Optogenetic stimulation of a hippocampal engram activates fear memory recall

Abstract

A specific memory is thought to be encoded by a sparse population of neurons1,2. These neurons can be tagged during learning for subsequent identification3 and manipulation4,5,6. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, a critical question of sufficiency remains: can one elicit the behavioral output of a specific memory by directly activating a population of neurons that was active during learning? Here we show that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behavior. We labeled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2)7,8 and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear conditioned mice with cells labeled by EYFP instead of ChR2. Finally, activation of cells labeled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context-specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.

Time scales of memory, learning, and plasticity

“…However, it is not clear whether spatiotemporal patterns or motifs are memory items [or cell assemblies, see (6)] and whether they are subject to long-term plasticity as suggested by Hebb. Nevertheless, recent experimental work shows that the activation of specific groups of neurons elicits memory-related behavior (Garner et al 2012;Liu et al 2012;Morris and Takeuchi 2012). (6) Long-/short-term memory-long-term plasticity (theoretical): As early as 1949 Hebb first speculated (Hebb 1949) that long-term plasticity should lead to memory.…”

Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

“…Our previously established method 11 for labeling memory engram cells combined c-fos-tTA transgenic mice with a doxycycline (DOX)-sensitive adeno-associated virus (AAV). However, in this study, we modified the method using a double-virus system to label memory engram cells in the early AD mice, which already carry two transgenes.…”

Activating positive memory engrams suppresses depression-like behaviour

“…appetitive responses, and that the mnemonic output elicited by these artificially reactivated cells can be updated with new information [6][7][8] . These findings raise the possibility of alleviating stress-induced behavioral impairments via a defined set of DG cells active during a positive experience.…”

“…To address this issue, we utilized our recently developed method that enables labelling and manipulation of memory engram cells (See Methods) [6][7][8] . Exposing animals that were taken off Dox to a naturally rewarding experience 8 (i.e.…”