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

项目摘要/摘要 此K01应用程序旨在通过以下方式为Ali Gheidi博士担任独立教职做好准备 专门训练啮齿动物的药物自我给药(IVSA)模型，神经元的化学操作 以及有针对性地删除神经元组。因此，盖迪博士将与精心挑选的培训一起工作 导师团队。Gheidi博士的培训将包括课程、与导师的会议、研讨会、科学 开会，做实验。盖迪博士的短期目标是了解去甲肾上腺素的作用 (Ne)调节可卡因寻找行为的神经细胞群。他的长期目标是获得一个独立的 作为一名研究人员兼教育家，他可以研究神经调节剂在调节神经元群中的作用 与吸毒有关。 除了推进盖迪博士的事业外，这项提议还将增加对实质内容的理解 总体来说，滥用，特别是可卡因复发。在过去的十年中，范式发生了转变 神经生物学，包括吸毒成瘾领域。在这些研究中，只有精选的、分布式的和稀疏的 分离和研究了一组神经元，被称为神经元集合，被认为是编码吸毒事件的。 这种选择性的方法提供了与传统方法相比的新见解，在传统方法中，药物诱导的扰动是 通常研究的是整个脑区或细胞类型。这项任务的重要手段是使用基于FOS的方法。 这些技术允许直接操作Fos阳性神经元，进而扩展到神经元集合， 而不影响与该行为无关的邻近区域或细胞类型。例如，使用Daun02 神经元消融方法在K01中，科学家们已经确定了前额叶皮质和 伏隔核对可卡因、海洛因、尼古丁和酒精的摄取和寻找行为至关重要。然而， 这种理解缺失了大脑的神经调节剂(如去甲肾上腺素)在塑造神经元中的作用 合奏和诱导吸毒复发。因此，这项赠款提案旨在阐明NE在 雌性和雄性大鼠的前额叶皮质神经元团参与寻找可卡因的行为。 拟议的研究将利用上述最先进的技术。本K01提案的目标1 将确定NE在内侧前额叶皮质(MPFC)控制可卡因寻找的整体中的作用。目标 2将利用DREADDS来灭活含有NE的蓝斑投射，该投射特异性地支配 MPFC进一步探讨NE在可卡因寻找中的作用。更好地理解这些过程是如何 在寻找可卡因的情况下运作可以为临床和基础科学提供信息，也可以为临床护理提供信息。 研究结果还将让基础科学家了解习得动机行为的神经元基础，以及 研究人员还可以设计临床策略，通过控制神经调节剂来靶向神经元群， 包括人类大脑中的NE，可以缓解导致复发的可卡因使用条件。

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.