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Orexin\/hypocretin, a neuropeptide expressed in the lateral hypothalamus (LH), has well\u2010established roles in homeostatic processes, such as energy metabolism, food intake, sleep, and wakefulness. Our laboratory and others have shown that orexin expression decreases with age, and this age\u2010related orexin decline is exacerbated in disease states. Additionally, it has recently been shown that orexin possesses anti\u2010inflammatory and neuroprotective properties. Based on these observations, we hypothesize that orexin is modulating neuroinflammation in brain regions that are critical in the development of ARCD. To test this hypothesis, we used lentiviral gene transfer to downregulate orexin expression in male and female young rats to mimic age\u2010related orexin deficiency and examined neuroinflammatory responses to peripheral administration of lipopolysaccharide (LPS). We found a significant reduction of basal forebrain (BF) microglial complexity and plasma BDNF in both males and females following orexin downregulation. Notably, orexin downregulation blocked the capacity of the neuroinflammatory system to respond to LPS. These results demonstrate that neuroinflammatory responses are dependent on orexin signaling, and this system becomes dysfunctional in aging in a sex\u2010dependent manner.<\/jats:p>","DOI":"10.1111\/jnc.70175","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T10:33:51Z","timestamp":1753785231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Orexin\/Hypocretin Modulates Neuroinflammatory Response to <scp>LPS<\/scp> in a Sex and Brain\u2010Region Specific Manner in Young Rats"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4432-3739","authenticated-orcid":false,"given":"M. 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