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

• 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
• 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' 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

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.

开发过程中通过视觉体验对皮质网络的重塑取决于突触的快速变化 结构和功能。这些活动驱动的合成变化的独家特异性使得 它们的实施方式。令人惊讶的是，我们最近表明，小胶质细胞是大脑的免疫细胞，是 在此过程中至关重要。但是，只有少数有助于可塑性的小胶质细胞机制 描述了他们。这些途径最初是研究了它们在神经炎症反应中的作用的研究 清楚地表明，这种机制也用于健康大脑中的小胶质细胞功能。去甲肾上腺素 已知通过小胶质肾上腺素受体的信号传导会影响病理环境中的小胶质功能 但是小胶质细胞对去甲肾上腺素对可塑性的影响的贡献尚未研究。肾上腺信号是 一个特别有趣的候选人，因为它直接反对小胶质细胞中的嘌呤能信号传导途径 表明对可塑性至关重要，表明小胶质细胞中的肾上腺肾上腺素信号传导也可能影响突触 重塑。此外，肾上腺肾上腺素信号调节睡眠和清醒之间的全球状态变化， 我们最近发现，唤醒的小胶质细胞动力学对小胶质细胞至关重要 突触相互作用。因此，在此提案中，我们将检验以下假设： 小胶质肾上腺素受体改变小胶质细胞功能，从而影响可塑性。严格 研究去甲肾上腺素如何影响物理小胶质细胞，我们将首先检查肾上腺素信号传导 影响体内的小胶质细胞动力学，监视和损伤反应（AIM1）。然后，我们将研究如何 小胶质细胞中的肾上腺素信号传导会影响视觉皮层的活动依赖性可塑性（AIM 2）和 可塑性期间小胶质细胞的相关功能（AIM 3）。我们将使用药物方法来改变 监测小胶质细胞和视觉反应时的肾上腺素信号传导，我们将确定效果是否是 使用β2的条件小胶质细胞特异性敲除小胶质细胞中的肾上腺肾上腺素信号传导。 肾上腺素受体（β2AR），在小胶质细胞内高水平表达。这些研究将提供 与突触相互作用时，对小胶质细胞使用的分子机制的重要见解 了解小胶质细胞如何促进合成可塑性至关重要。因为合成可塑性受到影响 在许多神经发育和神经系统疾病中，其中许多也与 我们的工作异常的肾上腺素信号传导将为恢复适当的干预提供潜在的目标 这些疾病中的塑性变化并改善症状。