Dissecting stress modulation of pnVTA nociceptin peptide-mediated approach-avoidance behavior

剖析 pnVTA 伤害感受肽介导的趋避行为的应激调节

基本信息

批准号：
10676589
负责人：
Carolyn Ann Stine
金额：
$ 4.77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-16 至 2025-06-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676589
关键词：
Acute Address Affect Anatomy Anxiety Automobile Driving Behavior Behavioral Model Biosensor Brain Cells Chronic Chronic stress Clinical Trials Color Complex Data Decision Making Depressive disorder Detection Development Development Plans Disease Electrophysiology (science)Exposure to Fiber Fluorescent in Situ Hybridization G-Protein-Coupled Receptors Goals Head Histology Hypothalamic structure Immunohistochemistry Individual Industry Investigation Label Laboratories Lateral Learning Ligands Link Major Depressive Disorder Mediating Mental Depression Mentors Messenger RNA Modeling Molecular Motivation Mus National Institute of Drug Abuse Neurons Neuropeptides ORL1 receptor Opioid Opioid Peptide Optics Pathogenesis Peptides Photometry Physiological Population Predisposition Process Property Proteins Psychological Stress Receptor Signaling Relapse Reporting Research Resolution Rewards Role Scientist Shock Signal Pathway Signal Transduction Slice Stress Substance Use Disorder Synapses System Techniques Testing Training Ventral Tegmental Area acute stress addiction approach avoidance behavior approach behavior biological adaptation to stress career career development conditional knockout dopaminergic neuron early life adversity endogenous opioids experience foot improved in vivo innovation insight molecular targeted therapies motivated behavior neural circuit neurotransmission nociceptin novel strategies novel therapeutics optogenetics physiologic stressor prepronociceptin psychologic psychological stressor receptor receptor expression response restraint skills stress reactivity stress state stressor therapeutic target

项目摘要

PROJECT SUMMARY: Chronic stress contributes to the pathogenesis and exacerbation of numerous disorders that frequently present with atypical motivation during reward-seeking behavior including substance use disorder (SUD), major depressive disorder (MDD), and anxiety. The extent to which motivation is disrupted by stress can depend on the form of stress exposure. Hence, it is critical to understand the neural circuitry regulating motivated behaviors become disrupted under diverse chronic stress states to improve our understanding of how these disorders develop, what makes some individuals more susceptible, and to identify more effective molecular therapeutic targets. Our laboratory previously reported that neurons producing the endogenous opioid peptide nociceptin in the paranigral ventral tegmental area (pnVTAPnoc neurons) act locally on nociceptin receptor (NOPR) to limit motivation for reward (Parker et al, Cell, 2019), while others have identified a role for nociceptin signaling in the orchestrated stress response. Preliminary data show that pnVTA nociceptin neurons are dynamically engaged to different extents by distinct stressors. The central hypothesis of this proposal is that stress differentially engages pnVTA nociceptin signaling to regulate the expression of motivated behaviors such as approach-avoidance. This proposal is in direct response to NIDA’s Strategic Goal 1 which aims to investigate circuitry contributing to brain functions “such as reward, motivation, decision-making…and stress reactivity, ” alongside examining a NIDA high priority target for SUD. Aim 1 will determine how diverse physical and psychological stressors alter the VTA nociceptin opioid system on a molecular and functional level. Aim 1A will evaluate how various stressors acutely and chronically alter VTA nociceptin/NOPR expression and neuron activity. Aim 1B uses a new genetically encoded biosensor for the nociceptin peptide (NOPLight), and head- fixed approach-avoidance (Ap-Av) behavioral models to determine how nociceptin release in the VTA is altered during Ap-Av decision making following stress exposure. Aim 1C uses prepronociceptin (Pnoc) conditional knockout line created in-house and optogenetics to manipulate VTA nociceptin peptide expression and activity following stress. Aim 2 will determine the anatomical and functional involvement of the lateral hypothalamus (LH) as an afferent input regulating pnVTAPnoc neuron activity in naïve and stressed states using electrophysiology and fiber photometry to simultaneously record LH terminal activity and nociceptin release in the VTA following chronic stress exposure. Leveraging these new approaches will enable us to provide brand new insight into this poorly understood system. During my training period I will learn to utilize cutting-edge techniques in order to perform powerful, high-resolution investigations of neuropeptide circuitry, and gain valuable career development training across a host of scientific, intellectual, and mentored programming. This F31 mechanism will allow me to pursue my individual development plan and prepare me for a career as an independent neuroscientist.

项目摘要：慢性压力导致多种疾病的发病和恶化在寻求奖励的行为中经常表现出非典型动机，包括物质使用障碍（SUD）、重度抑郁症（MDD）和焦虑压力会扰乱动机的程度。取决于压力暴露的形式，因此，了解调节动机的神经回路至关重要。在不同的慢性压力状态下，行为会受到干扰，以提高我们对这些行为如何发生的理解疾病的发展，是什么使一些人更容易受到影响，并确定更有效的分子我们的实验室之前报道过产生内源性阿片肽的神经元。旁黑质腹侧被盖区（pnVTAPnoc 神经元）的伤害感受肽局部作用于伤害感受肽受体（NOPR）限制奖励动机（Parker et al, Cell, 2019），而其他人已经确定了伤害感受肽的作用初步数据显示 pnVTA 伤害感受素神经元中的信号传导。该提案的中心假设是，不同程度的动态参与。压力差异性地参与 pnVTA 伤害感受素信号传导来调节动机行为的表达，例如该提案是对 NIDA 旨在调查的战略目标 1 的直接回应。有助于大脑功能“如奖励、动机、决策……和压力反应”的电路除了检查 NIDA 的 SUD 高优先级目标外，目标 1 将确定物理和生物多样性的多样性。心理压力源会在分子和功能水平上改变 VTA 伤害感受素阿片系统。评估各种应激源如何急性和慢性改变 VTA 伤害感受素/NOPR 表达和神经元 Aim 1B 使用一种新的基因编码生物传感器来检测伤害肽 (NOPLight) 和头 - 固定接近-回避 (Ap-Av) 行为模型，以确定 VTA 中伤害感受素的释放如何改变在压力暴露后的 Ap-Av 决策过程中，Aim 1C 使用前诺西肽 (Pnoc) 有条件。内部创建的敲除线和光遗传学来操纵 VTA 伤害感受肽表达和活性目标 2 将确定外侧下丘脑的解剖和功能参与情况。 (LH) 作为传入输入调节 pnVTAPnoc 神经元在天真和应激状态下的活动电生理学和纤维光度测定法同时记录 LH 末端活性和伤害感受素释放利用这些新方法，我们可以提供长期压力暴露后的 VTA。在我的培训期间，我将学习如何利用最先进的系统。技术，以便对神经肽电路进行强大的高分辨率研究，并获得涵盖一系列科学、智力和指导性规划的宝贵职业发展培训。 F31机制将使我能够追求我的个人发展计划，并为我的职业生涯做好准备独立神经科学家。