Journal
JOURNAL OF NEUROTRAUMA
Volume 37, Issue 16, Pages 1829-1843Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/neu.2020.7010
Keywords
neuroinflammation; sleep disruption; traumatic brain injury
Funding
- National Institute of Neurological Disorders and Stroke (NINDS) [R01NS109585]
- NINDS [R56NS090311]
- College of Medicine Dean's Discovery Grant
- Ohio State University Center for Brain and Spinal Cord Repair
- National Institute of Dental and Craniofacial Research Training Grant [T32DE014320]
- P30 Core Grant (NINDS) [P30NS045758]
- Chronic Brain Injury Discovery Grant
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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.
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