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

小胶质细胞-神经元多巴胺信号传导——多巴胺回路调节的新机制

• 批准号: 10752453
• 负责人: Emma Hays
• 金额: $ 4.75万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752453
• 关键词: Ablation; Adolescent; Adult; Attention deficit hyperactivity disorder; Behavior; Brain; Brain region; Cells; Central Nervous System; Characteristics; Chronic; Cocaine; Corpus striatum structure; Cues; DRD1 gene; Data; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Dorsal; Drug usage; Electrophysiology (science); Embryonic Development; Environment; Event; Exhibits; FOS gene; Fire - disasters; Functional disorder; Gene Expression; Gene Expression Profile; Genetic; Growth; Heterogeneity; Human; Immediate-Early Genes; Immune; In Situ Hybridization; Invaded; Investigation; Level of Evidence; Link; Literature; Macrophage; Maintenance; Measures; Mediating; Mental Depression; Microglia; Motivation; Mus; Neurodegenerative Disorders; Neurons; Neuropeptides; Neurotransmitters; Parkinson Disease; Phenotype; Physiological; Play; Regulation; Reporting; Research; Rewards; Role; Signal Transduction; Stains; Substance Use Disorder; System; Techniques; Time; Tissues; Transcript; Transgenic Mice; Transplantation; Wild Type Mouse; behavioral response; dopamine transporter; dopaminergic neuron; effective therapy; experimental study; hindbrain; immune function; motor behavior; mouse model; nervous system disorder; neuronal excitability; neuropsychiatric disorder; new therapeutic target; novel; patch clamp; postnatal development; prenatal; receptor; receptor expression; recruit; response; reuptake

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.

项目摘要 该提案将探索多巴胺能调节的新轴 - 多巴胺的膜表达 受体DRD1及其对神经元活性的调节，并响应变化的多巴胺而令人兴奋 水平。小胶质细胞是中枢神经系统的常驻免疫小球，暴露了各种功能， 有些对巨噬细胞的刻板印象，有些是大脑独有的。我们实验室和其他人的最新研究 已经证明了一个这样的功能是调节神经元活动，但是如何以及为什么仍在调节神经元活动 投资不足。小胶质细胞在形式和功能上表现出高度的区域异质性，也许 解释了不同大脑区域的当地提示和需求的多样性。越来越多的文学作品 表明小胶质细胞具有表达接收器成绩单的能力并响应 神经递质和神经肽，它们的表达可能因区域，活性或疾病而有所不同 状态。我们的实验室发现了表达多巴胺受体DRD1的小胶质细胞的独特亚群 （D1）在纹状体中。多巴胺是参与奖励，动机，自愿运动行为的神经递质， 和药物使用障碍。如何，何时以及为什么小胶质drd1表达紧急情况尚不清楚，以及 我将通过提出的实验来面对这些问题。我将追踪小胶质的个体发育 DRD1通过开发使用几种转基因小鼠模型来研究小胶质细胞DRD1 表达开始，从d1+小胶质细胞起源，如果不是纹状体，以及表达/维护是否为 取决于多巴胺能输入。我还将使用尖端的小胶质细胞移植技术来确定是否是否 小胶质细胞可以在纹状体中获取DRD1，这将为局部线索在 小胶质表型确定，这是现场的一个空旷问题。此外，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对神经元和行为反应 多巴胺。整体上的小胶质细胞和D1+小胶质细胞的消融都特别扩大了运动反应 慢性可卡因，通过阻止再摄取来增加多巴胺水平。变化的多巴胺水平是 许多身体，发育和环境事件的特征。在这个建议中，我将 探索两个与纹状体介质刺神经元兴奋性相关的两个相关的：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 并回应多巴胺，以调整整个多巴胺水平的刺激性神经元 寿命。探索D1+小胶质细胞在多巴胺能信号中的作用对于理解 多巴胺能功能障碍表征了许多神经精神病和神经系统疾病，包括 药物使用障碍，帕金森氏病，抑郁症和多动症，可以提供新颖的疗法 到目前为止发现有效的治疗选择的人的目标。