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素/受体系统如何调节中脑边缘 多巴胺(DA)系统和与压力、厌恶和动机行为相关的行为反应。 我们最近发现了一组黑质旁腹侧被盖区(PnVTA)伤害素(PNOC+)神经元 这限制了动机行为，并规范了自然寻求奖励的动机。这些PNOC+PnVTA 神经元在动机过程中被激活，并且在被激活时带有负价态。我们广博的身体 初步发现强烈暗示这些神经元在调节动机行为、应激反应、 和回避行为。与其他项目(特别是项目1和项目3)密切合作， 项目4将使用新开发的小鼠模型来访问内源性伤害性感受电路，并将重点放在 前胶原系统参与多巴胺系统调节的神经生物学机制 动机-抑郁障碍的一个关键组成部分，包括本中心项目中概述的那些。这个 本项目为期5年的研究目标是：(1)确定关节的解剖和功能特征 在腹侧中脑内表达伤害素的神经元，并识别行为状况(急性与慢性 压力、动机和接近-回避)，由该系统调节；(2)识别和表征 PnVTA伤害素神经元及其传入参与驱动负性情绪的动机行为 行为。该项目将使用新颖和经过验证的鼠标核心驱动程序模型，允许无与伦比的访问 VTA中的PNOC+神经元，结合光发生、化学发生、钙成像、病毒追踪和 揭示这些神经元如何受到厌恶刺激调控的电路机制的行为。这 项目直接与Conte Center中概述的其他项目在两个关键方面进行协同：1)使用 尖端的小鼠模型，它将允许解剖前胶原系统在动机中的作用，以及2)它将 全面研究伤害素回路在多巴胺依赖行为中的作用，与直接相关 动机状态、回避和压力诱导的负面情绪。项目4的成果将：(1)直接 通知尸检分析探测死于死亡的MDD患者pnVTA中的伤害性神经元 自杀(项目1)；(2)与药理学挑战协同作用，用于测试伤害素的假说 受体拮抗将使人类接近/回避行为的神经基础正常化 MDD和焦虑症(项目1)；和(3)结合使用PNOC-IRES-cre小鼠的研究来确定 伤害素神经元的特定群体(纹状体和室旁核)如何调节动机、快感缺失和 进场/回避决策(项目3)。从项目4中涌现的数据S的目标，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.