Brain macrophages after brain injury leads to negative behavioral outcomes

项目总结:

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.