Dissection and optogenetic manipulation of the Habenula-IPN cell-specific neuronal networks in the control of pain and addiction

缰核-脚间核（Hb-IPN）通路是一种新兴的、特征不明显的边缘-中脑中继结构，其调节胆碱能和阿片类物质传递并影响多巴胺能和多巴胺能系统。由于其对多种神经递质系统的影响，Hb的操纵影响非常不同的行为，包括尼古丁成瘾、疼痛和压力感知、焦虑、运动和负奖励（Frahm等人，2011年; Hikoiran，2010年）。Ibanez-Tallon实验室最近发现了三个新的神经元群体，除了两个经典的胆碱能（ChAT）和肽能（P物质）缰种群。本研究提案旨在通过利用最近开发的用于交叉和Cre依赖性病毒研究的转基因报告小鼠系来确定这些单个神经元群体的活性之间的因果关系，所述交叉和Cre依赖性病毒研究将用于递送光遗传载体、电生理记录和神经成像。重点将是尼古丁成瘾和戒断，Ibanez-Tallon研究小组已经确定了两个特定的人群，一个在缰核，一个在IPN。扩展到疼痛处理将进行表征的突触微电路在不同层次的网络复杂性，一个从P物质释放终端到IPN神经元和第二介导的阿片受体激活的Hb。具体而言，本文提出的光遗传学研究将操纵Hb和IPN中定义的神经元群体中的神经元活性，并将用作补充体内行为研究的基础，以产生与尼古丁成瘾和疼痛感知相关的定义输出。

The habenula-interpeduncular nucleus (Hb-IPN) pathway is an emerging, poorly characterized limbic- midbrain relay structure that regulates cholinergic and opioidergic transmission and influences both the serotonergic and the dopaminergic systems. Because of its influence on multiple neurotransmitter systems, manipulation of the Hb affects very diverse behaviors including nicotine addiction, pain and stress perception, anxiety, locomotion, and negative reward (Frahm et al., 2011; Hikosaka, 2010). The Ibanez-Tallon laboratory has recently identified three novel neuronal populations in addition to the two classical cholinergic (ChAT) and peptidergic (Substance P) habenular populations. The present research proposal aims at identifying causal relationships between the activity of these single neuronal populations by taking advantage of recently developed transgenic reporter mouse lines for intersectional and Cre-dependent viral studies that will be used for delivery of optogenetic vectors, electrophysiological recordings and neuroimaging. Emphasis will be drawn on nicotine addiction and withdrawal, for which the Ibanez-Tallon research group has already identified two specific populations, one in habenula and one in the IPN. Extension to pain processing will be performed by characterization of the synaptic microcircuitry at different levels of network complexity, one from Substance P releasing terminals onto IPN neurons and the second mediated by opioid receptor activation in the Hb. Specifically, the optogenetic studies proposed here will manipulate neuronal activity in defined neuronal populations in the Hb and IPN and will be used as the base for complementary in vivo behavioral studies to generate defined outputs related to nicotine addiction and pain perception.