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.

项目摘要/摘要 在目前阿片类药物流行处于国家危机水平的情况下，了解支配 海洛因的使用和吸毒复发是发现新的治疗策略的关键。暴露在刺激下 以前与海洛因的愉悦作用相结合，被认为保持了习惯性的海洛因使用和寻找 行为。因此，这些海洛因的条件性影响将毒品使用的负面后果延续了很久。 停止。背侧内侧前额叶皮质(DmPFC)调节失调是习惯性吸食海洛因的驱动因素 以及线索诱导的复吸，然而离散的神经网络组件如何协调海洛因寻找行为 目前还不太清楚。使用一种新的头部固定自我给药(SA)小鼠行为范式，并 同时双光子钙成像，来自我们实验室的最新数据显示独特的兴奋性神经元 组合出现并编码与海洛因条件线索和海洛因寻找行为相关的信息。 星形胶质细胞是神经元回路中的关键调节元件，而胶质细胞钙事件是调制所必需的 神经网络活动。然而，dmPFC星形胶质细胞如何参与海洛因相关的神经元编码 线索和寻找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)参与海洛因的整个使用和(2)对周围神经元的因果影响 合奏动力学与复发行为。为此，我们将使用当代战略的组合， 包括体内双光子成像和化学发生工具，以测量和操作dmPFC细胞活性 在海洛因使用和复发期间。 目前的提议将是第一次测量海洛因习惯性使用过程中星形胶质细胞钙动力学和 复发并确定星形胶质细胞活动对神经元编码和寻求海洛因的因果影响 行为。我建议使用多病毒方法和活体双光子显微镜来可视化和跟踪 头部固定小鼠海洛因依赖、消退和恢复过程中的单个星形胶质细胞钙事件(目的 1)。随后，我将采用双光子成像与头部固定海洛因-SA相结合的方法进行测量和跟踪 神经元活动与单细胞分辨率。然后我将刺激星形胶质细胞特异性的hM4D(GI)设计者受体 在复吸过程中并评估其对神经元群活动和寻求海洛因行为的影响(目的 2)。根据我的初步数据和我的指导团队发表的工作，我假设dmPFC 星形胶质细胞在海洛因开始使用和恢复寻求期间显示偏向激活(目标1) 星形细胞钙事件直接协调周围神经元网络动力学和复发 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 海洛因的习惯性使用和寻觅行为。目前的方案是第一个在整个过程中跟踪星形细胞活动的方案。 药物使用和因果关系表明，神经胶质细胞参与药物条件线索和复发行为的神经元编码。