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.

项目概要/摘要 压力是成瘾的危险因素，也是戒毒者复吸的危险因素。超过 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得最充分的区域对于成瘾的行为反应也至关重要 压力表明压力和成瘾之间存在相互作用。最近的研究表明，内侧 缰核-脚间 (MHb-IPN) 轴是滥用药物病理生理学中的重要回路， 尤其是尼古丁。具体来说，该电路控制啮齿动物模型中的尼古丁摄入量，同时还调节 高剂量尼古丁的急性厌恶作用。此外，IPN 还被认为是一个重要的枢纽。 用于尼古丁戒断期间的焦虑。具体而言，应激神经肽 CRF 被释放并激活 IPN 中的 CRF1 受体引发焦虑，表明 IPN 是下丘脑外神经的一个组成部分 大脑中的压力网络。然而，IPN 如何响应体内压力以及 IPN 是否/如何发挥作用 压力引起的行为尚不清楚。因此，本应用的目标是检验 IPN 的假设： 压力反应性大脑区域和压力诱发行为失调的关键调节因素 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 将 GCaMP 表达与光纤光度测定和光遗传学相结合，测试 IPN 是否受应激激活 GABA 能神经元对于压力诱发的行为至关重要。目标 2 还将 GCaMP 表达与 纤维光度测定法并测试尼古丁调节 IPN 中对压力的反应以驱动的假设 复发。最后，目标 3 将检验压力源通过激活 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。预计阐明电路和神经元 未充分研究的大脑区域中压力诱发行为的潜在机制，该区域正在成为关键的区域 尼古丁依赖节点应该能够深入了解与成瘾相关的行为，并设定 为新疗法的治疗策略奠定基础。