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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

基本信息

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
项目类别：
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

项目摘要

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/文摘