Bidirectional switch of the valence associated with a hippocampal contextual memory engram | Nature

An optogenetic approach in mice was used to investigate the neural mechanisms underlying memory valence association; dentate gyrus, but not amygdala, memory engram cells exhibit plasticity in valence associations, suggesting that emotional memory associations can be changed at the circuit level. Memories are not made in a vacuum and typically carry an emotional value or valence, a quantity that need not necessarily be fixed. However, the neural mechanisms underlying memory-valence associations or valence switching are not known. Here, Susumu Tonegawa and colleagues labelled specific fear- (negative valence) or reward-based (positive valence) memory traces or engrams with optogenetic tools, allowing for later artificial memory reactivation. Memory engram ensembles could be re-associated with the opposite valence following a second round of association training combined with engram activation. These changes were apparent within the engram cells located within the dentate gyrus. Thus, dentate gyrus memory engram cells exhibit a plasticity in valence associations, and these data suggest that emotional memory associations can be changed at the circuit level. The valence of memories is malleable because of their intrinsic reconstructive property1. This property of memory has been used clinically to treat maladaptive behaviours2. 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 technique3,4. 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....