Dopamine signaling as a cognate microglia-neuron interaction in the striatum

项目总结/摘要 小胶质细胞是大脑中的组织驻留巨噬细胞，其执行多种功能以维持大脑 体内平衡小胶质细胞吞噬死亡细胞和碎片，分泌生长因子，并修剪功能性神经元。 突触为了维持这种内稳态，小胶质细胞需要感知神经元内的同源变化。 神经元活动小胶质细胞感知神经活动变化的一种令人兴奋的可能机制是， 表达其微环境中神经递质的受体。通过这种方式，小胶质细胞可以 采样局部神经递质水平的波动，推断神经活动的变化，并相应地修改 维持回路稳态的整体神经活动。因此，我发现，在大脑中的小胶质细胞亚群， 纹状体表达多巴胺1受体（D1R）。多巴胺能神经支配对精神病至关重要 功能和失调与神经和神经精神障碍有关。我假设 纹状体中表达D1R的小胶质细胞的独特亚群可能主动感知神经元的变化。 多巴胺水平，并通过调节纹状体神经元的活性将这些变化传递给纹状体神经元。该项目将 研究D1R信号如何影响小胶质细胞基因表达和功能，并评估如何消除 小胶质细胞对多巴胺的反应影响中等多刺神经元和多巴胺依赖性行为。我会 使用尖端的分子和遗传技术，结合行为模式，充分评估 D1R+小胶质细胞亚群。在这个项目中获得的数据将有助于揭示新的机制， 同源小胶质细胞神经元通信，并帮助我们了解小胶质细胞如何感觉和响应特定的 神经活动的变化。识别小胶质细胞中D1R信号传导的功能可能揭示小胶质细胞 在神经精神疾病和成瘾中，多巴胺系统功能障碍。

Project Summary/Abstract Microglia are the tissue resident macrophages in the brain that perform diverse functions to maintain brain homeostasis. Microglia phagocytose dying cells and debris, secrete growth factors, and prune afunctional synapses. In order for this homeostasis to be maintained, microglia need to sense cognate changes in neuronal activity. One exciting possible mechanism by which microglia sense changes in neural activity is by expressing receptors for the neurotransmitters present in their microenvironment. In this way, microglia could sample fluctuations in local neurotransmitter levels, infer changes in neural activity, and corresponding modify overall neural activity to maintain circuit homeostasis. Accordingly, I found that a subset of microglia in the striatum express the dopamine 1 receptor (D1R). Dopaminergic innervation is crucial for psychomotor functioning, and dysregulation is associated with neurological and neuropsychiatric disorders. I hypothesize that the unique subpopulation of D1R-expressing microglia in the striatum may actively sense changes in dopamine levels and relay these changes to striatal neurons by modulating their activity. This project will investigate how D1R signaling influences microglial gene expression and function and assess how abrogating the microglial response to dopamine impacts medium spiny neurons and dopamine-dependent behaviors. I will use cutting-edge molecule and genetic techniques coupled with behavioral paradigms to fully assess the role of this D1R+ microglial subpopulation. The data obtained in this project will help uncover novel mechanisms of cognate microglia-neuron communication and help us understand how microglia sense and respond to specific changes in neural activity. Identifying the function of D1R signaling in microglia may reveal how microglia contribute to dopamine system dysfunction in neuropsychiatric disorders and addiction.