Involvement of habenulo-interpeduncular circuitry in nicotine reward and aversion

缰核-脚间回路参与尼古丁奖赏和厌恶

• 批准号: 10579841
• 负责人: Timothy Glenn Freels
• 金额: $ 7.38万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2025-01-19
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579841
• 关键词: Acetylcholine; Adult; Affect; Affective; Animal Model; Animals; Antismoking; Attenuated; Automobile Driving; Behavior; Behavioral; Biological Assay; Brain; Calcium; Cessation of life; Cholinergic Receptors; Data; Development; Dopamine; Dose; Equilibrium; FOS gene; Fiber; Glutamates; Goals; Habenula; Health; Human; Measures; Medial; Modeling; Modernization; Motivation; Mus; Neurons; Neurosciences; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Pathway interactions; Performance; Pharmacological Treatment; Pharmacotherapy; Photometry; Play; Population; Procedures; Property; Proxy; Psychological reinforcement; Reporting; Research; Rewards; Rodent Model; Role; Smoking; Smoking Cessation Intervention; Smoking treatment; Symptoms; System; Testing; Tobacco; Ventral Tegmental Area; Withdrawal Symptom; addiction liability; behavioral study; calcium indicator; conditioned place preference; gamma-Aminobutyric Acid; in vivo; insight; interpeduncular nucleus; neural; neuromechanism; neurophysiology; nicotine exposure; nicotine reward; nicotine seeking behavior; nicotine treatment; nicotine use; novel; optogenetics; pharmacologic; prevent; preventable death; response; reward circuitry; sensor; smoking cessation

Project Summary/Abstract Smoking tobacco is one of the leading causes of preventable mortality in adults worldwide. However, there is currently a lack of pharmacological smoking cessation aids and their efficacy is limited. Therefore, there is an urgent need to better understand the neural mechanisms that underlie nicotine addiction for the development of novel smoking cessation treatments. Much of our understanding of the reinforcing effects of nicotine are derived from studies focused on canonical mesolimbic dopamine reward circuitry in the brain. Research suggests that the habenulo-interpeduncular pathway consisting of the medial habenula (MHb) and interpeduncular nucleus (IPN) contributes to the aversive motivational properties of high nicotine doses. It is speculated that activation of nicotinic cholinergic receptors (nAChRs) stimulates excitatory acetylcholine/glutamate (ACh/Glu) co-releasing projection neurons which activate ɣ-aminobutyric acid (GABA) neurons in the IPN. However, silencing IPN neurons in rodent models has also been shown to reduce nicotine consumption and reward. Thus, it is possible that modulation of MHb→IPN circuit activity may contribute to the balance of nicotine reward and aversion, a critical component of nicotine addiction liability. However, it is unknown how MHb→IPN neurons respond to nicotine within the context of reward related behavior. It is also unclear whether nicotine-induced activation of this circuit is necessary to elicit nicotine’s aversive properties. In the proposed project, I aim to test the hypothesis that modulation of IPN GABAergic neuron activity by nicotine is critical for balancing nicotine reward/aversion. I also aim to test the hypothesis that nicotine-induced control of ACh/Glu projection neuron activity from the MHb to IPN controls nicotine reward/aversion balance. Thus, I will assess the influence of rewarding or aversive nicotine doses on MHb or IPN neural activity during the performance of conditioned place preference/conditioned place aversion (CPP/CPA) procedures using in vivo fiber photometry combined with genetically encoded calcium indicators (GCaMPs). Finally, I will use in vivo optogenetics to selectively activate or silence MHb or IPN neurons to investigate whether specific components of this circuit are sufficient to drive nicotine reward/aversion balance. The goal of this project is to provide a better understanding of circuit-specific mechanisms that may contribute to nicotine reward/aversion balance, which will aid in the development of precise pharmacological treatments for smoking cessation.

项目总结/摘要 吸烟是全世界成年人可预防死亡的主要原因之一。不过有 目前缺乏药物戒烟辅助剂，并且它们的功效有限。因此，有一个 迫切需要更好地了解尼古丁成瘾的神经机制， 新的戒烟治疗。我们对尼古丁强化作用的理解， 来自于对大脑中典型的中脑边缘多巴胺奖赏回路的研究。研究表明 由内侧缰核和脚间核组成的缰-脚间通路 (IPN)有助于高剂量尼古丁的厌恶性动机特性。据推测， 烟碱胆碱能受体（nAChRs）刺激兴奋性乙酰胆碱/谷氨酸（ACh/Glu）共释放 投射神经元，其激活IPN中的γ-氨基丁酸（GABA）神经元。然而，沉默IPN 啮齿动物模型中的神经元也显示出减少尼古丁消耗和奖励。因此能够 MHb→IPN回路活动的调节可能有助于尼古丁奖赏和厌恶的平衡， 尼古丁成瘾倾向的重要组成部分。然而，尚不清楚MHb→IPN神经元如何响应 尼古丁与奖赏相关行为的关系目前还不清楚尼古丁诱导的细胞活化是否 这个回路是引起尼古丁厌恶性的必要条件。在提议的项目中，我的目标是测试假设 尼古丁对IPN GABA能神经元活性的调节对于平衡尼古丁奖赏/厌恶是至关重要的。我 本研究还旨在验证尼古丁诱导的MHb对ACh/Glu投射神经元活动的控制 IPN控制尼古丁奖赏/厌恶平衡。因此，我将评估奖励或厌恶的影响 尼古丁剂量对条件性位置偏爱/条件性位置偏爱过程中MHb或IPN神经活动的影响 使用体内纤维光度法结合遗传编码钙的位置厌恶（CPP/CPA）程序 指标（GCaMP）。最后，我将使用体内光遗传学选择性地激活或沉默MHb或IPN神经元 研究该回路的特定成分是否足以驱动尼古丁奖赏/厌恶平衡。 这个项目的目标是提供一个更好的理解电路的具体机制，可能有助于 尼古丁奖励/厌恶平衡，这将有助于开发精确的药物治疗方法， 戒烟。