Engram cell connectivity: an evolving substrate for information storage.
Ryan Tomás J,de San Luis Clara Ortega,Pezzoli Maurizio,Sen Siddhartha
Current opinion in neurobiology
Understanding memory requires an explanation for how information can be stored in the brain in a stable state. The change in the brain that accounts for a given memory is referred to as an engram. In recent years, the term engram has been operationalized as the cells that are activated by a learning experience, undergoes plasticity, and are sufficient and necessary for memory recall. Using this framework, and a growing toolbox of related experimental techniques, engram manipulation has become a central topic in behavioral, systems, and molecular neuroscience. Recent research on the topic has provided novel insights into the mechanisms of long-term memory storage, and its overlap with instinct. We propose that memory and instinct may be embodied as isomorphic topological structures within the brain's microanatomical circuitry.
Engram-specific transcriptome profiling of contextual memory consolidation.
Rao-Ruiz Priyanka,Couey Jonathan J,Marcelo Ivo M,Bouwkamp Christian G,Slump Denise E,Matos Mariana R,van der Loo Rolinka J,Martins Gabriela J,van den Hout Mirjam,van IJcken Wilfred F,Costa Rui M,van den Oever Michel C,Kushner Steven A
Sparse populations of neurons in the dentate gyrus (DG) of the hippocampus are causally implicated in the encoding of contextual fear memories. However, engram-specific molecular mechanisms underlying memory consolidation remain largely unknown. Here we perform unbiased RNA sequencing of DG engram neurons 24 h after contextual fear conditioning to identify transcriptome changes specific to memory consolidation. DG engram neurons exhibit a highly distinct pattern of gene expression, in which CREB-dependent transcription features prominently (P = 6.2 × 10), including Atf3 (P = 2.4 × 10), Penk (P = 1.3 × 10), and Kcnq3 (P = 3.1 × 10). Moreover, we validate the functional relevance of the RNAseq findings by establishing the causal requirement of intact CREB function specifically within the DG engram during memory consolidation, and identify a novel group of CREB target genes involved in the encoding of long-term memory.
Long-Term Memory Engram Cells Are Established by c-Fos/CREB Transcriptional Cycling.
Miyashita Tomoyuki,Kikuchi Emi,Horiuchi Junjiro,Saitoe Minoru
Training-dependent increases in c-fos have been used to identify engram cells encoding long-term memories (LTMs). However, the interaction between transcription factors required for LTM, including CREB and c-Fos, and activating kinases such as phosphorylated ERK (pERK) in the establishment of memory engrams has been unclear. Formation of LTM of an aversive olfactory association in flies requires repeated training trials with rest intervals between trainings. Here, we find that prolonged rest interval-dependent increases in pERK induce transcriptional cycling between c-Fos and CREB in a subset of KCs in the mushroom bodies, where olfactory associations are made and stored. Preexisting CREB is required for initial c-fos induction, while c-Fos is required later to increase CREB expression. Blocking or activating c-fos-positive engram neurons inhibits memory recall or induces memory-associated behaviors. Our results suggest that c-Fos/CREB cycling defines LTM engram cells required for LTM.
Bidirectional switch of the valence associated with a hippocampal contextual memory engram.
Redondo Roger L,Kim Joshua,Arons Autumn L,Ramirez Steve,Liu Xu,Tonegawa Susumu
The valence of memories is malleable because of their intrinsic reconstructive property. This property of memory has been used clinically to treat maladaptive behaviours. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.