Dynamics of and Function Cerebellar Microglia

小脑小胶质细胞的动力学和功能

• 批准号: 10267692
• 负责人: Mark Blohm Stoessel
• 金额: $ 4.6万
• 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: 2020-09-30 至 2023-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267692
• 关键词: Ablation; Address; Adrenergic Receptor; Adult; Affect; Area; Behavior; Behavioral; Biological Assay; Brain; Brain region; Cell membrane; Cells; Cerebellum; Cerebral cortex; Consensus; Corpus striatum structure; Defect; Developmental Process; Disease; Electron Microscopy; Electrophysiology (science); Elements; Epigenetic Process; Excitatory Postsynaptic Potentials; Exhibits; Fellowship; Genetic Transcription; Goals; Health; Heterogeneity; Hippocampus (Brain); Immune; Inflammatory; Injury; Knowledge; Learning; Light; Mediating; Memory; Mental disorders; Microglia; Molecular; Morphology; Neuraxis; Neuronal Plasticity; Neurons; Norepinephrine; Pathologic; Pathway interactions; Phagocytes; Pharmacology; Physiological; Physiology; Play; Population; Population Heterogeneity; Process; Property; Purinoceptor; Purkinje Cells; Receptor Signaling; Reflex action; Role; Sensory; Shapes; Signal Pathway; Signal Transduction; Slice; Stimulus; Surveys; Synapses; Synaptic plasticity; Testing; Training; Work; brain parenchyma; cell motility; experience; experimental study; genetic manipulation; insight; nervous system disorder; neuronal cell body; relating to nervous system; response; response to injury

Abstract: Synaptic plasticity allows the central nervous system (CNS) to incorporate new sensory experiences and information, and its disruption is associated with many neurological and psychiatric disorders. Much recent work has focused on the contribution of non-neuronal CNS cells, especially microglia, the innate immune cells of the CNS, to synaptic plasticity. Though classically thought of in their immune capacities, microglia are vital to many homeostatic and developmental processes, including synaptic plasticity of nascent and adult neuronal networks. Despite the emerging consensus that microglial dynamics are critical to brain function during physiological as well as pathological conditions, it is unclear whether these microglial roles and their underlying mechanisms are universal or differ between brain regions. There is a growing body evidence to suggest microglia exhibit a high degree of regional specialization; existing on a continuum from homeostatic (cortex, striatum) to immune vigilant (cerebellum) even in the absence of pathological stimuli. Indeed, microglia in the cerebellum represent a distinct population, exhibiting unique transcriptional and epigenetic profiles, along with distinct functional properties, such as being more phagocytic, morphologically less ramified and less densely distributed. As a consequence, cerebellar microglia survey less of the brain parenchyma than cortical microglia, but compensate for this by undergoing frequent somatic translocations under homeostatic conditions, a phenomenon not observed in cortex. Despite these differences, cerebellar microglia maintain common microglial functions, exhibiting a robust injury response and dynamic interactions with surrounding neural elements. Understanding the common and unique roles of cerebellar microglia, along with the mechanisms that mediate such roles, will be critical to understanding both cerebellar function and plasticity, as well as the heterogeneity of microglia throughout the brain. In this proposal, I will address the hypothesis that cerebellar microglia use a subset of the conserved mechanisms that modulate microglial dynamics to directly interact with the cerebellar microcircuit to modulate cerebellar neuronal plasticity. To test this hypothesis I have developed the following specific aims: In Aim 1 I will investigate how two important mechanisms that are known to be key to microglial mediated neural plasticity in the cortex shape the dynamics and injury response of cerebellar microglia. In Aim 2 I will investigate the importance of one of these mechanisms, b2 adrenergic receptor signaling, with known roles in cerebellar plasticity, to microglial modulation of cerebellar circuits and behavior. The results obtained from these complementary but independent aims will further our understanding of cerebellar microglia, illuminating both the signaling pathways that govern their dynamics and their contribution to cerebellar neuronal plasticity. From there, we can begin to unravel how different microglial populations serve their roles in the brain and gain insight into how defects in microglia- mediated synaptic plasticity contribute to neurological and psychiatric diseases.

摘要：突触可塑性使中枢神经系统（CNS）能够融入新的感觉体验 和信息，其破坏与许多神经和精神疾病有关。最近的 工作重点是非神经元中枢神经系统细胞的贡献，特别是小胶质细胞，先天免疫细胞 中枢神经系统，突触可塑性。尽管传统上认为小胶质细胞具有免疫能力，但它对于免疫功能至关重要 许多稳态和发育过程，包括新生和成年神经元的突触可塑性 网络。尽管人们逐渐达成共识，认为小胶质细胞动力学对大脑功能至关重要 生理和病理条件下，目前尚不清楚这些小胶质细胞的作用及其潜在的作用是否 机制是通用的或在大脑区域之间有所不同。越来越多的身体证据表明小胶质细胞 表现出高度的区域专业化；存在于从稳态（皮层、纹状体）到 即使在没有病理刺激的情况下，免疫警惕（小脑）。事实上，小脑中的小胶质细胞 代表一个独特的群体，表现出独特的转录和表观遗传特征，以及独特的 功能特性，例如更具吞噬性、形态上分支较少且分布较不密集。 因此，小脑小胶质细胞对脑实质的调查少于皮质小胶质细胞，但 通过在稳态条件下进行频繁的体细胞易位来补偿这一点， 在皮层中未观察到的现象。尽管存在这些差异，小脑小胶质细胞仍保持共同的小胶质细胞 功能，表现出强大的损伤反应以及与周围神经元件的动态相互作用。 了解小脑小胶质细胞的常见和独特作用以及介导机制 这些角色对于理解小脑功能和可塑性以及异质性至关重要 整个大脑的小胶质细胞。在本提案中，我将提出以下假设：小脑小胶质细胞使用 调节小胶质细胞动力学以直接与小脑相互作用的保守机制的子集 调节小脑神经元可塑性的微电路。 为了检验这个假设，我制定了以下具体目标： 在目标 1 中，我将研究两个 已知对皮层小胶质细胞介导的神经可塑性至关重要的重要机制塑造了 小脑小胶质细胞的动力学和损伤反应。在目标 2 中，我将研究其中一项的重要性 机制，b2 肾上腺素受体信号转导，在小脑可塑性中具有已知的作用，对小胶质细胞的调节 小脑回路和行为。从这些互补但独立的目标中获得的结果将 进一步我们对小脑小胶质细胞的理解，阐明了控制其的信号通路 动力学及其对小脑神经元可塑性的贡献。从那里，我们可以开始解开如何 不同的小胶质细胞群在大脑中发挥各自的作用，并深入了解小胶质细胞的缺陷如何 介导的突触可塑性有助于神经和精神疾病。