In vivo studies of microglial functions in brain plasticity and pathology

描述（由申请人提供）：本提案的目的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，并且显示占据非重叠区域的高度运动过程。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。在病理条件下，小胶质细胞可能包含组织损伤，吞噬细胞碎片，并促进神经元可塑性。尽管小胶质细胞参与了许多生理和病理过程，但其在中枢神经系统中的功能仍然是未知的。阻碍努力描绘小胶质细胞的确切作用是缺乏工具，专门扰乱小胶质细胞的功能在体内。我们最近已经产生了一个有针对性的基因插入允许他莫昔芬诱导的Cre重组酶在CX3CR1表达的小胶质细胞和外周骨髓细胞的表达的小鼠。通过利用小胶质细胞和外周骨髓细胞的不同周转率，我们建议建立一种方法，使我们能够第一次在活体小鼠中特异性地干扰小胶质细胞的功能。通过特异性切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（BDNF），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性突触可塑性中的功能。此外，我们将揭示小胶质细胞激活在控制创伤性脑损伤后神经元损伤、胶质瘢痕形成和突触重塑中的作用。由于激活的小胶质细胞参与大脑中几乎所有的病理状态，因此确定小胶质细胞精确功能的拟议研究将为许多神经系统疾病的理解和治疗提供重要见解。

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.