Serotonin receptor signaling in the interpeduncular nucleus and nicotine withdrawal

项目摘要/摘要 虽然吸烟对健康的不利影响使其成为可预防的死亡的主要原因 世界上，目前的戒烟疗法效果微乎其微，这突显了更好的戒烟方法的必要性 了解尼古丁成瘾的病理生理学基础。最近的研究发现了一种 未被研究的回路，缰核-脚间核(HB-IPN)轴，作为尼古丁的关键回路 戒断症状。特别是，在尼古丁戒断小鼠模型中，IPN内的神经元 表现出活动增加会引发躯体(身体)戒断症状以及情绪性戒断症状 症状包括焦虑增加。尽管对神经递质的输入和释放知之甚少 先前的工作和初步数据表明，IPN内调节神经元活动的受体信号 起源于中缝正中核的5-羟色胺能神经元支配IPN。因此，这款R21的目标是 确定IPN 5-羟色胺和5-羟色胺能受体信号在尼古丁戒断行为中的作用。目标1 将检验中缝中缝5-羟色胺能神经元投射到并调节IPN放电的假设 通过5-羟色胺受体信号传导的神经元。这一假说将使用光遗传、 急性中脑片的生物物理、分子和药理学方法。目标2将测试 5-羟色胺能神经传入体内将调节躯体和/或情感的假说 尼古丁依赖小鼠的尼古丁戒断症状。这一假设将通过以下方式进行检验 结合行为和脑区域特定药物注射的体内光遗传方法。它是 预计在尼古丁戒断过程中5-羟色胺在IPN中的作用将导致 识别用于戒烟的新的5-羟色胺受体靶点。

Project Summary/Abstract While adverse health consequences of smoking make it the primary cause of preventable mortality in the world, current therapies for smoking cessation are minimally effective highlighting the need for a better understanding of the pathophysiology underlying nicotine addiction. Recent work has identified an understudied circuit, the habenulo-interpeduncular nucleus (Hb-IPN) axis, as a critical circuit in nicotine withdrawal symptoms. In particular, during nicotine withdrawal in mouse models, neurons within the IPN exhibit increased activity triggering both somatic (physical) withdrawal symptoms, as well as affective symptoms including increased anxiety. Although little is known regarding the neurotransmitter input and receptor signaling within the IPN that modulates neuronal activity, previous work and preliminary data indicate serotonergic neurons originating in the median raphe nucleus innervate the IPN. Thus, the goal of this R21 is to identify a role for IPN serotonin and serotonergic receptor signaling in nicotine withdrawal behaviors. Aim 1 will test the hypothesis that median raphe serotonergic neurons project to, and modulate the firing of IPN neurons via serotonin receptor signaling. This hypothesis will be tested using a combination of optogenetic, biophysical, molecular, and pharmacological approaches in acute midbrain slices. Aim 2 will test the hypothesis that activation of serotonergic inputs into the IPN in vivo will modulate somatic and/or affective nicotine withdrawal symptoms in a mouse model of nicotine dependence. This hypothesis will be tested using in vivo optogenetic approaches in combination with behavior and brain region specific drug infusions. It is anticipated that characterizing the role of serotonin in the IPN during nicotine withdrawal will lead to identification of novel serotonin receptor targets for smoking cessation.