Differences in an aversive teaching signal produce brainwide and behavioral substrates of susceptibility

Abstract

Some individuals are susceptible to chronic stress, and others are more resilient. While pioneering work has uncovered differences across susceptible and resilient mice after chronic social defeat stress (CSDS), much less is known about the neural signals during stress itself that drive differences in susceptibility. Do the same neural teaching signals implicated in other forms of aversive learning also drive changes during stress, and if so, does their presence before or during the stress predict and produce maladaptive changes? We found that after - but not before - CSDS, the lateral habenula (LHb) is active when susceptible mice are in the proximity of an aggressor strain, but not other strains, consistent with the strain-specific aversion produced by CSDS. During CSDS itself, LHb activity was higher in susceptible mice at the onset of attack by the aggressor, even on the first day of stress. Attack-triggered activation of the LHb during CSDS biased mice towards susceptibility. Brainwide neural activity after stress revealed a striking organization in resilient versus susceptible mice: cortical regions are active in resilient mice, while subcortical regions in susceptible mice. Moreover, LHb activation during CSDS generates sustained and widespread changes in activity that closely resemble the brain-wide correlates of susceptibility. Taken together, our results point to a stronger aversive teaching signal in the LHb from the first day of stress contributing to the formation of the neural and behavioral substrates of susceptibility.