Sleep fragmentation engages stress-responsive circuitry, enhances inflammation and compromises hippocampal function following traumatic brain injury.
Sleep fragmentation engages stress-responsive circuitry, enhances inflammation and compromises hippocampal function following traumatic brain injury.
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DOI：
10.1016/j.expneurol.2022.114058
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发表时间：
2022-07
影响因子：
5.3
通讯作者：
Kokiko-Cochran, Olga N.
中科院分区：
文献类型：
--
作者：
Tapp, Zoe M.;Cornelius, Sydney;Oberster, Alexa;Kumar, Julia E.;Atluri, Ravitej;Witcher, Kristina G.;Oliver, Braedan;Bray, Chelsea;Velasquez, John;Zhao, Fangli;Peng, Juan;Sheridan, John;Askwith, Candice;Godbout, Jonathan P.;Kokiko-Cochran, Olga N.
关键词：
创伤性脑损伤（TBI）损害了应激时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。许多应激源导致睡眠障碍，因此机械性睡眠片段化（SF）提供了一种生理相关的方法来研究创伤后应激的影响。我们假设SF应激参与了TBI后HPA轴的失调，加剧了损伤后神经炎症并损害了恢复。为了测试这一点，雄性和雌性小鼠给予中度横向流体冲击TBI或假损伤，并保持不受干扰或每天暴露于短暂的SF，持续损伤后7天或30天（DPI）。TBI后SF增加干扰素和应激相关基因的皮质表达，其特征在于抑制编码糖皮质激素受体（GR）的上游调节因子NR 3C 1。此外，TBI后SF增加海马中的神经元活性，海马是应激免疫轴的关键交叉点。到30 DPI时，TBI SF增强皮质小胶质细胞增生并增加促炎性胶质细胞信号传导基因的表达，其特征在于持续抑制NR 3C 1上游调节因子。在海马内，TBI后SF加重了小胶质细胞增生并降低了CA 1神经元活性。在海马的下游，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时将GR激动剂地塞米松直接应用于CA 1增加了TBI动物的GR活性，但不增加假手术动物的GR活性，表明GR介导的海马作用不同。电生理学评估显示，TBI和SF诱导Schaffer侧支长时程增强功能的缺陷与微量恐惧条件反射的受损收购，反映背侧海马依赖的认知缺陷。总之，这些数据表明，损伤后SF参与损伤后HPA轴功能障碍，增强炎症，并损害海马功能。因此，干扰睡眠的外部应激源在脑损伤后的结果中起着不可或缺的作用。
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.
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影响因子：
4.6
作者：
Di Filippo M;de Iure A;Giampà C;Chiasserini D;Tozzi A;Orvietani PL;Ghiglieri V;Tantucci M;Durante V;Quiroga-Varela A;Mancini A;Costa C;Sarchielli P;Fusco FR;Calabresi P
通讯作者：
Calabresi P
影响因子：
3.8
作者：
Bartelt-Kirbach, Britta;Slowik, Alexander;Golenhofen, Nikola
通讯作者：
Golenhofen, Nikola
影响因子：
5.3
作者：
Bangasser, Debbie A.;Shors, Tracey J.
通讯作者：
Shors, Tracey J.
影响因子：
9.3
作者：
Bachstetter, Adam D.;Xing, Bin;Van Eldik, Linda J.
通讯作者：
Van Eldik, Linda J.
影响因子：
3.5
作者：
DIAMOND, DM;BENNETT, MC;ROSE, GM
通讯作者：
ROSE, GM