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

项目 4_Bruchas：用于解剖小鼠伤害感受素系统介导的接近/回避行为的电路级方法

• 批准号: 10383688
• 负责人: Michael R. Bruchas
• 金额: $ 48.57万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383688
• 关键词: Acute; Affective; Anatomy; Anhedonia; Animals; Anterior; Anxiety; Anxiety Disorders; Autopsy; Aversive Stimulus; Behavior; Behavioral; Biological; Biological Assay; Biological Process; Brain region; Calcium; Cell Nucleus; Cells; Characteristics; Chronic stress; Collaborations; Complex; Computer Models; Corpus striatum structure; Cre driver; Cues; Data; Decision Making; Depressive disorder; Disease; Dopamine; Dorsal; Excision; Exposure to; Fiber; Functional disorder; G Protein-Coupled Receptor Signaling; Genetic; Goals; Habenula; Heterogeneity; Human; Image; Individual; Internal Ribosome Entry Site; Investigation; Lead; Link; Major Depressive Disorder; Medial; Mediating; Mental Depression; Midbrain structure; Modeling; Mood Disorders; Motivation; Mus; Negative Valence; Neurons; Neuropeptides; Nociception; ORL1 receptor; Opioid; Organism; Pathway interactions; Pharmacology; Photometry; Play; Population; Process; Psychopathology; Regulation; Research; Rewards; Role; Specificity; Stimulus; Stress; Sucrose; Suicide; System; Tail Suspension; Techniques; Testing; Ventral Tegmental Area; Viral; acute stress; antagonist; anxious behavior; approach avoidance behavior; avoidance behavior; base; behavioral response; cell type; cingulate cortex; depressive symptoms; dopamine system; dopaminergic neuron; efficacious treatment; experimental study; improved; in vivo; insight; interpeduncular nucleus; mesolimbic system; motivated behavior; mouse model; negative affect; neural circuit; neurobiological mechanism; nociceptin; nonhuman primate; novel; optogenetics; preference; prepronociceptin; relating to nervous system; response; stressor; virus genetics

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.

项目概要 项目 4 的总体目标是确定伤害感受肽/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。 我们最近鉴定了一群旁黑质腹侧被盖区 (pnVTA) 伤害感受素 (PNOC+) 神经元 限制动机行为并调节自然奖励寻求的动机。这些 PNOC+ pnVTA 神经元在动机过程中参与，并在激活时携带负价。我们庞大的身体 初步研究结果强烈表明这些神经元与调节动机行为、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访问内源性伤害感受回路，并重点关注 前罗西肽系统如何参与多巴胺系统进行调节的神经生物学机制 动机——抑郁症的一个关键组成部分，包括本中心项目中概述的那些。这 这个为期五年的项目的研究目标是：（1）确定解剖学和功能特征 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 由该系统调节的压力、动机和回避）； (2) 识别和表征 pnVTA 伤害感受素神经元及其传入神经元参与驱动负面情感的动机行为 行为。该项目将使用新颖且经过验证的鼠标驱动程序模型，该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、病毒追踪和 行为来揭示这些神经元如何受到厌恶刺激调节的回路机制。这 该项目通过两个关键方式直接与该 Conte 中心概述的其他项目产生协同作用：1）使用新颖的 尖端的小鼠模型，它将允许剖析前诺西肽系统在动机中的作用，并且 2）它将 全面检查伤害感受肽回路在多巴胺依赖性行为中的作用，具有直接相关性 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 为死后MDD患者pnVTA中伤害感受神经元的尸检分析提供信息 自杀（项目1）； (2) 与药理学挑战协同作用，用于检验伤害感受肽的假设 受体拮抗作用将使人类接近/回避行为的神经底物正常化 MDD 和焦虑症（项目 1）； (3) 结合使用 PNOC-IRES-cre 小鼠的研究来确定 特定的伤害感受肽神经元群（纹状体与 VTA）如何调节动机、快感缺失和 接近/回避决策（项目 3）。项目 4 的目标以及三个目标中出现的数据 其他项目和计算建模核心将从根本上增强我们对 伤害感受肽/NOPR系统对动机和抑郁/焦虑行为的影响，并确定新的治疗目标。