Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio, USA.
J Neurotrauma. 2020 Aug 15;37(16):1829-1843. doi: 10.1089/neu.2020.7010. Epub 2020 Apr 21.
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 and 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.
创伤性脑损伤 (TBI) 改变了应激反应，这可能会影响神经炎症和行为结果。睡眠中断 (SD) 是一种研究不足的损伤后环境应激源，它直接参与应激免疫途径。因此，我们预测 TBI 后下丘脑-垂体-肾上腺 (HPA) 轴的适应性变化会损害对 SD 的神经内分泌反应，并加剧神经炎症。为了验证这一点，我们在 8-10 周龄的雌性和雄性 C57BL/6 小鼠中诱导侧方液体冲击 TBI 或假损伤，然后让它们不受干扰或暴露于 3 天的短暂 SD。在损伤后 3 天 (DPI)，TBI 小鼠的血浆皮质酮 (CORT) 与假手术组相比降低，表明 HPA 介导的对 SD 的应激反应发生改变。这种反应与接近回避冲突行为和皮质神经炎症的夸大有关。损伤后 SD 特别增强了中性粒细胞向损伤大脑的迁移，同时伴随着水通道蛋白-4 (AQP4) 极化的失调。在损伤后 SD 结束后 4 天（即 7 DPI）确定了损伤后 SD 的延迟和持续影响。SD 延长了焦虑样行为，无论是否有损伤，并且与 sham 和 TBI 小鼠的皮质 Iba1 标记增加有关。值得注意的是，与 TBI 小鼠相比，TBI SD 小鼠在损伤部位附近有更多的 CD45 细胞，皮质神经胶质纤维酸性蛋白 (GFAP) 免疫标记增强，并且在 7 DPI 时仍持续表达 和 。这些结果支持这样的假设，即损伤后 SD 改变了 TBI 后的应激免疫途径和炎症结果。这些数据为 TBI、应激和炎症之间的动态相互作用提供了新的见解。
