Microglia-neuron dopamine signaling - a novel mechanism of dopamine circuit modulation

项目摘要 这项建议将探索一个新的多巴胺能调节轴-小胶质细胞表达的多巴胺 受体DRD 1及其对多巴胺变化的神经元活性和兴奋性的调节 程度.小胶质细胞，中枢神经系统的常驻免疫细胞，表现出广泛的功能， 有些是典型的巨噬细胞，有些是大脑特有的。我们实验室和其他机构的最新研究 已经证明了这样的功能之一是调节神经元的活动，但他们如何以及为什么这样做仍然是 在研究中小胶质细胞在形式和功能上表现出高度的区域异质性， 解释了不同大脑区域的局部线索和需求的多样性。越来越多的文献 表明小胶质细胞具有表达受体转录本的能力，并对一系列的 神经递质和神经肽，这些的表达可能因地区、活动或疾病而异 状态我们的实验室发现了一个独特的表达多巴胺受体DRD 1的小胶质细胞亚群 (D1)在纹状体。多巴胺是一种神经递质，与奖赏、动机、自主运动行为有关， 和物质使用障碍。小胶质细胞DRD 1表达的方式、时间和原因尚不清楚， 我将用我提出的实验来回答这些问题。我会追踪小胶质细胞的个体发育 DRD 1通过使用几种转基因小鼠模型开发，以研究小胶质细胞DRD 1 表达开始于D1+小胶质细胞起源的地方，如果不是纹状体，并且如果表达/维持是 依赖于多巴胺能的输入我还将使用尖端的小胶质细胞移植技术来确定 小胶质细胞可以在纹状体中获得DRD 1，这将为局部线索在小胶质细胞中的作用提供重要证据。 小胶质细胞表型决定，这是该领域的一个开放性问题。另外，我们实验室的初步数据 已经证明D1+小胶质细胞可能能够调节神经元和行为反应， 多巴胺小胶质细胞整体消融和D1+小胶质细胞特异性消融都放大了运动反应， 慢性可卡因，通过阻断再摄取增加多巴胺水平。多巴胺水平的变化 具有许多生理、发育和环境事件的特征。在这份提案中，我将 探索两个与纹状体中型棘神经元兴奋性适应相关的：青少年 多巴胺能发育和慢性可卡因。根据我们的数据，我假设D1+小胶质细胞感觉 并对多巴胺作出反应，以调整神经元的兴奋性，以改变整个过程中的多巴胺水平。 辈子探索D1+小胶质细胞在多巴胺能信号传导中的作用对于理解多巴胺能信号传导的机制至关重要。 多巴胺能功能障碍是许多神经精神和神经系统疾病的特征，包括 物质使用障碍，帕金森氏病，抑郁症和多动症，并可以提供新的治疗 这些目标是迄今为止几乎没有找到有效治疗方案的人。

Project Summary This proposal will explore a new axis of dopaminergic regulation–microglial expression of the dopamine receptor DRD1 and their modulation of neuronal activity and excitability in response to changing dopamine levels. Microglia, the resident immune cells of the central nervous system, exhibit a wide array of functions, some stereotypical of macrophages and some unique to the brain. Recent research from our lab and others has demonstrated that one such function is to modulate neuronal activity, but how and why they do so is still under investigation. Microglia exhibit a high degree of regional heterogeneity in form and function, perhaps to account for the diversity of local cues and demands of different brain regions. A growing body of literature suggests that microglia possess the ability to express receptor transcripts for and respond to an array of neurotransmitters and neuropeptides, and that expression of these may vary by region, activity, or disease state. Our lab has uncovered a unique subpopulation of microglia that express the dopamine receptor DRD1 (D1) in the striatum. Dopamine is a neurotransmitter involved in reward, motivation, voluntary motor behavior, and substance use disorders. How, when, and why microglial DRD1 expression emerges remains unclear, and I will confront each of these questions with my proposed experiments. I will trace the ontogeny of microglial DRD1 through development using several transgenic mouse models to investigate when microglial DRD1 expression begins, from where D1+ microglia originate, if not the striatum, and if expression/maintenance is dependent upon dopaminergic input. I will also use cutting-edge microglia transplant techniques to determine if microglia can acquire DRD1 in the striatum, which will provide important evidence for the role of local cues in microglial phenotypic determination, an open question in the field. Additionally, preliminary data from our lab have demonstrated that D1+ microglia may be able to modulate the neuronal and behavioral response to dopamine. Ablation of microglia overall and D1+ microglia specifically both amplify the locomotor response to chronic cocaine, which increases dopamine levels by blocking reuptake. Changing dopamine levels are characteristic of a number of physiological, developmental, and environmental events. In this proposal, I will explore two that are associated with an adaptation of striatal medium spiny neuron excitability: juvenile dopaminergic development and chronic cocaine. Based on our data, I hypothesize that D1+ microglia sense and respond to dopamine in order to tune neuronal excitability to changing dopamine levels throughout the lifetime. Exploring the role of D1+ microglia in dopaminergic signaling is critical to understanding the dopaminergic dysfunction that characterizes numerous neuropsychiatric and neurological disorders, including substance use disorder, Parkinson’s disease, depression, and ADHD, and could provide novel therapeutic targets for those that have thus far found few effective treatment options.