Blunted Diurnal Firing in Lateral Habenula Projections to Dorsal Raphe Nucleus and Delayed Photoentrainment in Stress-Susceptible Mice

Abstract

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.

Chronic social stress blunts core body temperature and molecular rhythms ofRbm3andCirbpin mouse lateral habenula

“…Stress-induced thermogenesis of brown adipose tissue resulting in emotional hyperthermia may be driven by the Lateral Habenula (LHb) and Ventral Tegmental Area (VTA) [16,17] -two regions that exhibit elevated pathophysiological firing in stress susceptible mice [18][19][20][21].…”

Stress-induced translation of KCNB1 contributes to the enhanced synaptic transmission of the lateral habenula

“…Stress certainly impacts neuronal and synaptic properties in various brain areas and one such area is the lateral habenula (LHb), a part of the epithalamus (Li et al, 2011;Proulx et al, 2014;Kim and Chung, 2021). Animal models of depression have demonstrated potentiated synaptic activities (Li et al, 2011;Park et al, 2017a) as well as increased neuronal activity in the LHb (Liu et al, 2021). An intriguing aspect of LHb neurons is their heterogeneity, as they can be divided into several subpopulations based on anatomical (Hu et al, 2020) or molecular differences (Hashikawa et al, 2020;Wallace et al, 2020).…”

“…For instance, the intensity of stress may determine the number of activated neurons within the LHb but not all neurons in the LHb are stress-responsive (Park et al, 2017b). Circuit-specific studies focusing on specific projecting areas, such as the ventral tegmental area, dorsal raphe nucleus, and hypothalamus have provided well-established insights into the LHb's involvement in animal models of depression (Li et al, 2011;Liu et al, 2021;Zheng et al, 2022). Additionally, increased expression of certain proteins (e.g., p11 and βCaMKII) has been shown to enhance LHb activity and mediate depression-like behaviors (Li et al, 2013;Seo et al, 2018), suggesting that molecular switches responding to stress may underlie the observed heterogeneity.…”