Brain macrophages after brain injury leads to negative behavioral outcomes

项目摘要： TBI是一个严重的公共卫生问题，仅在2014年就有253万次急诊、住院和 死亡发生在美国。在人类死后研究中，小胶质细胞/单核细胞源性 巨噬细胞（MDM），慢性神经炎症的关键介质被检测到，即使在几年后， 关于TBI小胶质细胞-常驻免疫细胞-维持脆弱的神经元微环境， 通过监视和增殖，当需要时，在损伤或病理条件下， 条件在TBI损伤CNS后，单核细胞进入脑并分化成MDM，并成为 在形态上与活化的小胶质细胞无法区分。据报道，小胶质细胞/MDM 创伤性脑损伤（TBI）病理学。然而，目前尚不清楚单核细胞/MDM是如何被激活的。 在亚细胞（RNA）、细胞和网络水平上与小胶质细胞功能不同。我们的核心假设 TBI后，小胶质细胞和MDM对慢性炎症反应的贡献不同，神经元 兴奋性和行为缺陷因此，本研究的目的是深入了解 i）MDM/小胶质细胞中的mRNA变化如何影响损伤进展，ii）它们如何相互作用，以及 血管，以及iii）MDM如何影响神经元活动和随后的行为结果， 到小胶质细胞这一认识可能有助于发展有效的诊断学、诊断学和 治疗学我们建议使用双转基因报告小鼠，RNA测序，慢性双光子成像 爆炸性脑外伤条件下的电生理工具是提供所需知识的首次尝试。

Project Summary: TBI is a serious public health concern, and in 2014 alone 2.53 million emergency visits, hospitalizations, and death occurred in USA. In human post-mortem studies, accumulation of microglia/monocyte-derived macrophages (MDM), the key mediators of chronic neuroinflammation were detected, even after several years of TBI. Microglia -the resident immune cells- maintain the delicate neuronal microenvironment under physiological conditions through surveillance and proliferate when needed under injury or pathological conditions. Upon injury to the CNS from TBI, monocytes enter the brain and differentiate into MDM, and become morphologically indistinguishable from the activated microglia. Microglia/MDMs have been reported to contribute significantly to traumatic brain injury (TBI) pathology. However, it remains unclear how monocytes/MDM are functionally distinct from microglia at the subcellular (RNA), cellular, and network levels. Our central hypothesis is that after TBI, microglia and MDM contribute differently to the chronic inflammatory response, neuronal excitability, and behavioral deficits. Hence, the objective of this study is to develop an in-depth understanding of: i) how mRNA changes in MDMs/microglia affect injury progression, ii) how they interact with each other and blood vessels, and iii) how MDMs influence neuronal activity and subsequent behavioral outcomes, compared to resident microglia. This understanding may help the development of effective diagnostics, prognostics and therapeutics. Our proposal to use double transgenic reporter mice, RNA sequencing, chronic-two photon imaging and electrophysiological tools in blast TBI condition is the very first attempt to provide the needed knowledge.