Interactions between microglia and dopaminergic neurons regulates dopamine neurotransmission

小胶质细胞和多巴胺能神经元之间的相互作用调节多巴胺神经传递

• 批准号: 9314711
• 负责人: Habibeh Khoshbouei
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314711
• 关键词: Acute; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Behavioral; Biochemical; Biological Models; Brain; Brain-Derived Neurotrophic Factor; Cd68; Cell Membrane Permeability; Cells; Central Nervous System Infections; Cessation of life; Cocaine; Communication; Comorbidity; Control Groups; Data; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dopaminergic Agents; Drug abuse; Electrophysiology (science); Engineering; Enzymes; Exposure to; Goals; Growth Factor; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Health; Histologic; Histology; IL6 gene; Image; Immune Targeting; Immune system; Impairment; Individual; Infection; Inflammatory; Interleukin-1 beta; Interleukin-6; Knowledge; Lead; Literature; Measures; Mediating; Methamphetamine; Microglia; Midbrain structure; Molecular; Mus; NTF3 gene; Neurocognitive; Neurons; Pharmaceutical Preparations; Physiology; Prevalence; Process; Production; Proteins; Recycling; Regulation; Reporting; Role; Signal Transduction; Site; Slice; Structure; Surface; Synapses; TNF gene; Testing; Transcript; Transforming Growth Factor beta; Transgenic Mice; Work; antiretroviral therapy; base; cellular transduction; combinatorial; cytokine; dopamine transporter; dopaminergic neuron; experimental study; immune function; immunoreactivity; in vivo; insight; macrophage; methamphetamine exposure; nervous system disorder; neuropsychiatric disorder; neurotransmission; patch clamp; synaptogenesis; tat Protein; two-photon; uptake

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.

神经元和小胶质细胞之间的通讯是双向的。小胶质 调节神经传递，促进突触形成和溶解，以及 提供神经元保护，但细胞/分子机制不完全 明白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支持小胶质细胞 让它们对神经信号做出反应。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， （3）影响多巴胺神经传递。这里我们将使用膜片钳 电生理学、双光子成像、生物化学和组织学方法 以确定小胶质细胞是否以及如何影响多巴胺 以及HIV-1达特（一种在小胶质细胞中产生的蛋白质） 在HIV-1感染后，通过改变多巴胺的神经传递， 小胶质细胞/DA神经元的相互作用（Aim 1）。我们将研究小胶质细胞 在存在或不存在HIV的情况下， 1达特，反之，如何小胶质细胞的产品可以调节多巴胺 神经传递（Aim 2）。最后，由于存在较高的协方差， HIV-1感染和药物滥用，以及由于甲基苯丙胺和HIV-1达特 改变多巴胺神经传递并影响免疫系统，在目标3中，我们 将决定HIV-1达特和甲基苯丙胺的联合暴露 影响这些过程。拟议的工作将解决两个重大问题 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信，以及2） 确定HIV-1达特对这种双向通讯的调节如何减少 多巴胺神经传递