Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility.

Some individuals are susceptible to chronic stress, and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After (but not before) chronic social defeat stress, the LHb is active when susceptible mice are in proximity of the aggressor strain. During stress, activity is higher in susceptible mice during aggressor interactions, and activation biases mice toward susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical vs. cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.