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.

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Chronic social stress in mice causes behavioral and physiological changes resulting in perturbed rhythms of body temperature, activity and sleep-wake cycle. To further understand the link between mood disorders and temperature rhythmicity, we measured core body temperature (Tcore) in mice before and after exposure to the chronic social defeat stress (CSDS) paradigm. Our results revealed that Tcore amplitudes of stress resilient and susceptible mice are dampened during exposure to CSDS. However, after exposure to social stress, the temperature amplitude of resilient mice recovered faster than the susceptible mice. There were minimal changes in locomotor activity after stress exposure which correlates with regular rhythmic expression of Prok2, an output signal of the SCN (Suprachiasmatic nucleus). We also investigated the molecular changes associated with these dampened temperature rhythms, and determined the expression levels of thermosensitive genes Cirbp, Rbm3 and Hsf1. Expression of Rbm3 and Cirbp in the LHb (Lateral habenula) were blunted 1 day after CSDS. These molecular rhythms recovered 10 days later such that daytime expression was higher compared to nighttime, similar to stress-naive controls. Hsf1 did not show robust rhythmic expression in the LHb.

Daily rhythms are disrupted in patients suffering from 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 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 (cells LHb®DRN ) and DRN cells alone.We also performed optogenetic experiments to investigate if increased firing in cells LHb®DRN during exposure to subthreshold social defeat stress (SSDS), induces stresssusceptibility. Last we investigated whether exposure to CSDS affected the ability of mice to phototentrain to a new LD cycle. The cells LHb®DRN and DRN cells alone of stresssusceptible mice express greater blunted diurnal firing compared to stress-naive (control) and stress-resilient mice. Day-time optogenetic activation of cells LHb®DRN during SSDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stresssusceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that CSDS induces blunted daily rhythms in firing in cells LHb®DRN and slow rate of photoentrainment in susceptible-mice. In contrast, resilientmice may undergo homeostatic adaptations that maintain daily rhythms in firing in cells LHb®DRN and also show rapid photoentrainment to a new LD-cycle.

AbstractDominance hierarchies of social animal groups are influenced by complex factors such as stress. Stress experienced by an animal prior to social interactions with a conspecific may be a determinant of their future social dynamics. Additionally, long-term occupancy of a specific hierarchical rank can have psychophysiological effects, leading to vulnerability to future stress.The current study aimed to delineate differential effects of stress acting before or after hierarchy formation. Using the chronic social defeat stress (CSDS) paradigm we performed behavioural investigations to determine whether exposure to CSDS before hierarchy formation predicted the new dominance status. Moreover, in another study we investigated whether social rank predicted stress vulnerability.We found that CSDS did not impede the establishment of dominance in new hierarchies as both stress-susceptible (socially avoidant) and –resilient (social) mice were able to attain dominant ranks. In contrast, within newly established hierarchies of stress-naïve mice, the subordinate, but not dominant, mice exhibit significantly greater avoidance of novel social targets. However, following exposure to CSDS, both lowest- and highest-ranked mice exhibit strong susceptibility to stress as measured by decreased interactions with a novel social target.These results suggest that the response to chronic social stress 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.HighlightsStress susceptibility to chronic social defeat did not impede the establishment of dominance in new hierarchies.Subordinate mice exhibit reduced social preference after hierarchy formation.Following chronic social defeat stress, both subordinate and dominant mice exhibit susceptible-like reduction in social interaction, but dominant mice exhibit the greater decrease in social preference as compared to baseline.