DEFINING DYNORPHIN-CRF CIRCUITS IN STRESS AND NICOTINE BEHAVIORS

定义压力和尼古丁行为中的强啡肽-CRF 回路

• 批准号: 9021634
• 负责人: Ream Al-Hasani
• 金额: $ 14.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9021634
• 关键词: Adverse effects; Affective; Amygdaloid structure; Anxiety; Anxiety Disorders; Attention; Award; Behavior; Behavior Control; Behavioral Paradigm; Brain region; CRF receptor type 1; Cell Nucleus; Cells; Cessation of life; Characteristics; Chronic; Chronic stress; Corticotropin-Releasing Hormone; Data; Development; Drug Addiction; Drug abuse; Dynorphins; Exposure to; Goals; Health; Incidence; Intake; Internal Ribosome Entry Site; Knockout Mice; Lead; Learning; Link; Measures; Mediating; Mediation; Mediator of activation protein; Mental Depression; Mentors; Microdialysis; Modeling; Mus; Negative Reinforcements; Neurons; Neuropeptides; Neurosciences; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Opioid; Opioid Receptor; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Population; Process; Property; Receptor Activation; Regulation; Relapse; Research; Role; Serotonergic System; Signal Transduction; Site; Source; Stress; Substance Withdrawal Syndrome; System; Technical Expertise; Technology; Testing; Therapeutic; Tobacco use; Training; Wireless Technology; Withdrawal; Work; acute stress; anxiety-like behavior; behavioral pharmacology; behavioral response; biological adaptation to stress; cell type; cigarette smoking; driving behavior; drug abuse vulnerability; drug withdrawal; dysphoria; in vivo; insight; liquid chromatography mass spectrometry; multidisciplinary; negative emotional state; neural circuit; neurochemistry; novel; optical fiber; optogenetics; small molecule; smoking cessation; success; transmission process

DESCRIPTION (provided by applicant): The overall goal of this research is to better understand role of dynorphin and CRF in negative affective behaviors that are associated with nicotine withdrawal. Both dynorphin and CRF systems have been shown to drive stress and aversive behaviors but few studies have determined how these systems modulate one another to drive these behaviors through the extended amygdala. Dynorphin/Kappa Opioid Receptor (KOR) activity has been known to mediate negative emotional states inducing, dysphoria, aversions, and depression. CRF also produces dysphoria, aversion and anxiety-like behavior via dynorphinergic interactions, and it has been hypothesized that the increased release of CRF may be a primary contributor in the development of anxiety disorders. Therefore, we propose to examine the role and interactions of CRF and dynorphin in the mediation of aversive behaviors and whether this in turn modulates nicotine withdrawal. This five-year project has three specific aims. In the first aim (during the K99 phase) we will determine whether dynorphin regulates aversion in the ventral NAc. The second aim (during the K99 phase) is to examine the mechanisms in which nicotine interacts with the dynorphin/kappa opioid system to regulate negative affective behaviors. Here we will determine whether stimulation of dynorphin containing neurons in the NAc mediates aversion and withdrawal behavior and whether this is KOR-dependent. In these aims we will quantify dynorphin release in the NAc following optogenetic stimulation. During the R00 independent phase (Aim 3) we will quantify dynorphin release in the NAc before and following chronic nicotine exposure. We will also optogenetically stimulate CeA- CRF containing neurons and measure dynorphin release in the NAc, to examine whether CRF regulates dynorphin release and behavior characteristic of withdrawal. Since, both CRF and dynorphin are involved in the stress response and preliminary data has shown that chronic stress can block KOR-induced drug seeking, we will also determine the role of CRF1-R/KOR interactions in reinstatement of nicotine seeking, following exposure to stress. Together this work has important therapeutic implications as it will enhance our understanding of dynorphin/CRF cell-types, neural circuits that modulate negative affective behaviors.

描述（由申请人提供）：这项研究的总体目标是更好地了解与尼古丁戒断相关的负面情感行为中的dynorphin和CRF的作用。 Dynorphin和CRF系统均已证明可以驱动压力和厌恶行为，但是很少有研究决定了这些系统如何相互调节以通过扩展的杏仁核来驱动这些行为。众所周知，Dynorphin/Kappa阿片受体（KO）活性会介导负面的情绪状态，引起吞咽困难，厌恶和抑郁。 CRF还通过脑电图相互作用产生烦躁不安，厌恶和焦虑行为，并且已经假设CRF释放的增加可能是焦虑症发展的主要因素。因此，我们建议检查CRF和Dynorphin在厌恶行为的介导中的作用和相互作用，以及这是否又调节了尼古丁的戒断。这个五年的项目具有三个特定的目标。在第一个目标（在K99阶段）中，我们将确定dynorphin是否调节腹侧NAC中的厌恶。第二个目的（在K99阶段）是检查尼古丁与Dynorphin/Kappa阿片类系统相互作用以调节负面情感行为的机制。在这里，我们将确定刺激NAC中含有神经元的dynorphin是否介导了厌恶和戒断行为，以及这是否依赖于kor。在这些目标中，我们将在光遗传学刺激后量化NAC中的Dynorphin释放。在R00独立阶段（AIM 3），我们将在慢性尼古丁暴露之前和之后的NAC中量化Dynorphin释放。我们还将在NAC中刺激含有神经元的CEA-CRF，并测量NAC中的Dynorphin释放，以检查CRF是否调节dynorphin释放和戒断的行为特征。由于CRF和Dynorphin都参与了压力反应，因此初步数据表明，慢性应激可以阻止KOR诱导的药物寻求药物，因此我们还将确定CRF1-R/KOR相互作用在恢复尼古丁寻求尼古丁的作用，暴露于压力之后。这项工作共同具有重要的治疗意义，因为它将增强我们对Dynorphin/CRF细胞类型的理解，即调节负面情感行为的神经回路。

项目成果

Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum.

• DOI: 10.1038/s41467-018-04654-2
• 发表时间: 2018-07-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wolfman SL;Gill DF;Bogdanic F;Long K;Al-Hasani R;McCall JG;Bruchas MR;McGehee DS
• 通讯作者: McGehee DS

Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement.

• DOI: 10.1038/s41593-021-00898-2
• 发表时间: 2021-10
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Al-Hasani R;Gowrishankar R;Schmitz GP;Pedersen CE;Marcus DJ;Shirley SE;Hobbs TE;Elerding AJ;Renaud SJ;Jing M;Li Y;Alvarez VA;Lemos JC;Bruchas MR
• 通讯作者: Bruchas MR