Can reactivating a negative memory reduce social interaction in mice?

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The hippocampus has been strongly implicated in depression symptoms. Recent findings suggest that the expression of and susceptibility to these symptoms are related to enhanced hippocampal functioning. The researchers proposed that hippocampal engrams—ensembles of neurons with increased activity after memory formation—could underlie some of the hippocampus’s contributions to depression symptoms.

Using the chronic social defeat stress (CSDS) model, they studied social defeat-related hippocampal engrams in mice susceptible or resilient to the stressor. They used TetTag mice and LacZ to label hippocampal ensembles related to social defeat. Engram cells were ensembles reactivated by the same stressor.

Compared with resilient and non-stressed control mice, susceptible mice showed greater reactivation of social defeat-related LacZ-labeled cells in both the dorsal and ventral hippocampal CA1 regions. CA1 engram cell density correlated with the level of social avoidance. Using DREADD, the researchers found that reactivating CA1 engram cells related to social defeat decreased social interaction, whereas reactivating those related to neutral contextual stimuli did not. The increase in engram cells in susceptible mice was region-specific and was not found in the dentate gyrus. In the dorsal hippocampus, susceptible mice had more CA1 engram cells related to negative stimuli, but not neutral stimuli, than resilient mice. A chronic social defeat protocol, but not a short, subthreshold protocol, was necessary to increase CA1 engram cell density.

The researchers concluded that negative-memory hippocampal CA1 engrams regulate susceptibility to CSDS. They suggested that hippocampal engrams for negative memories may underlie vulnerability to and expression of cognitive symptoms in depression. The study provides evidence that these engrams contribute to susceptibility to depression-related behavior after chronic social defeat stress. Previous work has shown that activating positive-memory engrams can alleviate depression-related behaviors; these findings instead reveal potential pathological roles for negative-memory engrams that could lead to such behaviors. Increased negative-memory engrams could be a downstream effect of the high hippocampal activity reported in animal models and patients with depression. Much less is known about the cellular mechanisms of cognitive symptoms of depression than about those of affective symptoms. Given hippocampal engrams’ crucial role in memory formation, enhanced reactivation of negative-memory engrams could be an important cellular mechanism underlying cognitive symptoms of depression.