Neurobiological mechanisms underlying resiliency and vulnerability to opioid use disorder

阿片类药物使用障碍的弹性和脆弱性的神经生物学机制

• 批准号: 10740556
• 负责人: Brittany Nicole Kuhn
• 金额: $ 19.07万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740556
• 关键词: Affect; Attenuated; Behavior; Behavioral; Behavioral Model; Cells; Characteristics; Cluster Analysis; Complex; Confocal Microscopy; Cues; Dendrites; Dendritic Spines; Development; Diameter; Disease; Drug Regulations; Electrophysiology (science); FOS Protein; Female; Genetic; Globus Pallidus; Habenula; Head; Heroin; Heterogeneity; Human; Immunohistochemistry; Individual; Label; Lateral; Link; Measures; Mediating; Modeling; Morphology; N-Methylaspartate; Network-based; Neurobiology; Neuronal Plasticity; Neurons; Nucleus Accumbens; Output; Pathway interactions; Phase; Phenotype; Population; Prediction of Response to Therapy; Process; Rattus; Regulation; Relapse; Reporter; Rewards; Rodent Model; Signal Transduction; Structure; Structure of subthalamic nucleus; Substance Use Disorder; Symptoms; Synaptic Potentials; Techniques; Testing; Tracer; Training; Treatment Efficacy; United States; Vertebral column; Viral; Work; addiction; behavioral phenotyping; career; density; drug seeking behavior; experimental study; functional plasticity; genetic approach; genetic technology; heroin use; human model; individual variation; insight; male; network models; neural circuit; neurobiological mechanism; novel; opioid use disorder; optogenetics; patch clamp; postsynaptic; promote resilience; protein biomarkers; resilience; response; trait

PROJECT SUMMARY/ABSTRACT There has been a significant rise in opioid use disorder (OUD) in the United States over the past decade, making it imperative to gain a better understanding of the behavioral characteristics underlying OUD vulnerability. Current rodent models focus on how one or few traits interact in a linear manner to predict substance use disorder (SUD), however, OUD consists of several symptoms that interact with one another across the addiction process and can vary between individuals to affect OUD vulnerability or resiliency. I contributed toward a rat model that captures this behavioral complexity using male and female heterogeneous stock rats in an effort to better model human OUD. Bayesian stochastic block model (SBM) network-based clustering analysis is used to separate rats into resilient and vulnerable subpopulations. Using this model, we are able to assess the neurobiological mechanisms contributing toward OUD vulnerability and resiliency, the latter of which is not well understood. These opposing phenotypes are likely mediated by different cellular and circuitry adaptations, and will be the focus of this proposal. The K99 aims assess how functional and morphological neuroplasticity differences in nucleus accumbens core (NAcc) D1/D2 medium-spiny neuron (MSN) contribute to OUD resiliency and vulnerability. I will first use whole-cell patch-clamp electrophysiology to characterize changes in AMPA/NMDA ratios in vulnerable and resilient subpopulations following cued reinstatement (Aim 1). I will then inject an intracellular label into the recorded cell and examine differences in D1/D2-MSN dendritic spine morphology (Aim 2). This approach will allow for the tracking of NAcc neuroplastic adaptations within the same cell across the two phenotypes. The R00 portion of the proposal will assess how pathway specific regulation of dorsolateral ventral pallidum (dlVP) projections contribute to OUD resiliency and vulnerability. Comparable to the NAcc, the dlVP, the main functional output of the NAcc, shows cell-specific functional regulation of drug seeking and refraining behavior, making it an ideal structure to evaluate circuit heterogeneity in individual variation in OUD propensity. Using confocal microscopy and viral tracers, I will assess functional connectivity from the dlVP to the subthalamic nucleus (STN), a region known to enhance seeking and likely vulnerability, and to the lateral habenula (LHb), known to mediate aversion and hypothesized to promote resiliency (Aim 3a). I will then employ chemogenetic technology to selectively isolate and manipulate these pathways in OUD resilient and vulnerable rats. (Aim 3b). Lastly, using whole-cell patch-clamp electrophysiology, I will evaluate input adaptations in the STN and LHb following dlVP stimulation within the two phenotypes following cued reinstatement (Aim 4). Experiments in this proposal employ a novel rat model capturing individual variation in OUD propensity similar to what is observed in humans. Work from this proposal will greatly contribute to our knowledge of the cellular and circuitry mechanisms contributing to OUD resiliency versus vulnerability.

项目摘要/摘要 在过去的十年中，美国的阿片类药物使用障碍（OUD）显着增加，使 必须更好地了解OUD脆弱性的行为特征。 当前的啮齿动物模型集中于一个或几个特征如何以线性方式相互作用以预测药物使用障碍 （SUD），但是，OUD由几种症状组成，这些症状在整个成瘾过程中彼此相互作用 并且可以在个人之间有所不同，以影响Oud脆弱性或弹性。我为一个老鼠模型做出了贡献 使用男性和女性异质股票大鼠捕获这种行为复杂性，以更好地模型 人乌德。贝叶斯随机块模型（SBM）基于网络的聚类分析用于分离大鼠 进入弹性和脆弱的亚群。使用此模型，我们能够评估神经生物学 有助于OUD脆弱性和弹性的机制，后者的理解不佳。 这些相反的表型可能是由不同的细胞和电路适应介导的，将是 该提议的重点。 K99的目的评估功能和形态神经塑性的差异 伏隔核（NACC）D1/D2中跨神经元（MSN）有助于OUD弹性和 脆弱性。我将首先使用全细胞贴片钳电生理学来表征AMPA/NMDA的变化 提示恢复原状后，脆弱和弹性亚群的比率（AIM 1）。然后我会注入 细胞内标记进入记录的细胞并检查D1/D2-MSN树突状脊柱形态的差异（AIM 2）。这种方法将允许跟踪两者中同一细胞内NACC神经塑性适应 表型。提案的R00部分将评估途径如何特定的背外侧调节 Pallidum（DLVP）预测有助于OUD的弹性和脆弱性。与NACC DLVP相当 NACC的主要功能输出显示了寻求药物的细胞特异性功能调节 行为，使其成为评估OUD倾向单个变化中电路异质性的理想结构。 使用共聚焦显微镜和病毒示踪剂，我将评估从DLVP到丘脑的功能连通性 核（STN），一个已知可以增强寻求和可能脆弱性的区域，以及外侧Habenula（LHB）， 已知可以介导厌恶和假设以促进弹性（AIM 3A）。然后，我将采用化学生成 在OUD弹性和脆弱的大鼠中选择性隔离和操纵这些途径的技术。 （AIM 3B）。 最后，使用全细胞贴片钳电生理学，我将评估STN和LHB中的输入适应 在提示恢复原状的两个表型中DLVP刺激后（AIM 4）。实验 提案采用一种新型的大鼠模型来捕获与观察到的相似的OUD倾向变化 在人类中。该提案的工作将极大地有助于我们对细胞和电路的了解 有助于OUD弹性与脆弱性的机制。