Emerging Activity Dynamics and Noradrenergic Modulation of Prefrontal Neuronal Ensembles During Heroin Seeking

海洛因寻求过程中前额叶神经元群的新兴活动动态和去甲肾上腺素能调节

• 批准号: 10315748
• 负责人: Elizabeth Doncheck
• 金额: $ 6.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-07 至 2022-07-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315748
• 关键词: Behavior; Cells; Characteristics; Chronic; Clinical Research; Complex; Cues; Data; Development; Drug Controls; Drug usage; Exhibits; Exposure to; Extinction (Psychology); Future; Head; Heroin; Knowledge; Measures; Mediating; Mission; Monitor; Motivation; Mus; Neurons; Norepinephrine; Output; Pattern; Pharmaceutical Preparations; Predisposition; Prefrontal Cortex; Presynaptic Terminals; Procedures; Public Health; Publishing; Recurrent disease; Regulation; Relapse; Research; Resolution; Rewards; Self Administration; Stimulus; Substance Use Disorder; Testing; United States National Institutes of Health; Work; base; beta-adrenergic receptor; cell type; drug seeking behavior; effective therapy; excitatory neuron; executive function; experimental study; heroin use; in vivo; in vivo calcium imaging; in vivo two-photon imaging; insight; locus ceruleus structure; motivated behavior; neural circuit; neuronal excitability; neuropsychiatric disorder; neuroregulation; noradrenergic; novel; opioid use disorder; preclinical study; relating to nervous system; response; reward anticipation; reward processing; therapeutic development; therapy design; tool

PROJECT SUMMARY Opioid use disorder is a chronically relapsing disease characterized by compulsive drug seeking, but how precise neural circuits orchestrate these motivational states is unknown. This is in part due to a lack of experimental feasibility, as it has been difficult to control and monitor the activity of cell-type specific neurons in vivo. For example, development of functional hypoactivity in the dorsomedial prefrontal cortex (dmPFC) is a hallmark of substance use disorder that reliably predicts future relapse susceptibility, while re-exposure to drug-associated cues evokes robust dmPFC activity. However, how dynamic activity patterns in dmPFC neurons regulate drug seeking is unclear. Thus, the objective of this project is to use contemporary tools to study the precise activity dynamics and neurocircuitry that engages dmPFC for the control of drug seeking. Here I propose to identify the precise activity dynamics and noradrenergic modulation of dmPFC neurons for heroin-seeking behavior. Single-cell resolution of dmPFC neuronal activity dynamics will be identified using longitudinal in vivo two-photon calcium imaging in head-restrained mice undergoing heroin self-administration (Aim 1). Furthermore, as the rapid shifts in neuronal excitability observed during re-exposure to drug-associated cues may be mediated by noradrenaline, which is released in dmPFC by the locus coeruleus (LC), inhibitory chemogenetics will be used to determine the function of LC-dmPFC inputs on activity dynamics during cue- induced heroin seeking (Aim 2). Based on my preliminary data and published work by my sponsors and others, I hypothesize that cue-induced heroin-seeking reinstatement directly corresponds to excitatory activity reemergence in dmPFC ensembles (Aim 1) and that LC-dmPFC activation is necessary for both cue-induced reinstatement and reemergence of excitatory activity in dmPFC ensembles (Aim 2). These data would suggest heroin-seeking behavior is regulated by discrete activity dynamics in dmPFC neurons which are subject to noradrenergic regulation. Regardless of the results, the experiments proposed here will be the first to longitudinally track activity in single neurons from the onset of drug use to relapse. The studies will provide unprecedented insight into the characteristics and noradrenergic mechanisms of prefrontal excitatory neuronal ensemble dynamics during heroin seeking.

项目摘要 阿片类药物使用障碍是一种长期复发的疾病，其特征是寻求强迫性药物，但多么精确 神经回路协调这些动机状态是未知的。这部分是由于缺乏实验性 可行性，因为很难控制和监测体内细胞类型特定神经元的活性。为了 例如，在背额前额叶皮层（DMPFC）中的功能性不连贯性的发展是 可靠地预测未来复发易感性的药物使用障碍，同时重新暴露与药物相关 提示唤起强大的DMPFC活动。但是，DMPFC神经元中的动态活性模式如何调节药物 寻求不清楚。因此，该项目的目的是使用当代工具来研究精确的活动 与DMPFC一起控制药物的动力学和神经循环。 在这里，我建议确定DMPFC神经元的精确活性动力学和去甲肾上腺素能调节 寻求海洛因的行为。 DMPFC神经元活性动力学的单细胞分辨率将使用 纵向在体内双光子钙成像中的头壳小鼠进行海洛因自我管理 （目标1）。此外，随着在重新暴露与药物相关时观察到的神经元兴奋性的快速变化 提示可能是由去甲肾上腺素介导的，去甲肾上腺素是由dmpfc释放的，该基因座（LC），抑制作用 化学遗传学将用于确定提示过程中活性动力学的LC-DMPFC输入的功能 寻求海洛因（AIM 2）。根据我的初步数据和赞助商和其他人发表的工作， 我假设提示引起的海洛因寻求恢复直接对应于兴奋活动 DMPFC合奏中的重新出现（AIM 1）和LC-DMPFC激活对于两种提示诱导都是必要的 DMPFC合奏中兴奋活动的恢复和重新出现（AIM 2）。这些数据会暗示 寻求海洛因的行为受DMPFC神经元中离散活动动态的调节 去肾上腺素能调节。无论结果如何，这里提出的实验将是第一个 纵向跟踪药物使用开始中的单个神经元的活性。研究将提供 对额叶兴奋性的特征和去肾上腺素能机制的前所未有的见解 在寻求海洛因期间的神经元合奏动态。