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：
10077594
负责人：
Anna K Majewska
金额：
$ 33.29万
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/10077594
关键词：
Address Adrenergic Agents Adrenergic Receptor Affect Aging Alzheimer&apos s Disease Animals Arousal Behavior Biological Assay Brain Cells 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 Pharmacology Physiological Process Receptor Signaling 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 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质网络的重塑依赖于突触的快速变化这些活动驱动的突触变化的精致特异性引出了一个问题：令人惊讶的是，我们最近发现小胶质细胞（大脑的免疫细胞）是如何实现的。然而，只有少数有助于可塑性的小胶质细胞机制发挥了重要作用。最初研究了这些途径在神经炎症反应中的作用，并且已被描述。越来越清楚的是，这种机制也用于健康大脑中的小胶质细胞功能。已知通过小胶质细胞肾上腺素受体的信号传导会影响病理环境中的小胶质细胞功能但小胶质细胞对去甲肾上腺素可塑性影响的贡献尚未得到研究。一个特别有趣的候选者，因为它直接反对我们研究的小胶质细胞中的嘌呤能信号通路显示对可塑性至关重要，表明小胶质细胞中的肾上腺素信号传导也可能影响突触此外，肾上腺素信号调节睡眠和清醒之间的整体状态变化，我们最近发现唤醒会改变小胶质细胞的动力学，这对小胶质细胞至关重要因此，在本提案中，我们将测试去甲肾上腺素通过作用的假设。小胶质细胞肾上腺素受体改变小胶质细胞的功能，从而严格影响可塑性。研究去甲肾上腺素如何影响生理小胶质细胞，我们将首先检查肾上腺素信号传导如何然后我们将研究如何影响小胶质细胞动态、监测和体内损伤反应（目标1）。小胶质细胞中的肾上腺素信号传导影响视觉皮层的活动依赖性可塑性（目标 2）和小胶质细胞在可塑性过程中的相关功能（目标 3）。肾上腺素信号传导，同时监测小胶质细胞和视觉反应，我们将确定效果是否使用条件性小胶质细胞特异性敲除 β 2 来特异性针对小胶质细胞中的肾上腺素信号传导这些研究将提供在小胶质细胞内高水平表达的肾上腺素受体（β2 AR）。对小胶质细胞与突触相互作用时使用的分子机制的重要见解对于理解小胶质细胞如何促进突触可塑性至关重要，因为突触可塑性受到影响。在大量神经发育和神经系统疾病中，其中许多也与异常的肾上腺素信号传导，我们的工作将为干预提供潜在目标，以恢复适当的状态塑料变化并改善这些疾病的症状。