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

去甲肾上腺素调节控制可卡因寻求行为的内侧前额皮质神经元

• 批准号: 10753074
• 负责人: Ali Gheidi
• 金额: $ 10.62万
• 依托单位: MERCER UNIVERSITY MACON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-12 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753074
• 关键词: Norepinephrine; modulates; medial; prefrontal; cortex

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.

项目摘要/摘要 该K01申请旨在通过提供Ali Gheidi博士来为独立教师职位做准备 药物自我管理模型（IVSA）的啮齿动物模型的专业培训，神经元的化学生成操纵 并有针对性的神经元合奏的缺失。因此，Gheidi博士将与精心选择的培训一起工作 导师团队。 Gheidi博士的培训将包括课程，与导师，讲习班，科学培训 会议和执行实验。 Gheidi博士的短期目标是了解去甲肾上腺素的作用 （NE）在控制可卡因行为中控制神经元合奏时。他的长期目标是获得独立 作为研究人员教育者的位置，他可以研究神经调节剂在确定神经元合奏中的作用 吸毒。 除了促进Gheidi博士的职业外，该建议还将增加对主题的理解 总体而言，特别是可卡因救济。在过去的十年中，发生了范式转变 神经生物学，包括在药物成瘾领域。在这些研究中，只有选择，分布和稀疏 被称为神经元合奏的一组神经元被认为是孤立的和研究了药物。 这种选择性方法为传统方法提供了新的见解，在该方法中，药物引起的扰动是 通常在整个大脑区域或细胞类型中研究。对此任务有帮助的是使用基于FOS的方法。 这些技术允许直接操纵FOS阳性神经元，并通过扩展神经元合奏， 不影响行为不涉及的相邻区域或细胞类型。例如，使用daun02 在此K01中，神经元消融方法，科学家在前额叶皮层中鉴定了神经元合成 对可卡因，海洛因，尼古丁和饮酒和寻求行为至关重要。然而， 从这种理解中缺少的是大脑神经调节剂（例如NE）在雕刻神经元中的贡献 合奏和引起药物服用的继电器。这是该赠款提案旨在阐明NE的作用 前额叶皮质神经元集合涉及可卡因，在女性和雌性大鼠中寻求行为。 拟议的研究将利用上述最新技术的状态。本K01提案的目标1 将确定NE在媒体前额叶皮层（MPFC）的合奏控制可卡因寻求的作用。目的 2将利用恐怖分来灭活含有NE的基因座的凝聚力项目，这些项目专门支配了该项目 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 在可卡因寻求情况下运作可以为临床和基础科学提供信息，并为临床护理提供信息。 结果还将为基础科学家提供有关学到的动机行为的神经元基础的信息，以及 研究人员还可以通过控制神经调节剂来制定临床策略，以靶向神经元合奏。 包括NE在内，在人的大脑中可以缓解可卡因使用的疾病。