Interactions between microglia and dopaminergic neurons regulates dopamine neurotransmission

神经元和小胶质细胞之间的通讯是双向的。小胶质细胞 调节神经传递，促进突触的形成和溶解 提供神经元保护，但细胞/分子机制尚不完全 明白了。多巴胺神经元之间相互作用的大部分前提 小胶质细胞上的多巴胺受体的存在支持小胶质细胞 使它们能够对神经元信号做出反应。这个想法是多巴胺受体 对小胶质细胞的刺激改变了小胶质细胞的功能，进而可能 (反过来)影响多巴胺的神经传递。这里我们将使用膜片钳 电生理学、双光子成像、生化和组织学方法 确定耗竭的小胶质细胞是否以及如何影响多巴胺 神经传递和HIV-1Tat，一种小胶质细胞产生的蛋白质 感染HIV-1后，通过改变改变多巴胺神经传递 小胶质细胞/DA神经元的相互作用(目标1)。我们将研究小胶质细胞是如何 在存在或不存在HIV的情况下，活动受到多巴胺能信号的影响 1 TAT，反之，小胶质细胞产物如何调节多巴胺 神经传递(目标2)。最后，由于这两种疾病的发病率很高 艾滋病毒-1感染和药物滥用，而且由于甲基苯丙胺和艾滋病毒-1TAT 改变多巴胺神经传递和影响免疫系统，在目标3我们 将决定如何将艾滋病毒-1TAT和甲基苯丙胺的联合暴露 会影响这些过程。拟议的工作将涉及两个重要的 知识差距：1)揭示潜在的细胞/分子机制 多巴胺神经元和小胶质细胞之间的双向通讯，2) 确定此双向通信的HIV-1 TAT调制如何降低 多巴胺的神经传递。

The communication between neurons and microglia is bidirectional. Microglia modulate neurotransmission, facilitate synapse formation and dissolution, and provide neuronal protection, but cellular/molecular mechanisms are incompletely understood. Much of the premise for interactions between dopamine neurons and microglia is supported by presence of dopamine receptors on microglial cells allowing them to respond to neuronal signals. The idea is that dopamine receptor stimulation on microglial cells alters microglial function, which in turn could then (reciprocally) affect dopamine neurotransmission. Here we will use patch clamp electrophysiology, two-photon imaging, biochemical and histological approaches to determine whether and how depleting microglia affects dopamine neurotransmission and whether HIV-1 Tat, a protein produced in microglial cells following HIV-1 infection, disrupts dopamine neurotransmission by altering microglial/DA neurons interactions (Aim 1). We will examine how microglial activity is affected by dopaminergic signaling in the presence or absence of HIV- 1 Tat, and conversely how microglial products may modulate dopamine neurotransmission (Aim 2). Finally, since there is a high comorbidity between HIV-1 infection and drug abuse, and since both methamphetamine and HIV-1 Tat alter dopamine neurotransmission and affect the immune system, in Aim 3 we will determine how the combined exposure to HIV-1 Tat and methamphetamine influences these processes. The proposed work will address two significant knowledge gaps: 1) reveal the cellular/molecular mechanisms underlying bidirectional communication between dopamine neurons and microglia, and 2) determine how HIV-1 Tat modulation of this bidirectional communication reduces dopamine neurotransmission.