In vivo studies of microglial functions in brain plasticity and pathology

描述(申请人提供)：这项建议的目标是更好地了解小胶质细胞在生理和病理条件下调节大脑结构和功能的作用。小胶质细胞是中枢神经系统的常驻免疫细胞，显示出占据非重叠区域的高度能动性的突起。在生理条件下，小胶质细胞可能参与神经回路的发育和可塑性，并监测大脑微环境的损伤信号。病理条件下，小胶质细胞可能含有组织损伤，吞噬细胞碎片，促进神经元可塑性。虽然小胶质细胞参与了许多生理和病理过程，但它们在中枢神经系统中的功能仍不清楚。缺乏专门干扰体内小胶质细胞功能的工具，阻碍了描述小胶质细胞确切作用的努力。我们最近产生了一种靶向基因插入的小鼠，允许在表达小胶质细胞和外周髓系细胞的CX3CR1中表达他莫昔芬诱导的Cre重组酶。通过利用小胶质细胞和外周髓系细胞的不同周转率，我们建议建立一种方法，首次允许我们特异性地干扰活着的小鼠的小胶质细胞功能。通过特异性地去除小胶质细胞或去除小胶质细胞中的脑源性神经营养因子，我们将阐明小胶质细胞和小胶质细胞BDNF在突触发育和学习依赖突触可塑性中的作用。此外，我们还将揭示小胶质细胞激活在控制脑创伤后神经元损伤、胶质瘢痕形成和突触重构中的作用。由于激活的小胶质细胞几乎参与了大脑中的所有病理状态，因此对小胶质细胞精确功能的研究将为许多神经系统疾病的理解和治疗提供重要的启示。

DESCRIPTION (provided by applicant): The goal of this proposal is to better understand the role of microglia in regulating the structure and function of the brain under physiological and pathological conditions. Microglia are the resident immune cells of the central nervous system and display highly motile processes occupying a non- overlapping territory. Under physiological conditions, microglia may participate in the development and plasticity of neural circuits and monitor the brain's microenvironment for damage signals. Under pathological conditions, microglia may contain tissue damage, phagocytose cellular debris, and promote neuronal plasticity. Although microglia have been implicated in many physiological and pathological processes, their functions in the central nervous system remains elusive. Hampering efforts to delineate the precise role of microglia is the lack of tools to specifically perturb microglial function in vivo. We have recently generated mice with a targeted gene insertion allowing for the expression of tamoxifen-inducible Cre recombinase in CX3CR1 expressing microglial cells and peripheral myeloid cells. By taking advantage of different turnover rates of microglia and peripheral myeloid cells, we propose to establish an approach that will allow us, for the first time, to specifically perturb microglial functions in the living mice. By specifically ablating microglia or removing brain- derived neurotrophic factor (BDNF) from microglia in the living mice, we will elucidate the functions of microglia and microglial BDNF in synapse development and learning-dependent synaptic plasticity. In addition, we will reveal the role of microglial activation in controlling neuronal damage, glial scar formation and synaptic remodeling after traumatic brain injury. As activated microglia are involved in almost every pathological condition in the brain, the proposed studies of identifying precise functions of microglia will provide important insights for the understanding and treatment of many neurological diseases.