Central hypocretin/orexin administration alleviates sleep/wake disturbances, anhedonia, and neuroinflammation in an animal model of seasonal affective disorder.

BACKGROUND: Seasonal affective disorder (SAD) is a major depressive disorder recurring in fall and winter due to daytime light deficiency. To investigate underlying mechanisms of SAD, we previously developed a diurnal model using Nile grass rats (Arvicanthis niloticus), in which a winter-like dim daylight condition (dimLD) increased depression-like behaviors and neuroinflammation, while attenuating central orexinergic activity compared to grass rats housed in a summer-like bright daylight condition (brLD). MATERIALS AND METHODS: The present study tested the hypothesis that the behavioral and neuroinflammatory responses induced by the winter-like dimLD condition are due to attenuated central orexinergic output. Male and female grass rats housed in dimLD or brLD received intracerebroventricular orexin A (OXA) or vehicle (aCSF) 6 h every morning for one week while sleep/wakefulness were continuously monitored. A saccharin-solution preference test was performed on the last infusion day to assess anhedonia, followed by brain collection for analyzing neuroinflammatory markers in the medial prefrontal cortex, dorsal hippocampus, and basolateral amygdala. RESULTS: OXA treatment promoted daytime wakefulness in females, improved nighttime sleep quality in males, and reduced anhedonia in both sexes of dimLD animals to levels comparable to brLD-aCSF controls. Additionally, treating dimLD animals with OXA increased expression of anti-inflammatory cytokines IL-4 and IL-10, and reduced pro-inflammatory markers including IL-6, CD11b, and the number and inflammatory morphology of microgliadepending on sex and brain site. CONCLUSIONS: These findings support the hypothesis that the orexinergic system mediates the effects of ambient light on sleep and affect, and may be a potential therapeutic target in SAD.