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Individual differences in cortical-striatal pathway utilization regulating flexibility

皮质-纹状体通路利用调节灵活性的个体差异

基本信息

批准号：
10379945
负责人：
Sara Keefer
金额：
$ 7.42万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379945
关键词：
Adaptive Behaviors Anterior Automobile Driving Behavior Behavioral Brain Brain region Cells Chronic Clinical Research Communication Complex Corpus striatum structure Cues Data Data Set Development Diagnosis Disease Drug Exposure Drug abuse Drug usage Electrophysiology (science)Ensure Faculty Fostering Goals Individual Individual Differences Maryland Measures Mediating Mentorship Motivation Nature Neural Pathways Neurobiology Neurons Nucleus Accumbens Outcome Pathway interactions Performance Pharmaceutical Preparations Phenotype Population Prosencephalon Rattus Relapse Research Resistance Rewards Satiation Scientist Substance Use Disorder Synapses Synaptic plasticity Techniques Testing Time Training Universities Work addiction base behavioral phenotyping drug of abuse experience experimental study flexibility in vivo individual variation learning outcome maladaptive behavior medical schools neural circuit neurobiological mechanism neuromechanism optogenetics patch clamp pre-clinical research relating to nervous system reward circuitry

项目摘要

Project Summary Addiction is a multifaceted, chronic neurobiological disorder occurring in only 15-30% of individuals who experiment with drugs of abuse. This individual variability suggests neurobiological differences present prior to any drug exposure, resulting in phenotypic behavioral differences across species. In rats, addiction-resistant “goal-trackers” (GT) flexibly adjust behavior when an outcome is devalued, independent of extent of training. Addiction-vulnerable “sign-trackers” (ST) fail to adjust their behavior and persistently show increased responding to learned cues despite outcome devaluation. I recently found this inflexibility in ST rats is only evident after limited training, as they become behaviorally flexible, similar to GT rats, after extended training. These transient behavioral differences suggest dissociable neurobiological mechanisms between phenotypes and across training. The long-term goal of this project is to understand the neurobiological differences underlying behavioral differences in addiction vulnerability phenotypes, and how these behavioral and neural differences change with training. I recently found communication between the anterior insular cortex (aIC) to nucleus accumbens core (NAcC) is necessary for outcome devaluation, specifically in GT rats, but not in ST rats. The aim of the current proposal is to examine how activation, excitability, and synaptic plasticity of the aICNAcC pathway mediates tracking- and experience-dependent behavioral flexibility. I hypothesize increased utilization of the aICNAcC pathway in GT rats compared to ST rats that regulates behavioral flexibility across training. In Aim 1, I will use pathway-specific chemogenetics to test the necessity and sufficiency of the aICNAcC pathway in outcome devaluation across training in GT and ST rats. In Aim 2, I will use ex vivo electrophysiological recordings in combination with pathway tracing and optogenetics to determine excitability and synaptic differences within the aICNAcC pathway between GT and ST rats after outcome devaluation. In Aim 3, I will use in vivo electrophysiological recordings in combination with optogenetics to measure real-time activity of the aICNAcC pathway in GT and ST during outcome devaluation. Investigating how the aICNAcC pathway mediates tracking- and experience-dependent differences in behavioral flexibility is necessary to further our understanding of neurobiological mechanisms that predispose individuals to addiction vulnerability prior to drug experience. The proposed experiments will advance my use of electrophysiological techniques and analysis of complex datasets. This application draws on the strong addiction expertise of faculty at University of Maryland School of Medicine to foster successful completion of the proposed training plan. Together, my proposed aims along with the strong mentorship and collaborative nature of my department ensures successful development as an independent scientist.

项目总结