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.

项目概要 阿片类药物使用障碍是一种慢性复发性疾病，其特征是强迫性寻求药物，但精确度如何 协调这些动机状态的神经回路尚不清楚。这部分是由于缺乏实验 可行性，因为很难控制和监测体内细胞类型特异性神经元的活动。为了 例如，背内侧前额皮质 (dmPFC) 功能减退的发展是 药物滥用障碍可以可靠地预测未来的复发易感性，同时重新暴露于与药物相关的药物 线索会引起强烈的 dmPFC 活动。然而，dmPFC 神经元的动态活动模式如何调节药物 寻求不清楚。因此，该项目的目标是使用当代工具来研究精确的活动 dmPFC 参与药物寻找控制的动力学和神经回路。 在这里，我建议确定 dmPFC 神经元的精确活动动力学和去甲肾上腺素能调节 寻求海洛因的行为。 dmPFC 神经元活动动力学的单细胞分辨率将使用 接受海洛因自我给药的头部受限小鼠的纵向体内双光子钙成像 （目标 1）。此外，由于在重新暴露于与药物相关的过程中观察到神经元兴奋性的快速变化， 线索可能是由去甲肾上腺素介导的，去甲肾上腺素是由蓝斑 (LC) 在 dmPFC 中释放的，具有抑制作用 化学遗传学将用于确定 LC-dmPFC 输入对提示期间活动动态的功能 诱导海洛因寻找（目标 2）。根据我的初步数据以及我的赞助商和其他人发表的工作， 我假设提示诱导的海洛因寻求恢复直接对应于兴奋性活动 dmPFC 整体中的重新出现（目标 1），并且 LC-dmPFC 激活对于提示诱导的两者都是必要的 dmPFC 整体兴奋性活动的恢复和重新出现（目标 2）。这些数据表明 海洛因寻求行为受到 dmPFC 神经元离散活动动态的调节，这些神经元受 去甲肾上腺素能调节。不管结果如何，这里提出的实验将是第一个 纵向跟踪单个神经元从吸毒开始到复发的活动。研究将提供 对前额叶兴奋性特征和去甲肾上腺素能机制的前所未有的洞察 海洛因寻找过程中的神经元群动态。