Zhukovskaya, A.; Christopher, Z.; Willmore, L.; Janarthanan, S.; Falkner, A.; Witten, I.

Some individuals are susceptible to the experience of 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 stress susceptible and resilient mice during stress to produce different outcomes. After but not before chronic social defeat stress (CSDS), the LHb is active when susceptible mice are in the proximity of the aggressor strain. During stress itself, LHb activity is higher in susceptible mice during aggressor proximity, and stimulation of the LHb during stress biases mice towards susceptibility. This stimulation generates a persistent and widespread increase in the balance of subcortical versus cortical activity that closely mimics the brainwide correlates of susceptibility. Taken together, our results indicate that a stronger aversive teaching signal in the LHb during stress produces brainwide and behavioral substrates of susceptibility.