Sleep fragmentation after traumatic brain injury impairs behavior and conveys long-lasting impacts on neuroinflammation

IF 3.7 Q2 IMMUNOLOGY Brain, behavior, & immunity - health Pub Date : 2024-05-13 DOI:10.1016/j.bbih.2024.100797
Samuel Houle , Zoe Tapp , Shannon Dobres , Sakeef Ahsan , Yvanna Reyes , Christopher Cotter , Jessica Mitsch , Zachary Zimomra , Juan Peng , Rachel K. Rowe , Jonathan Lifshitz , John Sheridan , Jonathan Godbout , Olga N. Kokiko-Cochran
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Abstract

Traumatic brain injury (TBI) causes a prolonged inflammatory response in the central nervous system (CNS) driven by microglia. Microglial reactivity is exacerbated by stress, which often provokes sleep disturbances. We have previously shown that sleep fragmentation (SF) stress after experimental TBI increases microglial reactivity and impairs hippocampal function 30 days post-injury (DPI). The neuroimmune response is highly dynamic the first few weeks after TBI, which is also when injury induced sleep-wake deficits are detected. Therefore, we hypothesized that even a few weeks of TBI SF stress would synergize with injury induced sleep-wake deficits to promote neuroinflammation and impair outcome. Here, we investigated the effects of environmental SF in a lateral fluid percussion model of mouse TBI. Half of the mice were undisturbed, and half were exposed to 5 h of SF around the onset of the light cycle, daily, for 14 days. All mice were then undisturbed 15–30 DPI, providing a period for SF stress recovery (SF-R). Mice exposed to SF stress slept more than those in control housing 7–14 DPI and engaged in more total daily sleep bouts during the dark period. However, SF stress did not exacerbate post-TBI sleep deficits. Testing in the Morris water maze revealed sex dependent differences in spatial reference memory 9–14 DPI with males performing worse than females. Post-TBI SF stress suppressed neurogenesis-related gene expression and increased inflammatory signaling in the cortex at 14 DPI. No differences in sleep behavior were detected between groups during the SF stress recovery period 15–30 DPI. Microscopy revealed cortical and hippocampal IBA1 and CD68 percent-area increased in TBI SF-R mice 30 DPI. Additionally, neuroinflammatory gene expression was increased, and synaptogenesis-related gene expression was suppressed in TBI-SF mice 30 DPI. Finally, IPA canonical pathway analysis showed post-TBI SF impaired and delayed activation of synapse-related pathways between 14 and 30 DPI. These data show that transient SF stress after TBI impairs recovery and conveys long-lasting impacts on neuroimmune function independent of continuous sleep deficits. Together, these finding support that even limited exposure to post-TBI SF stress can have lasting impacts on cognitive recovery and regulation of the immune response to trauma.

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脑外伤后的睡眠中断会损害行为,并对神经炎症产生长期影响
创伤性脑损伤(TBI)会导致中枢神经系统(CNS)在小胶质细胞的驱动下出现长时间的炎症反应。压力会加剧小胶质细胞的反应,而压力往往会引起睡眠障碍。我们之前已经证明,实验性创伤性脑损伤后的睡眠片段(SF)应激会增加小胶质细胞的反应性,并损害损伤后 30 天(DPI)的海马功能。神经免疫反应在创伤性脑损伤后的最初几周高度活跃,这也是检测到损伤引起的睡眠-觉醒障碍的时间。因此,我们假设,即使是几周的创伤性脑损伤 SF 应激也会与损伤诱导的睡眠-觉醒障碍协同作用,促进神经炎症并损害预后。在此,我们在小鼠创伤性脑损伤的侧液叩击模型中研究了环境 SF 的影响。一半小鼠不受干扰,一半小鼠每天在光周期开始前后暴露于 5 小时的 SF,持续 14 天。然后,所有小鼠在15-30 DPI期间不受干扰,这段时间为SF应激恢复期(SF-R)。与对照组的小鼠相比,暴露于SF应激的小鼠在7-14 DPI期间的睡眠时间更长,在黑暗期的每日睡眠总时间也更长。然而,SF应激并不会加剧创伤后睡眠障碍。在莫里斯水迷宫中进行的测试显示,创伤后9-14天的空间参照记忆存在性别差异,男性的表现比女性差。创伤后SF应激抑制了神经发生相关基因的表达,并在14 DPI时增加了大脑皮层的炎症信号传导。在15-30 DPI的SF应激恢复期,未发现组间睡眠行为的差异。显微镜检查显示,TBI SF-R 小鼠在 30 DPI 时皮质和海马 IBA1 和 CD68 百分比面积增加。此外,TBI-SF 小鼠神经炎症基因表达增加,突触生成相关基因表达受到抑制。最后,IPA典型通路分析表明,在14至30 DPI期间,创伤后SF损害并延迟了突触相关通路的激活。这些数据表明,创伤后瞬时 SF 应激会损害恢复,并对神经免疫功能产生长期影响,而与持续的睡眠障碍无关。总之,这些发现证明,即使是有限的创伤后自律神经应激也会对认知恢复和创伤免疫反应的调节产生持久影响。
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来源期刊
Brain, behavior, & immunity - health
Brain, behavior, & immunity - health Biological Psychiatry, Behavioral Neuroscience
CiteScore
8.50
自引率
0.00%
发文量
0
审稿时长
97 days
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