Role of astrocytes in dopamine signaling and psychostimulant effects

星形胶质细胞在多巴胺信号传导和精神兴奋作用中的作用

• 批准号: 9977148
• 负责人: Alfonso Araque
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977148
• 关键词: Acetylcholine; Acute; Adenosine; Affect; Amphetamines; Area; Astrocytes; Axon; Behavior; Brain; Calcium; Cells; Cocaine; Communication; Disease; Dopamine; Dopamine Receptor; Drug Addiction; Electrophysiology (science); Elements; Endocannabinoids; Energy Metabolism; Fiber; Future; Glutamates; Hippocampus (Brain); Image; Impairment; Ions; Learning; Mediating; Mediator of activation protein; Memory; Motivation; Neurons; Neurotransmitters; Norepinephrine; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacogenetics; Play; Property; Regulation; Rewards; Role; Signal Pathway; Signal Transduction; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Transgenic Mice; Viral; addiction; calcium indicator; cell type; designer receptors exclusively activated by designer drugs; dopamine transporter; drug of abuse; extracellular; gain of function; gamma-Aminobutyric Acid; loss of function; motor control; neuronal excitability; neuroregulation; neurotransmission; neurotransmitter release; novel; optogenetics; prevent; psychostimulant; receptor; synaptic function; therapeutic target; two-photon

Dopamine (DA) signaling is involved in a plethora of brain functions, including motor control, learning and memory, and reward. It is affected by the psychostimulants amphetamine and cocaine, which are thought to act by increasing the extracellular DA levels. In contrast to the extensive studies in neurons, the involvement of astrocytes in DA signaling and psychostimulant actions remain largely unexplored. Astrocytes play supportive roles in brain function, and they can also influence neuronal and synaptic activity through the bidirectional communication with neurons in tripartite synapses. Astrocytes respond with calcium elevations to several neurotransmitters (such as glutamate, acetylcholine, or endocannabinoids), and release gliotransmitters that modulate synaptic transmission. However, whether astrocytes respond to DA and consequently regulate neurotransmission remain largely unknown. The present proposal aims to define the involvement of astrocytes in DA signaling in the nucleus accumbens (NAc), a limbic area implicated in reward and addiction, and to identify the astrocyte contribution to the actions of the psychostimulant amphetamine. We hypothesize that astrocytes participate in the cellular mechanisms and functional consequences of DA signaling in the NAc and, as a consequence, they contribute to the synaptic effects of amphetamine. Our preliminary results indicate that DA activates astrocytes in the NAc, which stimulates the release of the gliotransmitter adenosine that regulates excitatory synaptic transmission. The present proposal will: 1) define the cellular mechanisms underlying DA control of the astrocyte activity in the NAc; 2) determine the consequences of DA-mediated astrocyte activity on synaptic transmission; 3) determine the actions of amphetamine on both astrocytic activity and astrocyte-mediated synaptic regulation. We will use state-of-the-art techniques, including pharmacogenetics (“designer receptors exclusively activated by designer drugs”, DREADDs), optogenetics to selectively stimulate dopaminergic axons, simultaneous two-photon Ca2+ imaging and electrophysiological recordings, and transgenic mice. The expected results will reveal astrocytes as cellular elements involved in DA signaling, thus contributing to the effects of amphetamine. They will define the astrocyte-neuron interactions in the NAc at the cellular level, paving the way for future studies recognizing astrocytes as elements involved in behaviors associated with reward as well as psychostimulant drugs. If astrocytes are involved in DA signaling, and astrocyte- neuron communication is affected by psychostimulants, this will reveal novel mechanisms that may serve as therapeutic targets in motivation disorders such as drug addiction.

多巴胺 (DA) 信号传导涉及多种大脑功能，包括运动控制、学习和 记忆、奖励。它受到精神兴奋剂安非他明和可卡因的影响，人们认为这两种物质 通过增加细胞外 DA 水平来发挥作用。与对神经元的广泛研究相反， 星形胶质细胞在 DA 信号传导和精神兴奋作用中的参与在很大程度上仍未被探索。 星形胶质细胞在大脑功能中发挥支持作用，它们还可以影响神经元和突触 通过与三方突触中的神经元进行双向通信来进行活动。星形胶质细胞做出反应 多种神经递质（如谷氨酸、乙酰胆碱或 内源性大麻素），并释放调节突触传递的胶质递质。然而，无论 星形胶质细胞对 DA 做出反应并因此调节神经传递仍然很大程度上未知。 本提案旨在定义星形胶质细胞参与细胞核内 DA 信号传导 伏隔核（NAc），一个与奖赏和成瘾有关的边缘区域，并识别星形胶质细胞 对精神兴奋剂安非他明的作用的贡献。我们假设星形胶质细胞参与 在 NAc 中 DA 信号传导的细胞机制和功能后果中， 结果，它们有助于安非他明的突触效应。我们的初步结果表明 DA 激活 NAc 中的星形胶质细胞，刺激神经胶质递质腺苷的释放， 调节兴奋性突触传递。目前的提案将：1）定义细胞机制 DA 对 NAc 中星形胶质细胞活性的控制； 2）确定DA介导的后果 星形胶质细胞对突触传递的活性； 3) 确定安非他明对星形胶质细胞的作用 活性和星形胶质细胞介导的突触调节。 我们将使用最先进的技术，包括药物遗传学（“专门设计的受体 由设计药物激活”，DREADDs），光遗传学选择性刺激多巴胺能轴突， 同时双光子 Ca2+ 成像和电生理记录以及转基因小鼠。 预期结果将揭示星形胶质细胞作为参与 DA 信号传导的细胞元件，从而有助于 安非他明的作用。他们将定义 NAc 中星形胶质细胞与神经元的相互作用 水平，为未来的研究铺平道路，将星形胶质细胞视为与相关行为有关的元素 给予奖励以及精神兴奋药物。如果星形胶质细胞参与 DA 信号传导，并且星形胶质细胞- 神经元通讯受到精神兴奋剂的影响，这将揭示可能起作用的新机制 作为药物成瘾等动机障碍的治疗靶点。