Brain macrophages after brain injury leads to negative behavioral outcomes

项目总结： TBI是一个严重的公共卫生问题，仅在2014年，就有253万人紧急就诊、住院和 死亡发生在美国。在人类尸检研究中，小胶质细胞/单核细胞来源的积聚 巨噬细胞(MDM)，慢性神经炎的关键介质，即使在几年后也被检测到 TBI的。小胶质细胞--常驻免疫细胞--维持微妙的神经元微环境 通过监测生理条件，并在受伤或病理情况下需要时进行增殖 条件。当颅脑损伤对中枢神经系统造成损伤时，单核细胞进入大脑，分化为MDM，并成为 在形态上与激活的小胶质细胞难以区分。据报道，小胶质细胞/MDM对 对创伤性脑损伤(TBI)的病理学意义重大。然而，目前尚不清楚单核细胞/MDM是如何 在功能上与小胶质细胞在亚细胞(RNA)、细胞和网络水平上不同。我们的中心假设 脑外伤后，小胶质细胞和MDM对慢性炎症反应、神经元的作用不同 兴奋性和行为缺陷。因此，这项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，比较 到常驻的小胶质细胞。这种理解可能有助于开发有效的诊断、预后和 治疗学。我们的建议使用双转基因报告鼠，RNA测序，慢性双光子成像 而冲击波脑损伤条件下的电生理工具是首次尝试提供所需的知识。

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.