Simvastatin Modulates Astrocyte and Microglial Reactivity and Aggressive Behavior After Chronic Sleep Deprivation in Rats.
- 1Medical School, Botucatu (FMB), São Paulo State University (UNESP), Botucatu, SP, Brazil.
- 2Laboratory of Nerve Regeneration, Institute of Biology (IB), State University of Campinas (UNICAMP), Campinas, SP, Brazil.
- 3Department of Anatomy, Institute of Biosciences of Botucatu (IBB), São Paulo State University (UNESP), Botucatu, SP, Brazil.
Abstract
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.
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BibTeX
@article{dias2026simvastatin,
title = {{Simvastatin Modulates Astrocyte and Microglial Reactivity and Aggressive Behavior After Chronic Sleep Deprivation in Rats.}},
author = {Higor Hernany Dias and Kevin Silva Müller and Gabriela Larissa Lima-da-Silva and Stephane da Silva Alves and Tatiane de Camargo Martins and Pedro Tadao Hamamoto Filho and José de Anchieta de Castro E Horta-Júnior},
journal = {Journal of neuroscience research},
year = {2026},
month = nov,
doi = {10.1002/jnr.70160},
url = {https://europepmc.org/article/MED/42967864},
note = {CC BY},
}
RIS
TY - JOUR
TI - Simvastatin Modulates Astrocyte and Microglial Reactivity and Aggressive Behavior After Chronic Sleep Deprivation in Rats.
AU - Higor Hernany Dias
AU - Kevin Silva Müller
AU - Gabriela Larissa Lima-da-Silva
AU - Stephane da Silva Alves
AU - Tatiane de Camargo Martins
AU - Pedro Tadao Hamamoto Filho
AU - José de Anchieta de Castro E Horta-Júnior
PY - 2026
DA - 2026/11/01
JO - Journal of neuroscience research
DO - 10.1002/jnr.70160
UR - https://europepmc.org/article/MED/42967864
AB - 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.
SN - 0360-4012
SN - 1097-4547
ER -