Sex differences in neuroimmune function and developmental vulnerability to early life traumatic brain injury

项目简介：儿童创伤性脑损伤是儿科急诊室的主要原因 根据疾控中心的数据，每年有超过80万儿童来急诊室就诊。儿科创伤性脑损伤 对行为健康的终生后果，增加ADHD、药物和酒精滥用的比率，长期 认知和社交缺陷、抑郁和焦虑。这表明幼儿时期是一个特殊的时期。 易受颅脑损伤后长期有害神经后果的影响。尽管有明确的证据表明 重大公共卫生问题，导致长期创伤性脑损伤的近期机制 人们对结果知之甚少。脑外伤诱导强健的神经炎症和脑内固有免疫 细胞，如小胶质细胞，调节正常的大脑发育，包括突触模式。TBI的影响 关于小胶质细胞-突触的相互作用，人们知之甚少。我们已经表现出了戏剧性的发育偏见 未成熟大鼠脑内神经免疫细胞的激活和性别差异 肥大细胞研究较少。肥大细胞在发育中的大脑中丰富，在成年人中稀少， 提示肥大细胞可能对儿童脑外伤后的神经免疫环境有独特的贡献。肥大细胞 是免疫侮辱的“第一反应者”，协调随后的免疫细胞(小胶质细胞和星形胶质细胞) 活化和血管通透性，但它们在脑损伤中的作用还没有得到很好的研究。在我们的项目中，我们将 利用幼年大鼠液压冲击伤建立儿童颅脑损伤模型，我们的初步数据表明 在海马区引起强大的肥大细胞激活，急性胶质细胞增生症，以及长期的，性别依赖性的转变 社交行为和压力荷尔蒙。因为人们对儿科对损伤的独特反应知之甚少， 我们将通过RNAseq和NanoString比较雄性和雌性大鼠对儿童和成人的伤害反应 在全面的时间进程研究中分离免疫细胞的概况(目标1)。测试对…的贡献 肥大细胞对儿童脑外伤，我们将使用一种急性肥大细胞抑制使用FDA批准的药理 全面描述神经炎性反应、血脑屏障(BBB)改变 通透性，以缩小在脑损伤后肥大细胞发挥作用的潜在机制，并相互关联 血脑屏障随着社交和压力相关行为的结果而变化(目标2)。为了确定小胶质细胞是否 对行为结果和塑造神经回路的长期神经发育规划很重要 儿童脑损伤后，我们将进行脑损伤后小胶质细胞耗竭/强迫翻转实验(目标3)。我们会 在所有研究中比较性别，我们预测男性在 发育中的大脑可能使他们更容易受到与脑外伤相关的后果的影响。我们的研究有可能 改善儿童创伤性脑损伤的长期预后并发现潜在的新治疗方法 针对发育中大脑独特的神经免疫环境的选项。

Project summary: Traumatic brain injury (TBI) in childhood is the leading cause of pediatric emergency room visits, with over 800,000 children visiting the ER each year according to the CDC. Pediatric TBI can have lifelong consequences for behavioral health, increases rates of ADHD, drug and alcohol abuse, long-term cognitive and social deficits, depression and anxiety. This suggests that early childhood is a period of particular vulnerability to long-term, deleterious neurological outcomes after TBI. Despite the clear evidence of a significant public health problem, the proximal mechanisms leading up to those long term TBI-related outcomes are poorly understood. TBI induces robust neuroinflammation and brain-resident innate immune cells, such as microglia, regulate normal brain development, including synaptic patterning. The impact of TBI on microglia-synaptic interactions is poorly understood. We have demonstrated dramatic developmental biases in activation and sex differences in the profile of neuroimmune cells in the immature rat brain, both microglia and the less studied mast cells. Mast cells are abundant in the developing brain and sparse in adults, suggesting that mast cells could contribute uniquely to the neuroimmune milieu after pediatric TBI. Mast cells are ‘first responders’ to immune insults and coordinate subsequent immune cell (microglia and astrocyte) activation as well as vascular permeability but their role in TBI has not been well studied. In our project, we will use lateral fluid percussion injury on juvenile rats to model pediatric TBI, which our preliminary data suggest elicits robust mast cell activation in the hippocampus, acute gliosis, and long-term, sex-dependent shifts in social behavior and stress hormones. Because so little is known about the unique pediatric response to injury, we will compare the pediatric versus adult injury response of male and female rats via RNAseq and Nanostring profiling of isolated immune cells in a comprehensive time course study (Aim 1). To test for a contribution of mast cells to pediatric TBI, we will use an acute mast cell inhibition using an FDA-approved pharmacological agent and comprehensively profile neuroinflammatory responses, alterations in blood brain barrier (BBB) permeability to narrow in on a potential mechanism through which mast cells are acting after TBI, and correlate BBB changes with social and stress-related behavior outcomes (Aim 2). To determine whether microglia are important for long-term neurodevelopmental programming of behavioral outcomes and sculpting neural circuits after pediatric TBI, we will perform microglia depletion/forced turnover experiments post-TBI (Aim 3). We will compare sexes in all studies, and we predict that males more robust basal neuroimmune tone in the developing brain may render them more vulnerable to TBI-related outcomes. Our studies have the potential to improving long-term outcomes following pediatric traumatic brain injury and uncover potential new therapeutic options targeted to the unique neuroimmune environment of the developing brain.