Interpeduncular circuitry in stress-responsive behaviors and nicotine dependence

应激反应行为和尼古丁依赖的脚间回路

• 批准号: 10539997
• 负责人: ANDREW R TAPPER
• 金额: $ 47.2万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539997
• 关键词: Acute; Animal Model; Anxiety; Area; Behavior; Behavioral; Brain; Brain region; Buffers; CRF receptor type 1; Calcium Signaling; Chronic; Data; Development; Dorsal; Dose; Drug Addiction; Drug abuse; Drug user; Extinction (Psychology); Fiber; Foundations; Functional disorder; Goals; Instinct; Intake; Lateral; Link; Measures; Medial; Mediating; Mediator of activation protein; Midbrain structure; Monitor; Mus; Neurons; Neuropeptides; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Opsin; Pathway interactions; Pharmaceutical Preparations; Photometry; Population; Proxy; Publishing; Regulation; Relapse; Risk Factors; Rodent Model; Shapes; Smoking; Somatostatin; Stimulus; Stress; Stress Tests; Stressful Event; Tegmentum Mesencephali; Testing; Ventral Tegmental Area; Withdrawal; Work; acute stress; addiction; anxiety-like behavior; avoidance behavior; base; behavioral response; biological adaptation to stress; conditioned place preference; dopaminergic neuron; drug development; drug of abuse; experimental study; in vivo; insight; interpeduncular nucleus; laterodorsal tegmentum; negative affect; neurotransmission; novel; novel therapeutic intervention; optogenetics; preference; relapse risk; response; restraint; reward circuitry; selective expression; sensor; single cell sequencing; stressor; vaping nicotine

Project Summary/Abstract Stress is a risk factor for the development of addiction, as well as for relapse in abstinent drug users. Over recent years, it is becoming increasingly clear that dopaminergic circuitry originating in the ventral tegmental area, which is the most well studied in the context of addiction, is also critical for the behavioral response to stress suggesting an interaction between stress and addiction. Recent studies have determined that the medial habenulo-interpeduncular (MHb-IPN) axis is an essential circuit in the pathophysiology of drugs of abuse, especially nicotine. Specifically, this circuit controls nicotine intake in rodent models, while also mediating the acute aversive effects of high doses of nicotine. In addition, the IPN has been implicated as an important hub for anxiety during nicotine withdrawal. Specifically, the stress neuropeptide, CRF is released and activates CRF1 receptors in the IPN triggering anxiety suggesting that the IPN is a component of the extrahypothalamic stress network in the brain. However, how the IPN responds to stress in vivo and if/how the IPN may contribute stress-induced behaviors is unknown. Thus, the goal of this application is to test the hypothesis that the IPN is a stress-responsive brain area and a critical mediator of stress-induced behaviors that becomes dysregulated in nicotine-dependence to drive stress effects on nicotine dependence-associated behaviors. In Aim 1, we will combine GCaMP expression with fiber photometry and optogenetics to test if stress-activation of IPN GABAergic neurons is critical for stress-induced behaviors. Aim 2 will also combine GCaMP expression with fiber photometry and test the hypothesis that nicotine dysregulates the response to stress in the IPN to drive relapse. Finally, Aim 3 will test the hypothesis that stressors engage dopaminergic pathways by activating IPN neurons that project to the lateral dorsal tegmentum. It is anticipated that elucidating circuitry and neuronal mechanisms underlying stress-induced behaviors in an understudied brain region that is emerging as a critical node for nicotine dependence should yield great insights into behaviors associated with addiction and set the foundation for therapeutic strategies for new treatment.

项目摘要/摘要 压力是成瘾的风险因素，也是戒毒者复发的风险因素。完毕 近年来，越来越清楚的是，起源于腹侧被盖的多巴胺能回路 在成瘾的背景下研究最充分的区域，也是对行为反应的关键 压力意味着压力和毒瘾之间的相互作用。最近的研究已经确定，内侧的 缰核-脚间轴(MHB-IPN)是药物滥用病理生理学中的重要环路， 尤其是尼古丁。具体地说，这个回路控制啮齿动物模型中尼古丁的摄入量，同时也调节 高剂量尼古丁的急性不良反应。此外，IPN还被认为是一个重要的枢纽 尼古丁戒断时的焦虑症。具体地说，应激神经肽CRF被释放并激活 孤束核CRF1受体触发焦虑提示孤束核是下丘脑外区的组成部分 大脑中的压力网络。然而，IPN如何在体内对压力做出反应以及IPN是否/如何做出贡献 应激诱导的行为是未知的。因此，此应用程序的目标是测试IPN是 应激反应脑区和应激诱导行为的关键中介变得失调 在尼古丁依赖中驱动压力对尼古丁依赖相关行为的影响。在目标1中，我们将 GCaMP表达与纤维光度和光遗传学相结合检测IPN应激激活 GABA能神经元是应激诱导行为的关键。AIM 2还将GCaMP的表达与 纤维光度测定法和检验尼古丁失调应激反应的假说在IPN驱动 旧病复发。最后，目标3将测试应激源通过激活IPN参与多巴胺能通路的假设 投射到外侧背侧被盖的神经元。据预计，阐明电路和神经元 在一个研究不足的大脑区域中，压力诱导行为的潜在机制正在成为一个关键的 尼古丁依赖的节点应该对与成瘾相关的行为有很好的洞察力，并设置 为新疗法的治疗策略奠定基础。