Dissecting Monoaminergic Physiology of Prefrontal Cortical Astrocytes

剖析前额皮质星形胶质细胞的单胺能生理学

• 批准号: 9912149
• 负责人: Kira Poskanzer
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912149
• 关键词: Acute; Address; Amphetamines; Animal Behavior; Astrocytes; Attention; Behavior; Behavioral; Biological; Brain; Brain region; CRISPR/Cas technology; Cells; Data; Detection; Dopamine; Drug Exposure; Exposure to; Feedback; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Glutamates; Goals; Heterogeneity; Image; Intervention; Learning; Literature; Long-Term Effects; Measures; Medial; Mediating; Mediator of activation protein; Mental disorders; Modeling; Motivation; Neuroglia; Neuromodulator; Neuronal Plasticity; Neurons; Neurotransmitters; Norepinephrine; Outcome; Output; Pharmaceutical Preparations; Physiological; Physiology; Play; Population; Population Dynamics; Positioning Attribute; Prefrontal Cortex; Protocols documentation; Psychostimulant dependence; Regulation; Research; Research Support; Rewards; Role; Scheme; Serotonin; Signal Transduction; Signaling Protein; Substance Use Disorder; Synaptic Transmission; System; Testing; Work; addiction; brain behavior; cell type; drug action; drug of abuse; experimental study; extracellular; monoamine; motivated behavior; nervous system disorder; neural circuit; neuroadaptation; neurobehavioral; nigrostriatal pathway; photoactivation; psychostimulant; relating to nervous system; response; signal processing; spatiotemporal; two-photon

PROJECT SUMMARY Motivated behaviors, included those altered in substance use disorders, are known to be regulated by monoaminergic circuits (containing neurons that release dopamine, serotonin, and norepinephrine) in multiple brain regions. Disentangling these circuits from the cell-level to the systems- and behavioral-levels has almost exclusively been limited to studying the physiology of neurons. However, recent data suggest that the activity of a non-neuronal cell type—astrocytes—may have profound effects on how monoaminergic networks function, but how astrocytes respond to monoamines and change their physiology in response to repetitive drug exposure remain almost completely unstudied. The current proposal aims to address gaps in our understanding of addiction, monoamine signaling, and multi-cell type population dynamics by uncovering fundamental cell biological signaling systems in astrocytes that are critical for the function of brain regions with monoaminergic input. In Aim 1, we will use two-photon imaging and photoactivation to interrogate the cell signaling mechanisms that prefrontal cortical astrocytes deploy to sense extracellular monoamine dynamics across cortical layers. In Aim 2, we will decode the mechanisms by which astrocytes change, both instrinsically and in their output to the neuronal population, after long-term exposure to a psychostimulant. With these aims, we will probe the roles of astrocyte physiology in baseline prefrontal cortex function and as mediators of circuit neuroplasticity in a model of addiction.

项目概要 众所周知，动机行为，包括那些因物质使用障碍而改变的行为，受到以下因素的调节： 单胺能回路（包含释放多巴胺、血清素和去甲肾上腺素的神经元） 大脑区域。将这些电路从细胞水平解开到系统和行为水平几乎已经 仅限于研究神经元的生理学。然而，最近的数据表明，该活动 非神经元细胞类型——星形胶质细胞——可能对单胺能网络的功能产生深远的影响， 但星形胶质细胞如何响应单胺并改变其生理机能以响应重复药物 暴露几乎完全未被研究。当前的提案旨在解决我们的差距 通过揭示成瘾、单胺信号传导和多细胞类型群体动态来了解 星形胶质细胞中的基本细胞生物信号系统对于大脑区域的功能至关重要 单胺能输入。 在目标 1 中，我们将使用双光子成像和光激活来探究细胞信号传导机制 前额皮质星形胶质细胞部署来感知跨皮质层的细胞外单胺动态。在 目标 2，我们将解码星形胶质细胞的变化机制，包括本质上的变化和其输出到 长期接触精神兴奋剂后的神经元群体。为了实现这些目标，我们将探讨 星形胶质细胞生理学在基线前额皮质功能中的作用以及作为模型中回路神经可塑性的中介 的成瘾。