Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210.
Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210.
J Neurosci. 2022 May 18;42(20):4215-4228. doi: 10.1523/JNEUROSCI.1910-21.2022. Epub 2022 Apr 19.
Traumatic brain injury (TBI) is associated with an increased risk of cognitive, psychiatric, and neurodegenerative complications that may develop after injury. Increased microglial reactivity following TBI may underlie chronic neuroinflammation, neuropathology, and exaggerated responses to immune challenges. Therefore, the goal of this study was to force turnover of trauma-associated microglia that develop after diffuse TBI and determine whether this alleviated chronic inflammation, improved functional recovery and attenuated reduced immune reactivity to lipopolysaccharide (LPS) challenge. Male mice received a midline fluid percussion injury (mFPI) and 7 d later were subjected to a forced microglia turnover paradigm using CSF1R antagonism (PLX5622). At 30 d postinjury (dpi), cortical gene expression, dendritic complexity, myelin content, neuronal connectivity, cognition, and immune reactivity were assessed. Myriad neuropathology-related genes were increased 30 dpi in the cortex, and 90% of these gene changes were reversed by microglial turnover. Reduced neuronal connectivity was evident 30 dpi and these deficits were attenuated by microglial turnover. TBI-associated dendritic remodeling and myelin alterations, however, remained 30 dpi independent of microglial turnover. In assessments of functional recovery, increased depressive-like behavior, and cognitive impairment 30 dpi were ameliorated by microglia turnover. To investigate microglial priming and reactivity 30 dpi, mice were injected intraperitoneally with LPS. This immune challenge caused prolonged lethargy, sickness behavior, and microglial reactivity in the TBI mice. These extended complications with LPS in TBI mice were prevented by microglia turnover. Collectively, microglial turnover 7 dpi alleviated behavioral and cognitive impairments associated with microglial priming and immune reactivity 30 dpi. A striking feature of traumatic brain injury (TBI), even mild injuries, is that over 70% of individuals have long-term neuropsychiatric complications. Chronic inflammatory processes are implicated in the pathology of these complications and these issues can be exaggerated by immune challenge. Therefore, our goal was to force the turnover of microglia 7 d after TBI. This subacute 7 d postinjury (dpi) time point is a critical transitional period in the shift toward chronic inflammatory processes and microglia priming. This forced microglia turnover intervention in mice attenuated the deficits in behavior and cognition 30 dpi. Moreover, microglia priming and immune reactivity after TBI were also reduced with microglia turnover. Therefore, microglia represent therapeutic targets after TBI to reduce persistent neuroinflammation and improve recovery.
创伤性脑损伤（TBI）与认知、精神和神经退行性并发症的风险增加有关，这些并发症可能在受伤后发展。TBI 后小胶质细胞反应增强可能是慢性神经炎症、神经病理学和对免疫挑战的反应过度的基础。因此，本研究的目的是迫使弥漫性 TBI 后形成的创伤相关小胶质细胞发生更替，并确定这是否能减轻慢性炎症、改善功能恢复并减轻对脂多糖（LPS）挑战的免疫反应减弱。雄性小鼠接受中线液动冲击伤（mFPI），7 天后接受 CSF1R 拮抗剂（PLX5622）进行强制小胶质细胞更替范式。在损伤后 30 天（dpi）评估皮质基因表达、树突复杂性、髓鞘含量、神经元连接、认知和免疫反应性。30 dpi 时，皮质中多种神经病理学相关基因表达增加，其中 90%的基因变化被小胶质细胞更替逆转。30 dpi 时明显出现神经元连接减少，小胶质细胞更替可减轻这些缺陷。然而，TBI 相关的树突重塑和髓鞘改变在 30 dpi 时仍然存在，与小胶质细胞更替无关。在功能恢复评估中，30 dpi 时的抑郁样行为和认知障碍增加被小胶质细胞更替改善。为了研究 30 dpi 时小胶质细胞的启动和反应性，用 LPS 对小鼠进行腹腔内注射。这种免疫挑战导致 TBI 小鼠出现长时间的昏睡、病态行为和小胶质细胞反应。小胶质细胞更替可防止 TBI 小鼠 LPS 引起的这些延长并发症。总之，7dpi 时的小胶质细胞更替减轻了与小胶质细胞启动和免疫反应性相关的行为和认知障碍。创伤性脑损伤（TBI）的一个显著特征，即使是轻度损伤，也有超过 70%的人有长期的神经精神并发症。慢性炎症过程与这些并发症的病理学有关，免疫挑战会加剧这些问题。因此，我们的目标是在 TBI 后 7 天强制小胶质细胞更替。这个亚急性的 7dpi 时间点是向慢性炎症过程和小胶质细胞启动转变的关键过渡时期。在小鼠中进行这种强制小胶质细胞更替干预可减轻 30dpi 时的行为和认知缺陷。此外，TBI 后小胶质细胞的启动和免疫反应性也随小胶质细胞更替而降低。因此，小胶质细胞是 TBI 后减少持续神经炎症和改善恢复的治疗靶点。
