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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

基本信息

批准号：
9797456
负责人：
Alfonso Araque
金额：
$ 33.97万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/9797456
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

项目摘要

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）信号参与了大量的大脑功能，包括运动控制、学习和认知