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Synapse-specific Representation of Overlapping Memory Engrams
Science 15 Jun 2018: Vol. 360, Issue 6394, pp. 1227-1231 Synapse-specific representation of the identity of overlapping memory engrams Kareem Abdou, et.al. Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan. Japan Science and Technology Agency, CREST, University of Toyama, Toyama 930-0194, Japan. Division of Animal Experimental Laboratory, Life Science Research Center, University of Toyama, Toyama 930-0194, Japan. Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi 3290498, Japan. Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan. [paraphrase] Memories are integrated into interconnected networks; nevertheless, each memory has its own identity. How the brain defines specific memory identity out of intermingled memories stored in a shared cell ensemble has remained elusive. We found that after complete retrograde amnesia of auditory fear conditioning in mice, optogenetic stimulation of the auditory inputs to the lateral amygdala failed to induce memory recall, implying that the memory engram no longer existed in that circuit. Complete amnesia of a given fear memory did not affect another linked fear memory encoded in the shared ensemble. Optogenetic potentiation or depotentiation of the plasticity at synapses specific to one memory affected the recall of only that memory. Thus, the sharing of engram cells underlies the linkage between memories, whereas synapse-specific plasticity guarantees the identity and storage of individual memories. Memories are formed through long-term changes in synaptic efficacy, a process known as synaptic plasticity, and are stored in the brain in specific neuronal ensembles called engram cells, which are reactivated during memory retrieval. When two memories are associated, cell ensembles corresponding to each memory overlap and are responsible for the association. Although multiple associated memories can be encoded in the overlapping population of cells, each memory has its own identity. Synaptic plasticity is essential for the retrieval, but not the storage, of associative fear memories. However, how the brain defines the identity of a particular memory amid the many memories stored in the same ensemble has been elusive. We asked whether individual memories stored in a shared neuronal ensemble would maintain their identities and have a different fate if one memory was erased by complete retrograde amnesia. We subjected mice to auditory fear conditioning (AFC), in which a tone was associated with a foot shock. This association is mediated by synaptic plasticity between neuron terminals of the auditory cortex (AC) and the medial part of the medial geniculate nucleus (MGm) and neurons of the lateral amygdala (LA). Two different tones, at 2 and 7 kHz, were used. Mice discriminated between the two tones and showed a freezing response only to the 7-kHz tone that was paired with shock. To completely erase memories, we used autophagy, which is a major protein degradation pathway wherein the autophagosome sequesters a small portion of the cytoplasm and fuses with the endosome-lysosome system to degrade the entrapped contents. Autophagy contributes to synaptic plasticity, and its induction by the peptide tat-beclin enhances destabilization of synaptic efficacy after reactivation of these synapses through the degradation of endocytosed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. When tat-beclin is combined with inhibition of protein synthesis after memory retrieval, complete retrograde amnesia is induced through enhanced memory destabilization and reconsolidation inhibition. Storing and distinguishing between several memories encoded in the same neurons are critically important for organizing unique memories. Our findings demonstrate that synapse-specific plasticity is necessary and sufficient for associative fear memory storage and that it guarantees uniqueness to the memory trace, pointing to plasticity as a substrate for the fear memory engram. This perspective is consistent with a recent observation that LTP is selectively induced in specific auditory pathways after fear memory formation. Engram cells retain a memory after anisomycin-induced amnesia, and synaptic plasticity is dispensable for memory storage. However, synaptic plasticity and functional connectivity between engram cell assemblies are indispensable for fear memory storage, because after LTD induction, the depressed synapses might be nonfunctional. Therefore, not only the natural cue, but also the optical stimulation of synapses between the engram cell assemblies failed to retrieve the memory. Furthermore, the engram network no longer retained the associative fear memory after Ani+tBC-induced complete amnesia. The LTP occlusion experiment showed that synaptic potentiation persisted even 2 days after behavioral training in the PBS control group and that complete amnesia accompanied a reset of LTP. This further supports the idea that LTP is important for memory maintenance. The combined evidence suggests that synaptic plasticity can build a specific connectivity within the engram cell assemblies and that the functional connectivity is a simple reflection of the enhanced synaptic strength, rather than an independent mechanism for memory storage. This study uncovered the mechanism by which the brain can maintain the uniqueness of a massive number of associated memories stored in shared cell ensembles. Furthermore, we achieved selective and total erasure of a fear memory from an engram network without affecting other memories stored in the shared ensemble by resetting the plasticity in a synapse-specific manner. These findings lead to a better understanding of the mechanisms underlying memory storage and may give insight into therapeutic approaches to treating post-traumatic stress disorder. [end of paraphrase]
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