Norepinephrine modulates medial prefrontal cortex neural ensembles that control cocaine seeking behavior

项目概要/摘要 此K 01应用程序的目的是准备博士阿里Gheidi为一个独立的教师职位，提供 在啮齿动物模型的药物自我管理（IVSA），神经元的化学操作的专门培训 和神经元集合的靶向缺失。因此，盖迪博士将与精心挑选的培训 导师团队。对盖迪博士的培训将包括课程、与导师会晤、讲习班、科学研究、 会议和实验。盖迪博士的短期目标是了解去甲肾上腺素的作用 (NE)在调节可卡因寻求行为的神经元集合中的作用。他的长期目标是获得独立的 作为一名研究教育工作者，他可以研究神经调质在调节神经元集合中的作用 到吸毒 除了推动盖迪博士的事业外，这项建议还将增进对实质性问题的理解， 滥用，特别是可卡因复吸。在过去十年中， 神经生物学，包括药物成瘾领域。在这些研究中，只有一个选择，分布，和稀疏的， 一组神经元，被称为神经元系综，被认为是编码药物服用事件的神经元被分离和研究。 这种选择性的方法提供了新的见解，传统的方法，其中药物引起的扰动是 通常在整个大脑区域或细胞类型中进行研究。这项任务的工具是使用基于Fos的方法。 这些技术允许直接操纵Fos阳性神经元，并通过扩展神经元集合， 而不影响不参与该行为的相邻区域或细胞类型。例如，使用Daun 02 神经元消融方法在这个K 01中，科学家们已经确定了前额叶皮层中的神经元集合， 对可卡因、海洛因、尼古丁和酒精的服用和寻求行为至关重要。然而，在这方面， 这种理解中缺少的是大脑神经调质的贡献（例如，NE）在塑造神经元 合奏和诱导吸毒复吸。因此，这项拨款建议旨在阐明东北大学在 雌性和雄性大鼠前额叶皮质神经元群参与可卡因寻求行为 拟议的研究将利用上述最先进的技术。本K 01提案的目标1 将确定NE在内侧前额叶皮层（mPFC）合奏控制可卡因寻求的作用。目的 2将利用DREADDs来抑制含有NE的蓝斑投射，该投射特异性地支配 mPFC进一步探索NE在可卡因寻求中的作用。更好地理解这些过程 在寻求可卡因的情况下进行手术可以为临床和基础科学以及临床护理提供信息。 研究结果还将为基础科学家提供有关学习动机行为的神经基础的信息， 研究人员还可以设计通过控制神经调质来靶向神经元集合的临床策略， 包括NE，在人类大脑中，可以缓解导致可卡因使用复发的条件。

PROJECT SUMMARY/ABSTRACT This K01 application aims to prepare Dr. Ali Gheidi for an independent faculty position by providing specialized training in rodent models of drug self-administration (IVSA), chemogenic manipulation of neurons and targeted deletion of neuronal ensembles. Therefore, Dr. Gheidi will work with a carefully selected Training Team of mentors. Training for Dr. Gheidi will consist of courses, meeting with mentors, workshops, scientific meetings, and performing experiments. Dr. Gheidi’s short term goal is to understand the role of norepinephrine (NE) in regulating neuronal ensembles in cocaine seeking behavior. His long-term goal is to gain an independent position as a researcher-educator, where he can study neuromodulators' role in regulating neuronal ensembles to drug abuse. In addition to advancing the career of Dr. Gheidi, this proposal will increase understanding of substance abuse, in general, and cocaine relapse, in particular. Over the past decade, a paradigm shift has occurred in neurobiology, including within the field of drug addiction. In these studies, only a select, distributed, and a sparse group of neurons, known as a neuronal ensemble, thought to code drug taking events is isolated and studied. This selective approach offers new insights over traditional methods, where drug-induced perturbations are usually studied in the whole brain area or cell type. Instrumental to this task is the use of Fos based approaches. These techniques allow the direct manipulation of Fos positive neurons, and by extension neuronal ensembles, without affecting adjacent areas or cell types not involved in the behavior. For example, using the Daun02 neuronal ablation method in this K01, scientists have identified neuronal ensembles in the prefrontal cortex and nucleus accumbens critical to cocaine, heroin, nicotine, and alcohol taking and seeking behaviors. However, missing from this understanding is the contribution of the brain's neuromodulators (e.g., NE) in sculpting neuronal ensembles and inducing relapse to drug taking. Thus, this grant proposal aims to elucidate the role of NE on prefrontal cortical neuronal ensembles involved in cocaine seeking behaviors in female and male rats. The proposed research will utilize state of the art techniques mentioned above. Aim 1 of this K01 proposal will determine the role of NE in the medial prefrontal cortex (mPFC) ensembles control of cocaine seeking. Aim 2 will utilize DREADDs to inactivate the NE-containing locus coeruleus projections that specifically innervate the mPFC to further explore the role of NE in cocaine seeking. A better understanding of how these processes operate in cocaine seeking situations can inform both clinical and basic science as well as inform clinical care. Results will also inform basic scientists on the neuronal underpinnings of learned motivated behaviors, and researchers may also devise clinical strategies to target neuronal ensembles by controlling neuromodulators, including NE, in the human brain that can ease conditions that lead to relapse of cocaine use.