Neuronal and Neuroimmune Responses to Sleep Deprivation Across Functionally Distinct Brain Regions

Lauren Elizabeth Harris, BS (Advisor: Long-Jun Wu, PhD)

Sleep deprivation disrupts brain function, impairs cognition, and contributes to numerous neurological disorders, yet the mechanisms linking prolonged wakefulness to altered neural activity remain incompletely understood. Although sleep deprivation affects both neuronal activity and microglial physiology, the functional relationship between these processes is unclear. This study investigated the neuroimmune consequences of sleep deprivation by characterizing neuronal and microglial responses across multiple brain regions and determining the role of microglia in regulating neuronal activity during prolonged wakefulness.

Adult mice underwent acute sleep deprivation for 6 hours daily over 3 consecutive days before tissue collection or behavioral testing. Neuronal activity was assessed using c-Fos immunohistochemistry, while microglial responses were evaluated by measuring cell density, soma area, and CD68 expression. Sleep deprivation produced widespread but region-specific increases in neuronal activity throughout sensorimotor, cognitive, memory, and sleep/wake related brain regions. These neural changes were accompanied by increased locomotor activity, indicating a generalized hyperactive behavioral state. Microglia exhibited heterogeneous, region-specific adaptations in density, morphology, and CD68 expression, suggesting that their responses to sleep deprivation are shaped by the local neural environment.

To determine the functional role of microglia, mice were treated with a CSF1R inhibitor to deplete microglia prior to sleep deprivation. Microglial ablation demonstrated that microglia actively regulate neuronal responses in a brain region-dependent manner. In sensorimotor cortices, microglia limit excessive neuronal activation, whereas in regions related to cognition, memory, and sleep/wake, they promote sleep deprivation-induced neuronal activity.

Together, these findings demonstrate that sleep deprivation induces coordinated neuronal and neuroimmune adaptations and identify microglia as active, region-specific regulators of neural circuit function during prolonged wakefulness. By establishing that microglia differentially modulate neuronal activity across distinct brain regions, this work provides new insight into the cellular mechanisms underlying the effects of insufficient sleep and highlights microglia as key contributors to neural circuit adaptations during prolonged wakefulness.

Advisory Committee:

• Long-Jun Wu, PhD, Chair
• Kristin Eckel-Mahan, PhD
• Qingchun Tong, PhD
• Jiaqian Wu, PhD
• Xinzhu Yu, PhD

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