Noradrenergic modulation of microglial dynamics and synaptic plasticity

小胶质细胞动力学和突触可塑性的去甲肾上腺素能调节

• 批准号: 9607397
• 负责人: Rianne Stowell
• 金额: $ 4.45万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9607397
• 关键词: Ablation; Affect; Alzheimer' s Disease; Astrocytes; Autistic Disorder; Behavior; Biological Assay; Brain; Cell physiology; Cells; Characteristics; Contralateral; Coupled; Dendritic Spines; Development; Disease; Environment; Eye; Growth; Immune; Impairment; Injury; Knowledge; Laboratories; Learning; Mediating; Microglia; Modeling; Modification; Monitor; Morphology; Mus; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic Process; Neuronal Plasticity; Neurons; Neurotransmitters; Norepinephrine; Ocular Dominance; Pathway interactions; Pharmacology; Physiological; Physiology; Process; Publishing; Receptor Signaling; Regulation; Role; Schizophrenia; Signal Pathway; Signal Transduction; Specificity; Structure; Surveys; Synapses; Synaptic plasticity; Tamoxifen; Testing; Time; Tissues; Visual; Visual Cortex; Visual system structure; Work; base; beta-2 Adrenergic Receptors; brain parenchyma; cell motility; cell type; critical period; experience; experimental study; genetic approach; improved; in vivo; insight; monocular deprivation; nervous system disorder; neural circuit; neurodevelopment; new therapeutic target; noradrenergic; novel; receptor; response; response to injury; synaptic function; therapeutic development

Abstract Microglia, the innate immune cells of the central nervous system (CNS), respond rapidly and dynamically to homeostatic perturbations of the CNS milieu. In the healthy unperturbed brain, microglial processes make frequent contacts with neurons at synapses, impacting synaptic remodeling and turnover of dendritic spines. However, it remains unclear what receptors and signaling pathways govern microglial surveillance and synapse monitoring. Noradrenaline is a powerful signal that can affect many aspects of synaptic function and plasticity. Because microglia express high levels of β2 adrenergic receptors (AR) compared to other cell types in the brain, we asked whether noradrenergic tone could alter microglial behavior with respect to synapses through β2-AR signaling. Preliminary findings from our laboratory, along with published work, suggest that β2-AR signaling inhibits microglial process motility and impairs experience-dependent plasticity in the visual cortex in mice. Based on this, I hypothesize that endogenous norepinephrine release alters microglial surveillance and microglia-synapse interactions through microglial β2-AR signaling, leading to altered synaptic plasticity. To test this hypothesis, I will explore the effects of selectively ablating microglial β2-AR signaling and altering endogenous norepinephrine release on microglial behavior and contributions to synaptic plasticity using the well-characterized model of ocular dominance plasticity during the visual critical period in mice. This study will be accomplished in three specific aims: I will investigate how both changes in norepinephrine and ablation of the β2-A R in microglia impact ocular dominance plasticity (Aim 1). I will determine the effects of modulating endogenous norepinephrine pharmacologically and ablating microglial β2-ARs on microglial physiology (Aim 2). Finally, I will investigate the effects of modulating noradrenergic tone on microglial interactions with synapses and synaptic remodeling (Aim 3). The results obtained from these complementary, but independent aims will greatly improve our understanding of the signaling mechanisms that govern microglial physiology and contributions to neural development and plasticity. Understanding the pathways that mediate microglial interactions with synapses will also provide novel therapeutic targets for neurodevelopmental and neurodegenerative disorders, where plasticity is affected.

摘要 小胶质细胞是中枢神经系统（CNS）的先天性免疫细胞，其快速且动态地响应于 CNS环境的稳态扰动。在健康的未受干扰的大脑中， 在突触处与神经元接触，影响突触重塑和树突棘的更新。但 目前还不清楚是什么受体和信号通路控制着小胶质细胞的监视和突触的监测。 去甲肾上腺素是一种强大的信号，可以影响突触功能和可塑性的许多方面。因为 与大脑中的其他细胞类型相比，小胶质细胞表达高水平的β2肾上腺素能受体（AR），我们问道， 去甲肾上腺素能紧张是否可以通过β2-AR信号改变小胶质细胞在突触方面的行为。 我们实验室的初步发现，沿着已发表的工作，表明β2-AR信号抑制了小胶质细胞 过程运动性和损害小鼠视觉皮层的经验依赖性可塑性。基于此，我 假设内源性去甲肾上腺素释放改变小胶质细胞监视和小胶质细胞-突触 通过小胶质细胞β2-AR信号传导的相互作用，导致突触可塑性改变。为了验证这个假设，我将 探索选择性消融小胶质细胞β2-AR信号传导和改变内源性去甲肾上腺素的作用 释放对小胶质细胞行为的影响和对突触可塑性的贡献， 小鼠视觉关键期的优势可塑性。这项研究将在三个具体的 目的：探讨去甲肾上腺素的变化和小胶质细胞β2-AR的去除对眼的影响 显性可塑性（Aim 1）。我将确定调节内源性去甲肾上腺素 切除和消融小胶质细胞β2-AR对小胶质细胞生理学的影响（目的2）。最后，我将调查 调节去甲肾上腺素能紧张性对小胶质细胞与突触的相互作用和突触重塑的影响（目的3）。 从这些互补但独立的目标中获得的结果将大大提高我们对 控制小胶质细胞生理学的信号机制以及对神经发育和可塑性的贡献。 了解介导小胶质细胞与突触相互作用的途径也将提供新的治疗方法。 神经发育和神经退行性疾病的靶点，其中可塑性受到影响。