Dynamics of and Function Cerebellar Microglia

翻译后摘要：突触可塑性允许中枢神经系统（CNS）纳入新的感觉经验 它的破坏与许多神经和精神疾病有关。很久以前 工作集中在非神经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 突触可塑性。虽然小胶质细胞的免疫能力被认为是经典的，但它对免疫系统至关重要。 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.尽管逐渐形成的共识是，小胶质细胞动力学对脑功能至关重要， 生理和病理条件下，目前还不清楚这些小胶质细胞的作用和它们的潜在的 机制是通用的，或者在大脑区域之间是不同的。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 免疫警惕（小脑），即使在没有病理刺激。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概况，沿着不同的 功能特性，如吞噬作用更强，形态上分支较少，分布密度较低。 因此，小脑小胶质细胞比皮质小胶质细胞更少地调查脑实质，但 通过在稳态条件下经历频繁的体细胞易位来补偿这一点， 在皮质中未观察到这种现象。尽管存在这些差异，小脑小胶质细胞保持着共同的小胶质细胞， 功能，表现出强大的损伤反应和与周围神经元的动态相互作用。 了解小脑小胶质细胞的共同和独特的作用，沿着调解机制 这些角色，对于理解小脑的功能和可塑性，以及小脑的异质性都是至关重要的。 大脑中的小胶质细胞在这个建议中，我将解决小脑小胶质细胞使用一个假设， 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 微电路调节小脑神经元可塑性。 为了验证这个假设，我制定了以下具体目标：在目标1中，我将研究两个 已知对皮质中小胶质细胞介导的神经可塑性起关键作用的重要机制形成了 小脑小胶质细胞的动力学和损伤反应。在目标2中，我将研究其中一个的重要性。 机制，b2肾上腺素能受体信号传导，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。从这些相互补充但独立的目标中获得的结果将 进一步了解小脑小胶质细胞，阐明了控制它们的信号通路， 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 不同的小胶质细胞群体在大脑中发挥作用，并深入了解小胶质细胞的缺陷是如何产生的。 介导的突触可塑性有助于神经和精神疾病。

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.