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Traumatic brain injury (TBI) is a global source of injury-related death and disability, and survivors often suffer functional and psychiatric consequences that persist for years. Neuroinflammation, mediated in part by microglia, perpetuates chronic dysfunction after TBI and leaves survivors vulnerable to the effects of secondary immune challenges. Previous data from our lab shows that 30 days of mechanical sleep fragmentation (SF) aggravates microglia- associated neuroinflammation in C57BL/6 mice, impairing recovery after TBI. To better understand the mechanisms through which microglia contribute to impairment following post-TBI SF, we used flow cytometry to analyze multiple cell types from brain and peripheral tissues of C57BL/6 mice who received a TBI or sham injury followed by 7 or 30 days of SF or control housing. Next, bulk RNA sequencing was used to analyze gene expression in microglia and coronal slice from the ipsilateral brain. We analyzed differentially expressed genes (DEGs) within each tissue type to determine how ipsilateral brain and microglia are independently influenced by TBI and SF. We also compared microglial DEGS directly to those of coronal slice, gaining novel insight into how microglia contribute to dysfunction in the ipsilateral brain after TBI and post-injury SF. Flow cytometry revealed transient increases in monocyte infiltration to the brain 7 days post-injury (DPI) that resolved by 30 DPI. SF did not exacerbate the immune response to injury within peripheral tissues or the brain at either of these time points. From our transcriptomic analysis, we identified distinct sets of DEGs which are uniquely dysregulated by TBI, SF, and the combination of TBI and SF. Notably, we found distinct subsets of olfactory genes that are differentially dysregulated by TBI and SF in the ipsilateral brain, as well as significant enrichment of cell-cell communication and steroidogenesis pathways that are specifically disrupted in microglia compared to the rest of the brain. Through in-depth transcriptional analysis we identify potential molecular targets that shed light on the mechanisms of TBI-induced microglial activity and reveal how SF after TBI alters this response. Together, these data could inform therapeutic strategies that target neuroinflammation to improve chronic recovery after brain injury.

Traumatic brain injury (TBI) alters stress responses, which may influence neuroinflammation and behavioral outcome. Sleep disruption (SD) is an understudied post-injury environmental stressor that directly engages stress-immune pathways. Thus, we predicted that maladaptive changes in the hypothalamic-pituitary-adrenal (HPA) axis after TBI compromise the neuroendocrine response to SD and exacerbate neuroinflammation. To test this, we induced lateral fluid percussion TBI or sham injury in female and male C57BL/6 mice aged 8–10 weeks that were then left undisturbed or exposed to 3 days of transient SD. At 3 days post-injury (DPI) plasma corticosterone (CORT) was reduced in TBI compared with sham mice, indicating altered HPA-mediated stress response to SD. This response was associated with approach-avoid conflict behavior and exaggerated cortical neuroinflammation. Post-injury SD specifically enhanced neutrophil trafficking to the injured brain in conjunction with dysregulated aquaporin-4 (AQP4) polarization. Delayed and persistent effects of post-injury SD were determined 4 days after SD concluded at 7 DPI. SD prolonged anxiety-like behavior regardless of injury and was associated with increased cortical Iba1 labeling in both sham and TBI mice. Strikingly, TBI SD mice displayed an increased number of CD45+ cells near the site of injury, enhanced cortical glial fibrillary acidic protein (GFAP) immunolabeling, and persistent expression of Trem2 and Tlr4 7 DPI compared with TBI mice. These results support the hypothesis that post-injury SD alters stress-immune pathways and inflammatory outcomes after TBI. These data provide new insight to the dynamic interplay between TBI, stress, and inflammation.