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 在过去的十年里，阿片类药物使用障碍(OUD)在美国显著上升，使 必须更好地了解OUD漏洞背后的行为特征。 目前的啮齿动物模型主要关注一个或几个性状如何以线性方式相互作用来预测物质使用障碍 然而，OUD由几个症状组成，这些症状在成瘾过程中相互作用 并且可以因个体而异，以影响OUD的脆弱性或弹性。我为建立一个老鼠模型做出了贡献 使用雄性和雌性不同种系大鼠捕捉这种行为复杂性，以努力更好地建立模型 人类的声音。采用基于贝叶斯随机区组模型(SBM)网络的聚类分析方法分离大鼠 变成了有弹性和脆弱的亚群。使用这个模型，我们能够评估神经生物学 促进我们的脆弱性和复原力的机制，后者还没有被很好地理解。 这些相反的表型可能是由不同的细胞和电路适应所介导的，并且将是 这项提案的重点。K99的目的是评估功能和形态神经可塑性的差异 伏隔核核(NAcc)D_1/D_2中棘神经元(MSN)参与OUD的复原性和 脆弱性。我将首先使用全细胞膜片钳电生理学来表征AMPA/NMDA的变化 恢复线索后脆弱和有弹性的亚群的比率(目标1)。然后我会给你注射一个 细胞内标记进入记录的细胞并检查D1/D2-MSN树突棘形态的差异(目的 2)。这种方法将允许跟踪同一细胞内跨越两个细胞的NAcc神经再生适应 表型。该提案的R00部分将评估通路对腹侧背外侧的特定调节 苍白球(Dlvp)预测有助于提高我们的复原力和脆弱性。可与NAcc相比，DlVP， NAcc的主要功能输出显示了细胞对药物寻找和戒断的特定功能调节 行为，使其成为评估在OUD倾向的个体差异中的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到丘脑下部的功能连接。 核(STN)，已知增强寻找和可能的脆弱性的区域，以及外侧缰核(LHb)， 已知会调解厌恶情绪，并假设会促进弹性(目标3a)。然后我会用化学遗传学 有选择地隔离和操纵这些通路的技术在有弹性和脆弱的大鼠身上。(目标3b)。 最后，我将使用全细胞膜片钳电生理学来评估STN和LHb的输入适应性 在提示恢复后刺激两种表型的dlVP(目标4)。在这方面的实验 建议采用一种新的大鼠模型，捕捉与观察到的相似的OUD倾向的个体差异 在人类身上。这项提案的工作将极大地有助于我们对细胞和电路的知识 有助于OUD复原力与脆弱性的机制。