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

项目摘要 这个提议将探索一个新的多巴胺能调节轴--多巴胺的小胶质细胞表达 DRD1受体及其在多巴胺改变时对神经元活性和兴奋性的调节 级别。小胶质细胞是中枢神经系统的常驻免疫细胞，具有广泛的功能， 有些是典型的巨噬细胞，有些是大脑独有的。我们实验室和其他机构最近的研究 已经证明了一种这样的功能是调节神经元的活动，但它们如何以及为什么这样做仍然是个问题 正在调查中。小胶质细胞在形态和功能上表现出高度的区域性异质性，可能是 考虑到不同大脑区域的局部线索和需求的多样性。越来越多的文学作品 提示小胶质细胞具有表达受体转录本的能力并对一系列 神经递质和神经肽，它们表达可能因区域、活动或疾病而异 州政府。我们的实验室发现了一种表达多巴胺受体DRD1的独特的小胶质细胞亚群 (D1)纹状体。多巴胺是一种神经递质，参与奖赏、动机、自愿运动行为， 和物质使用障碍。小胶质细胞DRD1表达的方式、时间和原因尚不清楚。 我将通过我提出的实验来面对这些问题。我将追踪小胶质细胞的个体发育 通过建立几种转基因小鼠模型来研究小胶质细胞DRD1何时 如果不是纹状体，表达从哪里开始，如果表达/维持是 依赖于多巴胺能输入。我还将使用尖端的小胶质细胞移植技术来确定 小胶质细胞可在纹状体获得DRD1，这将为局部信号在纹状体中的作用提供重要证据。 小胶质细胞表型测定，这在该领域是一个悬而未决的问题。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。完全消融小胶质细胞和D_1+小胶质细胞都能特异性地放大运动反应 慢性可卡因，通过阻止再摄取而增加多巴胺水平。多巴胺水平的变化是 以许多生理、发育和环境事件为特征的。在这份提案中，我将 探索与纹状体中棘神经元兴奋性适应相关的两个因素：幼年 多巴胺能发育与慢性可卡因。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，以调节神经元的兴奋性，以适应整个大脑 一辈子。探索D1+小胶质细胞在多巴胺能信号转导中的作用是理解 多巴胺能功能障碍是许多神经精神和神经疾病的特征，包括 物质使用障碍、帕金森氏病、抑郁症和ADHD，并可能提供新的治疗方法 为那些迄今几乎没有找到有效治疗选择的人提供目标。

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.