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 (cells(LHb -> DRN)) and unlabeled DRN cells. We also performed optogenetic experiments to investigate if increased firing in cells(LHb -> 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 cells(LHb -> DRN) and unlabeled DRN cells of stress-susceptible mice express greater blunted diurnal firing compared to stress-naive (control) and stress-resilient mice. Daytime optogenetic activation of cells(LHb -> 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 cells(LHb -> 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 cells(LHb -> DRN) and also show rapid photoentrainment to a new LD cycle.

Automated summary

The disruption of daily rhythms in patients with mood disorders may be attributed to the dysfunction of the lateral habenula and dorsal raphe nucleus. Stress-susceptibility in mice is associated with decreased firing rates in cells projecting from LHb to DRN, while stress-resilient mice show maintained daily rhythms in firing. This correlation between activity in this neural circuit and mood disorders highlights the importance of circadian timekeeping in regulating emotional well-being.