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: 10601138
• 负责人: Michael R. Bruchas
• 金额: $ 48.16万
• 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/10601138
• 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 Communication; 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; 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; 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; 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; neural circuit; neurobiological mechanism; nociceptin; nonhuman primate; novel; optogenetics; pharmacologic; preference; prepronociceptin; receptor; response; stressor; synergism

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.

项目摘要 项目4的总体目标是确定NociCeptin/受体系统如何调节中脑脱离 多巴胺（DA）系统和与压力，厌恶和成熟行为相关的行为反应。 我们最近确定了一个副腹侧对盖区（PNVTA）NociTptin（PNOC+）神经元的群体 这种限制的成熟行为并规范了寻求自然奖励的动机。这些PNOC+ PNVTA 神经元在动机过程中参与，并在激活时呈负面价。我们广泛的身体 初步发现强烈暗示这些神经元在控制动机行为，压力反应性， 和回避行为。与其他项目密切合作（特别是项目1和3）， 项目4将使用新开发的鼠标模型来访问内源性伤害感电路并专注于 前摄影系统如何与多巴胺系统进行调节的神经生物学机制 动机 - 抑郁症的关键组成部分，包括该中心项目中概述的疾病。 该5年项目的研究目的是：（1）确定的解剖学和功能特征 腹膜内脑内表达神经元并识别行为条件（急性与慢性） 该系统调节的压力，动机和避免进近）； （2）识别和表征 PNVTA NociTptin神经元及其传入涉及动机行为，这些行为推动了负面情感 行为。该项目将使用新颖和经过验证的鼠标CRE-DRIVER模型，允许无与伦比的访问 VTA中的PNOC+神经元，结合光学遗传学，化学遗传学，钙成像，病毒跟踪和 揭示这些神经元如何受到厌恶刺激调节的电路机制的行为。这 项目直接与该孔戴中心中概述的其他项目协同作用，这有两种关键方式：1）使用新颖 尖端的鼠标模型，它将允许剖析前摄影系统在动机中的作用，2） 全面检查Nocieptin电路在多巴胺依赖性行为中的作用，直接相关 激励状态，回避和压力引起的负面影响。项目4的结果将：（1）直接 告知验尸分析，以探测由MDD的人的PNVTA中的伤害感受神经元死亡 自杀（项目1）； （2）与用于测试NociTPTIN的假设的药物挑战协同作用 受体拮抗作用将使人类的神经底物标准化神经底物/避免行为 MDD和焦虑症（项目1）； （3）与使用PNOC-IRES-CRE小鼠的研究集成 Nocteptin神经元（纹状体与VTA）的特定种群如何调节动机，Anhedonia和 方法/避免决策（项目3）。来自项目4的目标的数据以及三个 其他项目和计算建模核心将从根本上增强我们对 Nocteptin/Nopr系统在动机和抑郁/焦虑行为中，并确定新的治疗靶标。