Simvastatin Modulates Astrocyte and Microglial Reactivity and Aggressive Behavior After Chronic Sleep Deprivation in Rats

Chronic sleep deprivation (SD) disrupts central nervous system homeostasis, promoting behavioral alterations and glial remodeling within limbic structures. Although simvastatin exhibits pleiotropic effects, its influence on astrocytic and microglial responses during prolonged sleep loss remains poorly understood. This study investigated the effects of SD and simvastatin on behavior, systemic inflammatory mediators, and glial reactivity in the dorsal hippocampus (HPC) and amygdala (AMY). Sixty male Wistar rats (~75 days old; n = 15/group) were assigned to Control (CG), Sleep Deprived (SD), Simvastatin 4.2 mg/kg (SIM4.2), or Simvastatin 20 mg/kg (SIM20) groups. Animals underwent the modified multiple platform method (18 h/day) for 45 consecutive days, with daily oral simvastatin administration. Social behavior was assessed using the resident-intruder test, circulating cytokines by ELISA, and glial responses by GFAP and IBA-1 immunohistochemistry, including microglial morphological classification (Types I-III). SD increased aggressive/reactive behavior and astrocytic and microglial reactivity in the dorsal HPC, accompanied by a shift from homeostatic (Type I) toward reactive (Types II and III) microglial phenotypes. Simvastatin attenuated these glial alterations, restoring a more homeostatic microglial profile and increasing non-social exploratory behavior. In contrast, glial alterations in the AMY were comparatively limited, indicating region-specific susceptibility to SD. Peripheral cytokine analysis revealed selective immunomodulatory effects, including reduced TGF-β and increased IL-8 in SIM20, whereas TNF-α and IL-6 remained unchanged. Overall, simvastatin modulated behavioral, systemic inflammatory, and glial responses to SD, supporting its pleiotropic effects and highlighting region-specific glial remodeling as a potential target for mitigating the consequences of chronic sleep loss.