Depletion of microglia immediately following traumatic brain injury in the pediatric rat: Implications for cellular and behavioral pathology
Depletion of microglia immediately following traumatic brain injury in the pediatric rat: Implications for cellular and behavioral pathology
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DOI：
10.1016/j.expneurol.2019.04.004
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发表时间：
2019-06-01
影响因子：
5.3
通讯作者：
Huh, Jimmy W.
中科院分区：
文献类型：
--
作者：
Hanlon, Lauren A.;Raghupathi, Ramesh;Huh, Jimmy W.
炎症反应是小儿创伤性脑损伤病理生理学的重要组成部分。在脑损伤儿童的脑脊液中发现了高水平的炎症介质，这与预后不良有关。针对炎症反应的各个方面，希望找到一种可行的损伤后治疗方案，这一点已经引起了人们的关注。小胶质细胞在很大程度上负责维持损伤诱导的炎症反应，但在发育中的大脑中，它们在正常和疾病状态下都发挥着有益的作用。在新生大鼠闭合性头部损伤后，脑内注射含氯膦酸盐的脂质体消耗小胶质细胞与损伤后早期（3天）神经变性增加相关，相对于注射空脂质体的情况，提示死亡细胞清除率降低。在假损伤的动物中，小胶质细胞在2-4周的时间内重新填充clodrosome介导的耗尽的脑区域，并表现出典型的静息表型的形态。在脑损伤的动物中，在注射了clodrosome的动物中重新填充的小胶质细胞表现出杆状和变形虫状的形态。然而，在这些脑区域中的fluoro-Jade B反应性比空脂质体注射的动物更广泛，表明活性小胶质细胞可能无法清除垂死的神经元。这伴随着局部皮质回路中的过度兴奋的诱导。白色物质束和丘脑内小胶质细胞的消耗并不影响损伤诱导的创伤性轴突损伤的程度。背侧下托神经退行性变的增加并不伴随着损伤引起的空间学习和记忆缺陷的任何变化。这些数据表明，小胶质细胞的激活可能是重要的，在创伤性损伤的未成熟的大脑中死亡的神经元的去除。
The inflammatory response is a significant component of the pathophysiology of pediatric traumatic brain injury. High levels of inflammatory mediators have been found in the cerebrospinal fluid of brain-injured children which have been linked to poor prognosis. Targeting aspects of the inflammatory response in the hopes of finding a viable post-injury therapeutic option has gained attention. Microglia are largely responsible for perpetuating the injury-induced inflammatory response but in the developing brain they play beneficial roles in both normal and disease states. Following closed head injury in the neonate rat, depletion of microglia with intracerebral injections of liposomes containing clodronate was associated with an increase in neurodegeneration in the early post-injury period (3 days) relative to those injected with empty liposomes suggestive of a decrease in clearance of dying cells. In sham-injured animals, microglia repopulated the clodrosome-mediated depleted brain regions over a period of 2-4 weeks and exhibited morphology typical of a resting phenotype. In brain-injured animals, the repopulated microglia in clodrosome-injected animals exhibited rod-like and amoeboid morphologies. However, fluoro-Jade B reactivity in these brain regions was more extensive than in empty liposome-injected animals suggesting that the active microglia may be unable to clear dying neurons. This was accompanied by an induction of hyperexcitability in the local cortical circuitry. Depletion of microglia within the white matter tracts and the thalamus did not affect the extent of injury-induced traumatic axonal injury. Increased neurodegeneration in the dorsal subiculum was not accompanied by any changes to injury-induced deficits in spatial learning and memory. These data suggest that activation of microglia may be important for removal of dying neurons in the traumatically-injured immature brain.