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.

Public Health Relevance

The goal of this proposal is to determine the function of microglia in the normal and pathological brain. We will establish a novel tool to specifically perturb microglia functions and elucidate the precise role of microglia in synaptic plasticity and pathology in the CNS. The experiments proposed here will allow us to reveal a number of key functions of microglia under normal and pathological conditions, including learning and memory, and traumatic brain injury.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS087198-01
Application #
8674876
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
New York University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
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Wang, Xu; Zhao, Lian; Zhang, Jun et al. (2016) Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina. J Neurosci 36:2827-42
Zhao, Lian; Zabel, Matthew K; Wang, Xu et al. (2015) Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Mol Med 7:1179-97
Parkhurst, Christopher N; Yang, Guang; Ninan, Ipe et al. (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596-609
Parkhurst, Christopher N; Gan, Wen-Biao (2010) Microglia dynamics and function in the CNS. Curr Opin Neurobiol 20:595-600