Project 4_Bruchas : Circuit-level Approaches for Dissecting Approach/Avoidance Behaviors Mediated by Nociceptin Systems in Mice

项目摘要 项目4的总体目标是确定伤害感受素/受体系统如何调节中脑边缘系统， 多巴胺（DA）系统以及与压力、厌恶和动机行为相关的行为反应。 我们最近发现了一个黑质旁腹侧被盖区（pnVTA）的伤害感受素（PNOC+）神经元群体 约束动机行为并调节自然奖励寻求的动机。这些PNOC+ pnVTA 神经元在动机期间参与，并且在激活时携带负价。我们庞大的身体 的初步研究结果强烈暗示这些神经元在调节动机行为，压力反应， 和回避行为。与其他项目（特别是项目1和3）密切合作， 项目4将使用新开发的小鼠模型来评估内源性伤害感受回路，并专注于 前感受肽系统如何参与多巴胺系统调节的神经生物学机制 动机-抑郁症的一个关键组成部分，包括在这个中心项目概述。的 本课题的研究目标是：（1）确定大鼠大脑皮层的解剖和功能特征， 腹侧中脑内表达伤害感受素的神经元，并识别行为状况（急性与慢性 压力、动机和回避）;（2）识别和表征 pnVTA伤害感受素神经元及其传入参与驱动负性情感的动机性行为 行为该项目将使用新颖和有效的鼠标cre-driver模型，允许无与伦比的访问， VTA中的PNOC+神经元，结合光遗传学，化学遗传学，钙成像，病毒示踪， 行为，揭示电路机制，这些神经元是如何调节厌恶刺激。这 该项目直接协同与其他项目概述了这个康特中心，在两个关键方面：1）使用新的 尖端的小鼠模型，它将允许解剖前原感受素系统在动机中的作用，2）它将 全面研究伤害感受素回路在多巴胺依赖性行为中的作用， 动机状态、回避和压力引起的负面影响。项目4的结果将：（1）直接 通知尸检分析探测MDD死亡的个体的pnVTA中的伤害感受神经元， 自杀（项目1）;（2）协同药理学的挑战，用于测试的假设，伤害感受素 受体拮抗作用将使人类接近/回避行为的神经基质正常化， MDD和焦虑症（项目1）;（3）与使用PNOC-IRES-cre小鼠的研究相结合，以确定 特定群体的伤害感受素神经元（纹状体与腹侧被盖区）如何调节动机、快感缺乏和 接近/回避决策（项目3）。项目4的目标中出现的数据，以及三个 其他项目和计算建模核心将从根本上增强我们对 伤害感受素/NOPR系统在动机和抑郁/焦虑行为中的作用，并确定新的治疗靶点。

Project Summary The overall goal of Project 4 is to determine how the nociceptin/receptor system modulates the mesolimbic dopamine (DA) system and behavioral responses associated with stress, aversion, and motivated behaviors. We recently identified a population of paranigral ventral tegmental area (pnVTA) nociceptin (PNOC+) neurons that constrain motivated behavior and regulate the motivation for natural reward seeking. These PNOC+ pnVTA neurons are engaged during motivation, as well as carry a negative valence when activated. Our extensive body of preliminary findings strongly implicate these neurons in regulating motivated behaviors, stress responsivity, and avoidance behavior. Working in close collaboration with the other Projects (in particular, Projects 1 and 3), Project 4 will use newly developed mouse model for accessing endogenous nociception circuits and focus on the neurobiological mechanisms of how the prepronociceptin system engages the dopamine system to regulate motivation – a key component of depressive disorders, including those outlined in this center project. The research aims of this 5-year project are: (1) to determine the anatomical and functional characteristics of nociceptin expressing neurons within the ventral midbrain and identify behavioral conditions (acute vs chronic stress, motivation and Approach-Avoidance) that are modulated by this system; (2) to identify and characterize pnVTA nociceptin neurons and their afferents involved in motivated behavior that drive negative affective behavior. The project will use novel and validated mouse cre-driver models that allow unparalleled access to PNOC+ neurons in the VTA, combined with optogenetic, chemogenetic, calcium imaging, viral tracing, and behavior to uncover circuit mechanisms that underlie how these neurons are regulated by aversive stimuli. This project directly synergizes with the other projects outlined in this Conte Center, in two key ways: 1) using novel cutting-edge mouse models, it will allow to dissect the role of prepronociceptin system in motivation, and 2) it will comprehensively examine the role of nociceptin circuits in dopamine-dependent behaviors, with direct relevance to motivational states, avoidance, and stress-induced negative affect. Results from Project 4 will: (1) directly inform post-mortem analyses probing nociception neurons in the pnVTA of individuals with MDD who died by suicide (Project 1); (2) synergize with pharmacological challenges used to test the hypothesis that nociceptin receptor antagonism will normalize neural substrates underlying approach/avoidance behaviors in humans with MDD and anxiety disorders (Project 1); and (3) integrate with studies using PNOC-IRES-cre mice to determine how specific populations of nociceptin neurons (striatal vs VTA) regulate motivation, anhedonia, and approach/avoidance decision making (Project 3). Data emerging from Project 4’s aims, together with the three other projects and the Computational Modeling Core will fundamentally enhance our understanding of the nociceptin/NOPR system in motivation and depressive/anxious behaviors, and identify novel treatment targets.