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.

项目总结/摘要 在过去的十年中，美国阿片类药物使用障碍（OUD）显著增加， 更好地理解OUD脆弱性背后的行为特征势在必行。 目前的啮齿动物模型集中在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 (SUD)然而，OUD由几种症状组成，这些症状在成瘾过程中相互作用 并且可以在个体之间变化以影响OUD脆弱性或弹性。我为一个老鼠模型做了贡献， 利用雄性和雌性异质大鼠捕捉这种行为复杂性，以更好地建模 人OUD。采用基于贝叶斯随机块模型（SBM）网络的聚类分析方法对大鼠进行分类 适应能力强的和脆弱的亚群。使用这个模型，我们能够评估神经生物学 导致OUD脆弱性和弹性的机制，后者尚未得到很好的理解。 这些相反的表型可能是由不同的细胞和电路适应介导的，并且将成为 这一提案的重点。K99的目的是评估功能和形态神经可塑性的差异， 延髓核核心（NAcc）D1/D2中棘神经元（MSN）有助于OUD弹性， 易损性.我将首先使用全细胞膜片钳电生理学来表征AMPA/NMDA的变化， 在线索恢复后，脆弱和弹性亚群的比率（目标1）。然后我会注射 细胞内标记到记录的细胞中，并检查D1/D2-MSN树突棘形态的差异（目的 2）。这种方法将允许在两个细胞中追踪同一细胞内的NAcc神经可塑性适应。 表型该提案的R 00部分将评估背外侧腹侧神经元的通路特异性调节 苍白球（dlVP）预测有助于OUD的弹性和脆弱性。与NAcc，dlVP， NAcc的主要功能输出，显示了药物寻找和抑制的细胞特异性功能调节 行为，使其成为一个理想的结构，以评估电路的异质性在个别变化的OUD倾向。 使用共聚焦显微镜和病毒示踪剂，我将评估从dlVP到丘脑底核的功能连接， 核（Numbers），一个已知增强寻求和可能的脆弱性的区域，以及外侧缰核（LHb）， 已知调解厌恶和假设，以促进弹性（目标3a）。然后我会用化学遗传学 技术选择性地隔离和操纵这些通路在OUD弹性和脆弱的大鼠。(Aim 3 b）。 最后，使用全细胞膜片钳电生理学，我将评估输入的适应，在小脑和LHb 在线索恢复后的两种表型中，在dlVP刺激后（目标4）。在这方面的实验 一个建议采用了一种新大鼠模型，该模型捕获了与所观察到的相似的OUD倾向的个体变化 在人类身上。这项工作将大大有助于我们的细胞和电路的知识 有助于OUD弹性与脆弱性的机制。