Acute sleep deprivation alters hypothalamic neuroinflammatory signaling independent of traumatic brain injury in the mouse.

STUDY OBJECTIVES: Traumatic brain injury (TBI) is frequently accompanied by sleep disturbances and neuroinflammatory responses that contribute to long-term neurological dysfunction. Sleep deprivation commonly occurs during the acute post-injury period, yet its influence on early neuroinflammatory signaling remains poorly understood. METHODS: Here, we investigated how acute sleep deprivation alters inflammatory gene expression following experimental TBI in mice. Adult male C57BL/6J mice underwent midline fluid percussion injury (mFPI) or sham surgery and were subsequently exposed to 6 hours of gentle-handling sleep deprivation or undisturbed sleep. Following the manipulation period, the hypothalamus, thalamus, hippocampus, motor cortex, and primary somatosensory cortex (S1BF) were collected for transcriptional profiling using the NanoString nCounter Mouse Neuroinflammation Panel. RESULTS: Sleep deprivation emerged as the dominant driver of transcriptional changes across brain regions at 6 hours post-injury, whereas TBI alone produced comparatively modest effects. Transcriptional responses to sleep deprivation were highly localized to the hypothalamus, where 23 genes were differentially expressed, with minimal responses observed in other regions. Differentially expressed genes included Mapk1, Jun, Map2k1, and Il1rap. Gene set enrichment analysis demonstrated coordinated suppression of MAPK/ERK signaling, NF-κB-mediated inflammatory pathways, cytokine and chemokine signaling, complement activation, and pathways related to cytoskeletal remodeling and neuronal signaling. The combination of TBI and sleep deprivation did not produce a synergistic transcriptional response, suggesting that sleep deprivation dominates early neuroinflammatory signaling. CONCLUSIONS: These findings identify acute sleep deprivation as a potent modulator of early neuroimmune signaling and highlight sleep as a potential therapeutic target following TBI.