Characteristics and Function of Prefrontal Astrocyte Activity in Heroin-Seeking Behavior

前额叶星形胶质细胞活性在海洛因寻求行为中的特征和作用

• 批准号: 10605367
• 负责人: Jacqueline Elizabeth Paniccia
• 金额: $ 6.91万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-11-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605367
• 关键词: Astrocytes; Automobile Driving; Behavior; Behavioral Paradigm; Calcium; Cells; Characteristics; Coupled; Cue-induced relapse; Cues; Data; Development; Dorsal; Drug usage; Environment; Event; Exposure to; Extinction; Genetic; Goals; Growth; Head; Heroin; Image; Individual; Knowledge; Label; Laboratories; Measurement; Measures; Medial; Membrane; Mentorship; Methods; Mus; Neuroglia; Neurons; Nucleus Accumbens; Patients; Pattern; Pharmaceutical Preparations; Population; Prefrontal Cortex; Publishing; Regulatory Element; Relapse; Research Personnel; Resolution; Saline; Self Administration; Stimulus; Technical Expertise; Testing; Training; Virus; Visualization; Work; behavioral outcome; calcium indicator; drug seeking behavior; excitatory neuron; experimental study; genetic approach; heroin use; in vivo; in vivo calcium imaging; in vivo two-photon imaging; interdisciplinary approach; neural circuit; neural network; neuromechanism; neuronal circuitry; novel; novel therapeutic intervention; opioid epidemic; opioid use disorder; receptor; response; restraint; tool; training opportunity; two photon microscopy; two-photon

Project summary/Abstract With the current opioid epidemic at a national crisis level, understanding the neural mechanisms governing heroin use and relapse to drug seeking is key to discovering new treatment strategies. Exposure to stimuli previously paired with the euphoric effects of heroin are thought to maintain habitual heroin use and seeking behaviors. These heroin-conditioned effects therefore extend the negative consequences of drug use well past cessation. Dysregulation of the dorsal medial prefrontal cortex (dmPFC) is a driving factor in habitual heroin use and cue-induced relapse, yet how discrete neural network components orchestrate heroin-seeking behavior remains less clear. Using a novel head-fixed self-administration (SA) mouse behavioral paradigm and simultaneous two-photon calcium imaging, recent data from our laboratory indicates unique excitatory neuronal ensembles emerge and encode information related to heroin-conditioned cues and heroin-seeking behaviors. Astrocytes are key regulatory elements in neuronal circuits and glial calcium events are necessary for modulating neuronal network activity. However, how dmPFC astrocytes contribute to neuronal encoding of heroin-related cues and heroin-seeking behaviors remains unknown. The goal of the current project is to investigate that dmPFC astrocytes (1) are engaged throughout heroin use and (2) causally influence surrounding neuronal ensemble dynamics and relapse behaviors. To this end, we will use a combination of contemporary strategies, including in vivo two-photon imaging and chemogenetic tools, to measure and manipulate dmPFC cellular activity during heroin use and relapse. The current proposal will be the first to measure astrocytic calcium dynamics throughout habitual heroin use and relapse and determine the causal influence of astrocytic activity on neuronal encoding and heroin-seeking behavior. I propose to use a multi-virus approach and in vivo two-photon microscopy to visualize and track individual astrocytic calcium events throughout heroin-SA, extinction, and reinstatement in head-fixed mice (Aim 1). Subsequently, I will employ two-photon imaging coupled with head-fixed heroin-SA to measure and track neuronal activity with single-cell resolution. I will then stimulate an astrocyte-specific hM4D(Gi) designer receptor during relapse and assess the consequence for neuronal ensemble activity and heroin-seeking behavior (Aim 2). Based on my preliminary data and published work of my mentorship team, I hypothesize that dmPFC astrocytes display biased activation during the onset of heroin use and reinstatement of heroin seeking (Aim 1) and that astrocytic calcium events directly coordinates surrounding neuronal network dynamics and relapse behavior (Aim 2). These data would provide a wholistic view of how dmPFC network activity orchestrates habitual heroin use and seeking behavior. The current proposal is the first to track astrocytic activity throughout drug use and causally implicate glia in the neuronal encoding of drug-conditioned cues and relapse behavior.

项目概要/摘要 当前阿片类药物流行已达到国家危机级别，了解控制神经机制 海洛因使用和重新吸毒是发现新治疗策略的关键。暴露于刺激 以前与海洛因的欣快作用相结合被认为可以维持海洛因的习惯性使用和寻求 行为。因此，这些海洛因条件作用使吸毒的负面后果远远超出了过去 停止。背侧内侧前额叶皮层 (dmPFC) 失调是习惯性使用海洛因的驱动因素 和线索诱发的复发，但离散的神经网络组件如何协调海洛因寻求行为 仍然不太清楚。使用新颖的头部固定自我管理（SA）小鼠行为范例和 同时双光子钙成像，我们实验室的最新数据表明独特的兴奋性神经元 集合出现并编码与海洛因条件暗示和海洛因寻求行为相关的信息。 星形胶质细胞是神经元回路中的关键调节元件，神经胶质钙事件对于调节是必要的 神经元网络活动。然而，dmPFC 星形胶质细胞如何参与海洛因相关的神经元编码 线索和寻求海洛因的行为仍然未知。当前项目的目标是调查 dmPFC 星形胶质细胞 (1) 在海洛因使用过程中发挥作用，(2) 对周围神经元产生因果影响 整体动力学和复发行为。为此，我们将结合当代的策略， 包括体内双光子成像和化学遗传学工具，用于测量和操纵 dmPFC 细胞活性 在海洛因使用和复发期间。 目前的提案将是第一个测量习惯性海洛因使用过程中星形胶质细胞钙动态的提案， 复发并确定星形胶质细胞活动对神经元编码和海洛因寻求的因果影响 行为。我建议使用多病毒方法和体内双光子显微镜来可视化和跟踪 头部固定小鼠中海洛因-SA、灭绝和恢复过程中的个体星形细胞钙事件（Aim 1）。随后，我将采用双光子成像结合头部固定海洛因-SA来测量和跟踪 具有单细胞分辨率的神经元活动。然后我将刺激星形胶质细胞特异性 hM4D(Gi) 设计受体 在复发期间评估神经元群活动和海洛因寻求行为的后果（目标 2）。根据我的初步数据和我的指导团队已发表的工作，我假设 dmPFC 在海洛因使用开始和海洛因恢复恢复期间星形胶质细胞表现出偏向激活（目标 1） 星形细胞钙事件直接协调周围神经元网络动态和复发 行为（目标 2）。这些数据将提供 dmPFC 网络活动如何协调的整体视图 习惯性使用海洛因和寻求行为。当前的提案是第一个全程跟踪星形胶质细胞活动的提案 药物使用并因果关系神经胶质细胞参与药物调节线索和复发行为的神经元编码。