Role of astrocytes in dopamine signaling and psychostimulant effects

多巴胺(DA)信号涉及过多的大脑功能，包括运动控制、学习和 记忆和奖赏。它受到精神刺激剂苯丙胺和可卡因的影响，这两种药物被认为是 通过增加细胞外多巴胺水平来起作用。与对神经元的广泛研究相比， 星形胶质细胞在DA信号和心理刺激作用中的作用在很大程度上仍未被探索。 星形胶质细胞在大脑功能中起着支持作用，它们还可以影响神经元和突触 通过与三体突触中的神经元进行双向交流而激活。星形胶质细胞反应 钙升高到几种神经递质(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神经胶质递质。然而，无论是 星形胶质细胞对多巴胺有反应，因此对神经传递的调节在很大程度上仍不清楚。 本研究旨在明确星形胶质细胞参与核内DA信号的作用。 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 对精神刺激剂安非他明的作用。我们假设星形胶质细胞参与 在NAC中DA信号的细胞机制和功能后果中，作为一个 结果，它们促进了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，从而刺激神经胶质递质腺苷的释放 调节兴奋性突触传递。本提案将：1)定义细胞机制 DA对NAc星形胶质细胞活动的潜在控制；2)决定DA介导的后果 星形胶质细胞在突触传递中的活性；3)测定苯丙胺对星形胶质细胞 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(“设计者独有的受体 由特制药物激活“，DREADDS)，选择性刺激多巴胺能轴突的光遗传学， 同时进行双光子钙离子成像和电生理记录，以及转基因小鼠。 预期的结果将揭示星形胶质细胞作为参与DA信号传递的细胞元素，从而对 对安非他明的影响。他们将在细胞内定义NAC中星形胶质细胞与神经元的相互作用 水平，为进一步研究将星形胶质细胞识别为参与相关行为的元素铺平了道路 既有奖励也有精神刺激药物。如果星形胶质细胞参与DA信号，而星形胶质细胞- 神经元通讯受到心理刺激剂的影响，这将揭示可能服务于 作为药物成瘾等动机障碍的治疗靶点。

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.