, most of them treat these subjects in an isolated manner, considering emotions only as a reward signal unrelated to a retrieved experience. To address this lack of direct interaction, we propose a computational model that covers the common processes that are related to memory and emotions. Specifically, this proposal focuses on affective evaluations of episodic memories. Neurosciences and psychology are the bases of this model. That is, the model's components and the processes that they carry out on the information they receive are designed based on evidence from these cognitive sciences. The proposed model is a part of Cuáyóllótl, a cognitive architecture for cybernetic entities such as virtual creatures and robots. Case studies validate our proposal. They show the relevance of the integration of emotions and memory in a virtual creature. The virtual creature endowed with our emotional episodic model improves its learning and modifies its behaviour according to planning and decision-making processes. 10.1155/2021/7954140
    Features of intracranial interictal epileptiform discharges associated with memory encoding. Epilepsia OBJECTIVE:Interictal epileptiform discharges (IEDs) were shown to be associated with cognitive impairment in persons with epilepsy. Previous studies indicated that IED rate, location, timing, and spatial relation to the seizure onset zone could predict an IED's impact on memory encoding and retrieval if they occurred in lateral temporal, mesial temporal, or parietal regions. In this study, we explore the influence that other IED properties (e.g., amplitude, duration, white matter classification) have on memory performance. We were specifically interested in investigating the influence that lateral temporal IEDs have on memory encoding. METHODS:Two hundred sixty-one subjects with medication-refractory epilepsy undergoing intracranial electroencephalographic monitoring performed multiple sessions of a delayed free-recall task (n = 671). Generalized linear mixed models were utilized to examine the relationship between IED properties and memory performance. RESULTS:We found that increased IED rate, IEDs propagating in white matter, and IEDs localized to the left middle temporal region were associated with poorer memory performance. For lateral temporal IEDs, we observed a significant interaction between IED white matter categorization and amplitude, where IEDs with an increased amplitude and white matter propagation were associated with reduced memory performance. Additionally, changes in alpha power after an IED showed a significant positive correlation with memory performance. SIGNIFICANCE:Our results suggest that IED properties may be useful for predicting the impact an IED has on memory encoding. We provide an essential step toward understanding pathological versus potentially beneficial interictal epileptiform activity. 10.1111/epi.17060
    Age-related decline in cortical inhibitory tone strengthens motor memory. Petitet Pierre,Spitz Gershon,Emir Uzay E,Johansen-Berg Heidi,O'Shea Jacinta NeuroImage Ageing disrupts the finely tuned excitation/inhibition balance (E:I) across cortex via a natural decline in inhibitory tone (γ-amino butyric acid, GABA), causing functional decrements. However, in young adults, experimentally lowering GABA in sensorimotor cortex enhances a specific domain of sensorimotor function: adaptation memory. Here, we tested the hypothesis that as sensorimotor cortical GABA declines naturally with age, adaptation memory would increase, and the former would explain the latter. Results confirmed this prediction. To probe causality, we used brain stimulation to further lower sensorimotor cortical GABA during adaptation. Across individuals, how stimulation changed memory depended on sensorimotor cortical E:I. In those with low E:I, stimulation increased memory; in those with high E:I stimulation reduced memory. Thus, we identified a form of motor memory that is naturally strengthened by age, depends causally on sensorimotor cortex neurochemistry, and may be a potent target for motor skill preservation strategies in healthy ageing and neurorehabilitation. 10.1016/j.neuroimage.2021.118681
    Identifying the neurophysiological effects of memory-enhancing amygdala stimulation using interpretable machine learning. Brain stimulation BACKGROUND:Direct electrical stimulation of the amygdala can enhance declarative memory for specific events. An unanswered question is what underlying neurophysiological changes are induced by amygdala stimulation. OBJECTIVE:To leverage interpretable machine learning to identify the neurophysiological processes underlying amygdala-mediated memory, and to develop more efficient neuromodulation technologies. METHOD:Patients with treatment-resistant epilepsy and depth electrodes placed in the hippocampus and amygdala performed a recognition memory task for neutral images of objects. During the encoding phase, 160 images were shown to patients. Half of the images were followed by brief low-amplitude amygdala stimulation. For local field potentials (LFPs) recorded from key medial temporal lobe structures, feature vectors were calculated by taking the average spectral power in canonical frequency bands, before and after stimulation, to train a logistic regression classification model with elastic net regularization to differentiate brain states. RESULTS:Classifying the neural states at the time of encoding based on images subsequently remembered versus not-remembered showed that theta and slow-gamma power in the hippocampus were the most important features predicting subsequent memory performance. Classifying the post-image neural states at the time of encoding based on stimulated versus unstimulated trials showed that amygdala stimulation led to increased gamma power in the hippocampus. CONCLUSION:Amygdala stimulation induced pro-memory states in the hippocampus to enhance subsequent memory performance. Interpretable machine learning provides an effective tool for investigating the neurophysiological effects of brain stimulation. 10.1016/j.brs.2021.09.009