Oxytocin restores cognitive function and attenuates neuroinflammation in chronic sleep-deprived aged rats

Background: Sleep is a fundamental biological process essential for maintaining mental, emotional, and physical health. Chronic sleep deprivation (SD), particularly in aging, is associated with oxidative stress, neuroinflammation, apoptosis, and cognitive and behavioral impairments. Oxytocin, a hypothalamic neuropeptide with reported antioxidant and anti-inflammatory properties, may modulate stress-related pathways; however, its role in mitigating SD-induced brain alterations remains unclear. This study investigated whether peripheral oxytocin administration influences brain and behavioral changes induced by chronic SD in aged rats. Methods: Male Sprague Dawley rats aged 20-24 months were divided into four groups: control, oxytocin-treated, SD, and SD with oxytocin treatment. Chronic SD was induced using a modified multiple platform method. Behavioral assessments were conducted to evaluate locomotor and exploratory activity. Serum cortisol was measured as a systemic stress marker, while brain tissues were analyzed for oxidative stress and inflammatory markers. Gene expression of Psen1 and Htr2a, oxytocin receptor protein levels, and histopathological changes, including gliosis and apoptosis, were also evaluated. Results: Chronic SD resulted in significant impairments in locomotor and exploratory behaviors, elevated serum cortisol levels, and increased oxidative stress and inflammatory markers. SD also altered the expression of Psen1 and Htr2a, reduced oxytocin receptor protein levels, and was associated with histological evidence of gliosis and apoptosis in brain tissues. Peripheral oxytocin administration attenuated many of these SD-induced alterations. However, because oxytocin was administered peripherally and central oxytocin levels or receptor engagement were not directly assessed, the findings cannot be interpreted as definitive evidence of direct central neuroprotection. Conclusion: The results suggest that oxytocin modulates stress responses, oxidative balance, and inflammatory pathways in aged rats subjected to chronic sleep deprivation. Although the precise central mechanisms remain unresolved, these findings support a potential role for oxytocin in mitigating SD-associated pathophysiological changes in aging and warrant further mechanistic studies to clarify its neuroprotective potential.