Activating positive memory engrams suppresses depression-like behaviour

Acute re-activation of a positive memory engram suppresses depression-like behaviour in mice exposed to chronic stress, mediated by a hippocampus–amygdala–nucleus-accumbens pathway. Can recalling positive memories alleviate depression? Susumu Tonegawa and colleagues addressed this question in mice using optogenetically labelled specific hippocampal memory engrams associated with a positive, neutral or negative experience. The memories could then be artificially activated with light at a later time. Acute reactivation of the positive engram was found to suppress depression-like behaviour in mice exposed to chronic stress, an effect mediated by the hippocampus–amygdala–nucleus-accumbens pathway. Importantly, chronic reactivation of the positive engram also prevented depression-like behaviour in stressed mice even after the reactivation had finished, indicating that the antidepressant effect is not dependent on real-time artificial activation of the engram. The authors suggest that direct activation of hippocampal dentate gyrus engram cells associated with a positive memory may offer a potential therapeutic node for alleviating a subset of depression-related behaviours, although at this stage it is not clear how these findings may translate into humans. Stress is considered a potent environmental risk factor for many behavioural abnormalities, including anxiety and mood disorders1,2. Animal models can exhibit limited but quantifiable behavioural impairments resulting from chronic stress, including deficits in motivation, abnormal responses to behavioural challenges, and anhedonia3,4,5. The hippocampus is thought to negatively regulate the stress response and to mediate various cognitive and mnemonic aspects of stress-induced impairments2,3,5, although the neuronal underpinnings sufficient to support behavioural improvements are largely unknown. Here we acutely rescue stress-induced depression-related behaviours in mice by optogenetically reactivating dentate gyrus cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projection-specific optogenetic blockade experiments, identified glutamatergic activity in the hippocampus–amygdala–nucleus-accumbens pathway as a candidate circuit supporting the acute rescue. Finally, chronically reactivating hippocampal cells associated with a positive memory resulted in the rescue of stress-induced behavioural impairments and neurogenesis at time points beyond the light stimulation. Together, our data suggest that activating positive memories artificially is sufficient to suppress depression-like behaviours and point to dentate gyrus engram cells as potential therapeutic nodes for intervening with maladaptive behavioural states.