Daytime light deficiency can modulate behavior, affective state, and cognition [1-5]. This is best illustrated by Seasonal Affective Disorder (SAD), a major depressive disorder with symptoms occurring in the fall and winter and remission in the spring and summer [1]. In order to study the neural mechanisms underlying the effects of light on behavior and cognition, our lab utilizes the diurnal Nile grass rat (Arvicanthis niloticus), as they provide an endogenously relevant and more translatable model to diurnal humans compared to nocturnal mice or rats. Grass rats housed in dim light during the day (dimLD, 50 lux) have shown increased anhedonia, behavioral despair, and impaired spatial learning/memory compared to those housed in bright light during the day (brLD, 1000 lux), as well as attenuation of the wakefulness-promoting and anti-inflammatory orexinergic system [6-11]. My previous work has also found that neuroinflammatory response is affected by seasonal lighting conditions; winter-like dimLD prompted sex- and corticolimbic brain region-specific activation of microglia and pro-inflammatory cytokine expression, compared to animals housed in summer-like brLD [12]. The behavioral and neural consequences of daytime light deficiency have been established, although the neural mechanism underlying and linking these effects remains unclear.These dissertation experiments test the central hypothesis that the hypothalamic orexin system mediates seasonal lighting-induced changes in behavior and other neural responses relevant to SAD. We hypothesized that 1) orexin can be upregulated by bright light (aim 1), and 2) enhanced orexin would be sufficient to alleviate associated deficits in sleep and affective state, and buffer dimLD induced deficits in neuroplasticity and inflammatory response (aim 2). The first aim establishes how orexin responds to light treatment using an early-morning bright light therapy (BLT) paradigm. The BLT group showed a higher level of wakefulness during light treatment, better sleep quality at night, and improved entrainment of daily rhythms compared to the control group. The impact of BLT on the orexin system was sex- and brain region-specific with males showing higher OX1R and OX2R in the CA1, while females showed higher prepro-orexin but lower OX1R and OX2R in the BLA, compared their the same-sex controls. The neuroinflammatory and neuroplasticity markers also responded to BLT in a sex- and brain region-specific manner. BLT reduced TNF- in the BLA of females, and upregulated CD11b in the mPFC and IL6 in the BLA in males. As for neuroplasticity markers, BLT upregulated BDNF in the BLA and CA1 in males, but downregulated BDNF in the CA1 and TrkB in all three brain regions in females. The second aim directly tests the modulatory role of orexin on sleep/arousal, anhedonia, neuroplasticity, and neuroinflammatory response, through intracerebroventricular (ICV) infusion of orexin-A (OXA). OXA infusion promoted wakefulness in females during daytime, and improved sleep quality at night in males, and reduced anhedonia in both males and females. OXA treatment increased anti-inflammatory cytokines IL-4 and IL-10 in the mPFC of females, and in the CA1 of both sexes. Although no significant changes were found in neuroplasticity or pro-inflammatory markers, microglia proliferation and activated microglia phenotypes were decreased across brain regions in both sexes in the OXA group compared to the dimLD controls, while astrocyte number was decreased in the mPFC of females and BLA of males. Collectively, these findings suggest that orexin alleviates sleep disturbances and anhedonia, and reduces neural inflammation. The findings of this study provide further understanding of the orexinergic system as a therapeutic target in affective disorders, as well as the mechanisms through which light influences the brain and behavior.
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