Involvement of habenulo-interpeduncular circuitry in nicotine reward and aversion

项目摘要/摘要 吸烟是全世界成年人可预防死亡的主要原因之一。然而，还有 目前缺乏药物戒烟辅助剂，其疗效有限。因此，有一个 迫切需要更好地了解尼古丁成瘾的神经机制，以促进 新型戒烟疗法。我们对尼古丁增强作用的大部分理解都源于 来自于专注于大脑中脑中缘多巴胺奖励回路的研究。研究表明， 缰核-脚间通路由内侧缰核和脚间核组成 (IPN)有助于高剂量尼古丁的厌恶动机特性。据推测，激活了 烟碱胆碱能受体(NAChRs)刺激兴奋性乙酰胆碱/谷氨酸(ACh/Glu)共同释放 激活孤束核内ɣ-氨基丁酸神经元的投射神经元。但是，禁用IPN 啮齿动物模型中的神经元也被证明可以减少尼古丁的消耗和奖励。因此，这是可能的 MHb→IPN环路活性的调节可能有助于尼古丁奖赏和厌恶的平衡，a 尼古丁成瘾倾向的关键组成部分。然而，目前尚不清楚MHb→ipn神经元对 尼古丁在奖赏相关行为的背景下。目前也不清楚尼古丁是否会诱导脑细胞的激活 这一环路对于诱导尼古丁的反作用力是必要的。在提议的项目中，我的目标是检验假设 尼古丁对IPN GABA能神经元活动的调节是平衡尼古丁奖赏/厌恶的关键。我 此外，还旨在验证尼古丁诱导MHb对ACh/Glu投射神经元活动的控制的假设 TO 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/条件性位置偏爱表现中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，我将使用活体光遗传学来选择性地激活或沉默MHB或IPN神经元 为了研究这个回路的特定成分是否足以驱动尼古丁奖赏/厌恶平衡。 本项目的目标是更好地了解可能有助于 尼古丁奖赏/厌恶的平衡，这将有助于开发精确的药物治疗 戒烟。

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.