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Formation and fate of an engram in the lateral amygdala supporting a rewarding memory in mice

Abstract

Memories allow past experiences to guide future decision making and behavior. Sparse ensembles of neurons, known as engrams, are thought to store memories in the brain. Most previous research has focused on engrams supporting threatening or fearful memories where results show that neurons involved in a particular engram (“engram neurons”) are both necessary and sufficient for memory expression. Far less is understood about engrams supporting appetitive or rewarding memories. As circumstances and environments are dynamic, the fate of a previously acquired engram with changing circumstances is unknown. Here we examined how engrams supporting a rewarding cue-cocaine memory are formed and whether this original engram is important in reinstatement of memory-guided behavior following extinction. Using a variety of techniques, we show that neurons in the lateral amygdala are allocated to an engram based on relative neuronal excitability at training. Furthermore, once allocated, these neurons become both necessary and sufficient for behavior consistent with recall of that rewarding memory. Allocated neurons are also critical for cocaine-primed reinstatement of memory-guided behavior following extinction. Moreover, artificial reactivation of initially allocated neurons supports reinstatement-like behavior following extinction even in the absence of cocaine-priming. Together, these findings suggest that cocaine priming after extinction reactivates the original engram, and that memory-guided reinstatement behavior does not occur in the absence of this reactivation. Although we focused on neurons in one brain region only, our findings that manipulations of lateral amygdala engram neurons alone were sufficient to impact memory-guided behavior indicate that the lateral amygdala is a critical hub region in what may be a larger brain-wide engram.

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Fig. 1: A small population of random LA principal neurons overexpressing CREB at training is biased for allocation to an engram supporting a cue-cocaine memory and is necessary for behavior consistent with subsequent memory retrieval.
Fig. 2: Increasing excitability of random LA neurons before training preferentially allocates these neurons to an engram supporting a rewarding cue-cocaine memory; allocated neurons are both necessary and sufficient for behavior consistent with subsequent cue-cocaine memory recall.
Fig. 3: LA neurons allocated to an engram at the time of training are necessary for behavior consistent with cocaine-primed reinstatement of an extinguished cue-cocaine memory.
Fig. 4: Post-extinction reactivation of LA neurons allocated to an engram supporting cue-cocaine memory in the absence of cocaine priming is sufficient to induce behavior consistent with reinstatement.

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Funding

This work was supported by NIH and Brain Canada grants to SAJ and PWF, as well as CIHR and NSERC grants (SAJ, PWF, JGH).

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All authors made significant contributions to this work. The project was conceived by SAH, PWF and JGH. AP and HLH acquired the data. ADJ helped acquire and analyse the data. The manuscript was written and revised by all authors. All authors approved the final version of this manuscript.

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Correspondence to John G. Howland or Sheena A. Josselyn.

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Park, A., Jacob, A.D., Hsiang, HL.(. et al. Formation and fate of an engram in the lateral amygdala supporting a rewarding memory in mice. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01472-5

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