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Mechanisms that Regulate Microglial Dynamics in the Context of Plasticity

可塑性背景下调节小胶质细胞动力学的机制

基本信息

批准号：
10543755
负责人：
Anna K Majewska
金额：
$ 31.86万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543755
关键词：
Adrenergic Agents Adrenergic Receptor Affect Aging Alzheimer&apos s Disease Anesthesia procedures Animals Arousal Behavior Biological Assay Brain Cells Communication Defect Development Disease Epilepsy Human Immune Intervention Knock-out Learning Mediating Microglia Modeling Molecular Monitor Morphology Neurodevelopmental Disorder Neuromodulator Neuronal Plasticity Neurons Norepinephrine Ocular Dominance Pathologic Pathway interactions Phagocytes Physiological Process Role Signal Pathway Signal Transduction Site Sleep Specificity Structure Synapses Synaptic Cleft Synaptic plasticity Testing Visual Visual Cortex Wakefulness Work autism spectrum disorder awake beta-2 Adrenergic Receptors brain circuitry cell motility conditional knockout critical period experience experimental study in vivo in vivo two-photon imaging insight nervous system disorder neuroinflammation new therapeutic target optogenetics pharmacologic reduce symptoms response response to injury

项目摘要

Remodeling of cortical networks by visual experience during development relies on rapid changes in synaptic structure and function. The exquisite specificity of these activity-driven synaptic changes begs the question of how they are implemented. Surprisingly we have recently shown that microglia, the brain’s immune cells, are critical in this process. However, only a handful of the microglial mechanisms that contribute to plasticity have been described. These pathways were initially studied for their roles in neuroinflammatory responses and it is becoming clear that such mechanisms are also used in microglial function in the healthy brain. Norepinephrine signaling through microglial adrenergic receptors is known to affect microglial function in pathological settings but microglial contributions to norepinephrine’s effects on plasticity are as yet unstudied. Adrenergic signaling is a particularly intriguing candidate as it directly opposes the purinergic signaling pathway in microglia that we showed to be critical for plasticity, suggesting that adrenergic signaling in microglia could also impact synaptic remodeling. Additionally, adrenergic signaling modulates global state changes between sleep and wakefulness, and we have recently discovered that arousal changes microglial dynamics, which are critical to microglia- synapse interactions. Therefore, in this proposal we will test the hypothesis that norepinpehrine acting through microglial adrenergic receptors alters microglial function thereby affecting plasticity. To rigorously investigate how norepinephrine affects physiological microglia, we will first examine how adrenergic signaling affects microglial dynamics, surveillance and injury response in vivo (Aim1). We will then examine how adrenergic signaling in microglia affects activity-dependent plasticity in the visual cortex (Aim 2) and the associated functions of microglia during plasticity (Aim 3). We will use pharmacological approaches to alter adrenergic signaling while monitoring microglia and visual responses, and we will determine whether effects are specific to adrenergic signaling in microglia using conditional microglia-specific knock-out of the beta 2 adrenergic receptor (β2 AR) which is expressed at high levels within microglia. These studies will provide important insight into the molecular mechanisms used by microglia when interacting with synapses which is critical for understanding how microglia contribute to synaptic plasticity. Because synaptic plasticity is affected in a large number of neurodevelopmental and neurological disorders, many of which are also associated with aberrant adrenergic signaling, our work will provide potential targets for intervention to reinstate appropriate plastic changes and ameliorate symptoms in these diseases.

发育过程中视觉经验对皮层网络的重塑依赖于突触的快速变化