Abstract
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.
Highlights
Mood disorders are associated with abnormalities in circadian rhythms in physiology and behaviour
Given the overlapping influence of the lateral habenula (LHb) and dorsal raphe nucleus (DRN) on circadian rhythmicity and mood disorders, we assessed whether exposure to chronic social defeat stress (CSDS) affects: (i) diurnal rhythmic activity of LHb cells projecting to the DRN; (ii) DRN cells; and (iii) the ability of mice to reentrain to a new photoperiod
We found that cellsLHb!DRN of susceptible, but not resilient mice, exhibit pathophysiological firing such that activity is elevated in both the day and the night
Summary
Mood disorders are associated with abnormalities in circadian rhythms in physiology and behaviour. We demonstrate that cellsLHb!DRN and DRN cells of stress-susceptible mice exhibit blunted daily rhythms in neural activity. The firing rate of cellsLHb!DRN was elevated in both, the day and night, in susceptible-mice, while resilient and stress-naïve mice display robust diurnal rhythms in firing with high activity in night and low in daytime. The blunted rhythms in firing rate in stress-susceptible mice is similar to observations that patients with mood disorders exhibit blunted daily rhythms in various physiological measures [5,6]. In addition to pathophysiological changes in firing in the cellsLHb!DRN and DRN cells, susceptible mice exhibit delayed rate of reentrainment to a new light cycle, while resilient mice were faster at adapting to the new light cycle. Our findings suggest that chronic social stress induces pathophysiological firing in cellsLHb!DRN and DRN cells of susceptible mice that leads to blunted diurnal activity in this circuit. The behavioural locomotor data suggest that molecular and cellular processes responsible for acute photoentrainment seem slower at responding to a new light stimulus in susceptible mice, while homeostatic adaptations in resilient mice increase their efficiency at adapting to the new light cycle
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