Dynamic and selective engrams emerge with memory consolidation

Abstract

Episodic memories are encoded by sparse populations of neurons activated during an experience1. These neural ensembles constitute memory engrams that are both necessary and sufficient for inducing recall even long after memory acquisition2. This suggests that following encoding, engrams are stabilized to reliably support memory retrieval. However, little is known about the temporal evolution of engrams over the course of memory consolidation or how it impacts mnemonic properties. Here we employed computational and experimental approaches to examine how the composition and selectivity of engrams change with memory consolidation. We modeled engram cells using a spiking recurrent neural network that yielded three testable predictions: memories transition from unselective to selective as neurons are removed from and added to the engram, inhibitory activity during recall is essential for memory selectivity, and inhibitory synaptic plasticity during memory consolidation is critical for engrams to become selective. Using the Cal-Light system to tag activated neurons in vivo with high spatiotemporal precision3 as well as optogenetic and chemogenetic techniques, we conducted contextual fear conditioning experiments that supported each of our model's predictions. Our results reveal that engrams are dynamic even within hours of memory consolidation and that changes in engram composition mediated by inhibitory synaptic plasticity are crucial for the emergence of memory selectivity. These findings challenge classical theories of stable memory traces and point to a close link between engram state and memory expression.

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

“…Although psilocybin induces inhibitory effects in many subcortical regions via 5HT1Rs, direct psychedelic-induced cellular inhibition in cortical neurons was reported for the first time recently 82 . This suppression of Acq-dominant neurons in psilocybin responders echoes recent findings that inhibitory plasticity in fear memory engrams in the hippocampus is necessary for the development memory selectivity, measured by the relative reduction of freezing in neutral contexts over time 83 .…”

Engram Stability and Maturation During Systems Consolidation Underlies Remote Memory

“…It has been shown (both theoretically and experimentally) that the engram for a particular memory is distributed across cortical and subcortical brain structures, therefore several brain regions need to be reactivated in order to support a strong recall (11)(12)(13). When a memory updates, the engram cells supporting it remodel as well (14,15).…”

Divergent Recruitment of Developmentally-Defined Neuronal Ensembles Supports Memory Dynamics

“…Their properties, such as specificity, accessibility, or susceptibility to disruption, evolve after encoding, and their content can be updated upon changes in external or internal contingencies (25,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). Likewise, activity patterns in brain areas where memory ensembles are established upon learning, like the hippocampus, evolve over time and experience (2,14,27,(43)(44)(45)(46)(47)(48)(49). New sets of neurons are recruited into memory ensembles over multiple learning sessions, while a neuron's probability of reactivation upon successive exposures to the same experience decreases as a function of time elapsed between them (a phenomenon known as "representational drift") (43,(50)(51)(52)(53)(54)(55)(56)(57).…”

“…Likewise, activity patterns in brain areas where memory ensembles are established upon learning, like the hippocampus, evolve over time and experience (2,14,27,(43)(44)(45)(46)(47)(48)(49). New sets of neurons are recruited into memory ensembles over multiple learning sessions, while a neuron's probability of reactivation upon successive exposures to the same experience decreases as a function of time elapsed between them (a phenomenon known as "representational drift") (43,(50)(51)(52)(53)(54)(55)(56)(57). These discoveries on the dynamic nature of memories and ensemble activity have raised several fundamental questions.…”