Dept. of Neuroscience, College of Medicine, The Ohio State University, 1858 Neil Ave, Columbus, OH 43210, USA.
Dept. of Neuroscience, College of Medicine, The Ohio State University, 1858 Neil Ave, Columbus, OH 43210, USA.
Exp Neurol. 2022 Jul;353:114058. doi: 10.1016/j.expneurol.2022.114058. Epub 2022 Mar 28.
Traumatic brain injury (TBI) impairs the ability to restore homeostasis in response to stress, indicating hypothalamic-pituitary-adrenal (HPA)-axis dysfunction. Many stressors result in sleep disturbances, thus mechanical sleep fragmentation (SF) provides a physiologically relevant approach to study the effects of stress after injury. We hypothesize SF stress engages the dysregulated HPA-axis after TBI to exacerbate post-injury neuroinflammation and compromise recovery. To test this, male and female mice were given moderate lateral fluid percussion TBI or sham-injury and left undisturbed or exposed to daily, transient SF for 7- or 30-days post-injury (DPI). Post-TBI SF increases cortical expression of interferon- and stress-associated genes characterized by inhibition of the upstream regulator NR3C1 that encodes glucocorticoid receptor (GR). Moreover, post-TBI SF increases neuronal activity in the hippocampus, a key intersection of the stress-immune axes. By 30 DPI, TBI SF enhances cortical microgliosis and increases expression of pro-inflammatory glial signaling genes characterized by persistent inhibition of the NR3C1 upstream regulator. Within the hippocampus, post-TBI SF exaggerates microgliosis and decreases CA1 neuronal activity. Downstream of the hippocampus, post-injury SF suppresses neuronal activity in the hypothalamic paraventricular nucleus indicating decreased HPA-axis reactivity. Direct application of GR agonist, dexamethasone, to the CA1 at 30 DPI increases GR activity in TBI animals, but not sham animals, indicating differential GR-mediated hippocampal action. Electrophysiological assessment revealed TBI and SF induces deficits in Schaffer collateral long-term potentiation associated with impaired acquisition of trace fear conditioning, reflecting dorsal hippocampal-dependent cognitive deficits. Together these data demonstrate that post-injury SF engages the dysfunctional post-injury HPA-axis, enhances inflammation, and compromises hippocampal function. Therefore, external stressors that disrupt sleep have an integral role in mediating outcome after brain injury.
创伤性脑损伤 (TBI) 损害了机体应对应激恢复体内平衡的能力，表明下丘脑-垂体-肾上腺 (HPA) 轴功能障碍。许多应激源会导致睡眠障碍，因此机械性睡眠碎片化 (SF) 提供了一种研究损伤后应激影响的生理相关方法。我们假设 SF 应激会使 TBI 后的失调 HPA 轴参与其中，从而加剧损伤后的神经炎症并损害恢复。为了验证这一点，雄性和雌性小鼠接受中度侧方液压冲击 TBI 或假损伤，并在损伤后 7 或 30 天 (DPI) 未受干扰或每天短暂暴露于 SF。TBI 后 SF 增加了皮质干扰素和应激相关基因的表达，其特征是抑制编码糖皮质激素受体 (GR) 的上游调节剂 NR3C1。此外，TBI 后 SF 增加了海马体中的神经元活动，海马体是应激免疫轴的关键交点。在 30 DPI 时，TBI SF 增强了皮质小胶质细胞增生，并增加了促炎神经胶质信号基因的表达，其特征是 NR3C1 上游调节剂持续抑制。在海马体中，TBI 后 SF 夸大了小胶质细胞增生并减少了 CA1 神经元活动。损伤后 SF 抑制下丘脑室旁核中的神经元活动，表明 HPA 轴反应性降低。在 30 DPI 时，GR 激动剂地塞米松直接应用于 CA1 会增加 TBI 动物而不是假损伤动物中的 GR 活性，表明 GR 介导的海马体作用存在差异。电生理评估显示 TBI 和 SF 诱导 Schaffer 侧支长时程增强缺陷，与痕迹恐惧条件反射获得受损相关，反映了背侧海马依赖性认知缺陷。这些数据表明，损伤后 SF 使失调的损伤后 HPA 轴参与其中，增强了炎症，并损害了海马体功能。因此，破坏睡眠的外部应激源在介导脑损伤后的结果中具有重要作用。
