Dissecting Monoaminergic Physiology of Prefrontal Cortical Astrocytes

项目总结 已知，动机行为，包括那些在物质使用障碍中改变的行为，是由 单胺能回路(包含释放多巴胺、5-羟色胺和去甲肾上腺素的神经元) 大脑区域。将这些电路从细胞级别分离到系统和行为级别几乎 仅限于研究神经元的生理学。然而，最近的数据表明，这种活动 一种非神经细胞类型--星形胶质细胞--可能会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对单胺类药物做出反应，并改变其对重复药物的生理反应 暴露几乎完全没有被研究过。目前的建议旨在解决我们在 通过揭示成瘾、单胺信号和多细胞类型的种群动力学 星形胶质细胞中的基本细胞生物信号系统，对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询问细胞信号机制 前额叶皮质星形胶质细胞通过皮层感知细胞外单胺的动态变化。在……里面 目标2，我们将破译星形胶质细胞改变的机制，包括间接改变和输出到 神经元群，在长期暴露于心理刺激剂后。带着这些目标，我们将探讨 基线前额叶皮质的星形胶质细胞生理学及其作为环路神经可塑性的介体 上瘾的人。

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.