Blunted diurnal firing in lateral habenula projections to dorsal raphe nucleus and delayed photoentrainment in stress-susceptible mice.

Daily rhythms are disrupted in patients with mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the 15-day chronic social defeat stress (CSDS) paradigm and in vitro slice electrophysiology, we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb→DRN) and unlabeled DRN cells. We also performed optogenetic experiments to investigate if increased firing in cellsLHb→DRN during exposure to a weak 7-day social defeat stress (SDS) paradigm induces stress-susceptibility. Last, we investigated whether exposure to CSDS affected the ability of mice to photoentrain to a new light-dark (LD) cycle. The cellsLHb→DRN and unlabeled DRN cells of stress-susceptible mice express greater blunted diurnal firing compared to stress-näive (control) and stress-resilient mice. Daytime optogenetic activation of cellsLHb→DRN during SDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that exposure to strong stressors induces blunted daily rhythms in firing in cellsLHb→DRN, DRN cells and decreases the initial rate of photoentrainment in susceptible-mice. In contrast, resilient-mice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb→DRN and also show rapid photoentrainment to a new LD cycle.

What it takes to be at the top: The interrelationship between chronic social stress and social dominance.

INTRODUCTION: Dominance hierarchies of social animal groups are very sensitive to stress. Stress experienced prior to social interactions between conspecifics may be a determinant of their future social dynamics. Additionally, long-term occupancy of a specific hierarchical rank can have psychophysiological effects which increase vulnerability to future stressors. METHODS: We aimed to delineate differential effects of stress acting before or after hierarchy formation. We studied whether exposure to the chronic social defeat stress (CSDS) paradigm before a two-week-long hierarchy formation affected the attainment of a dominant status using the social confrontation tube test (TT). These animals were singly housed for at least one week before CSDS to decrease confounding effects of prior hierarchy experience. Additionally, we investigated whether social rank predicted vulnerability to CSDS, measured by a social interaction test. RESULTS: In TT, mice termed as dominant (high rank) win the majority of social confrontations, while the subordinates (low rank) lose more often. Within newly established hierarchies of stress-naïve mice, the subordinate, but not dominant, mice exhibited significantly greater avoidance of novel social targets. However, following exposure to CSDS, both lowest- and highest-ranked mice exhibited susceptibility to stress as measured by decreased interactions with a novel social target. In contrast, after CSDS, both stress-susceptible (socially avoidant) and stress-resilient (social) mice were able to attain dominant ranks in newly established hierarchies. CONCLUSION: These results suggest that the response to CSDS did not determine social rank in new cohorts, but low-status mice in newly established groups exhibited lower sociability to novel social targets. Interestingly, exposure of a hierarchical social group to chronic social stress led to stress susceptibility in both high- and low-status mice as measured by social interaction.