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.

项目概要/摘要 此 K01 申请旨在通过提供以下内容为 Ali Gheidi 博士担任独立教职职位做好准备： 啮齿类动物药物自我给药模型（IVSA）、神经元化学操作的专门培训 并有针对性地删除神经元群。因此，Gheidi 博士将与精心挑选的培训一起工作 导师团队。盖迪博士的培训将包括课程、与导师会面、研讨会、科学 开会、做实验。 Gheidi 博士的短期目标是了解去甲肾上腺素的作用 （NE）调节可卡因寻求行为中的神经元群。他的长期目标是获得独立 作为一名研究教育者，他可以研究神经调节剂在调节神经元整体中的作用 滥用药物。 除了推进盖迪博士的职业生涯外，该提案还将增加对实质内容的理解 一般而言，滥用，特别是可卡因复发。在过去的十年里，范式发生了转变 神经生物学，包括毒瘾领域。在这些研究中，只有选择的、分布式的和稀疏的 一组被称为神经元集合的神经元被分离和研究，它们被认为编码吸毒事件。 这种选择性方法提供了相对于传统方法的新见解，在传统方法中，药物引起的扰动是 通常在整个大脑区域或细胞类型中进行研究。使用基于 Fos 的方法有助于完成此任务。 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， 不影响邻近区域或不参与行为的细胞类型。例如，使用 Daun02 在这个 K01 的神经元消融方法中，科学家们已经确定了前额皮质中的神经元群 伏隔核对可卡因、海洛因、尼古丁以及酒精的吸食和寻求行为至关重要。然而， 这种理解中缺少的是大脑的神经调节剂（例如，NE）在塑造神经元中的贡献 合奏并诱发吸毒复发。因此，本拨款提案旨在阐明 NE 在 前额皮质神经元群参与雌性和雄性大鼠的可卡因寻找行为。 拟议的研究将利用上述最先进的技术。 K01 提案的目标 1 将决定 NE 在内侧前额皮质 (mPFC) 整体控制可卡因寻求中的作用。目的 2 将利用 DREADD 来灭活含有 NE 的蓝斑投射，该投射专门支配 mPFC 进一步探讨 NE 在可卡因寻求中的作用。更好地理解这些过程是如何进行的 在寻找可卡因的情况下进行操作可以为临床和基础科学以及临床护理提供信息。 结果还将为基础科学家提供有关习得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设计针对神经元群的临床策略， 包括人脑中的 NE，可以缓解导致可卡因复发的情况。