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

• 批准号: 10613933
• 负责人: Sara Keefer
• 金额: $ 3.95万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10613933
• 关键词: Adaptive Behaviors; Anterior; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Cells; Chronic; Clinical Research; Communication; Corpus striatum structure; Cues; Data; Data Set; Development; Diagnosis; Disease; Drug Experimentation; Drug Exposure; Drug abuse; Drug usage; Electrophysiology (science); Ensure; Faculty; Fostering; Genetic; Goals; Individual; Individual Differences; Learning; 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; Vulnerable Populations; Work; addiction; behavioral phenotyping; complex data; drug of abuse; experience; experimental study; flexibility; in vivo; individual variation; learning outcome; maladaptive behavior; medical schools; neural; neural circuit; neurobiological mechanism; neuromechanism; optogenetics; patch clamp; pre-clinical research; reward circuitry

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.

项目摘要 成瘾是一种多方面的慢性神经生物学障碍，仅发生在15-30%的个体中， 尝试滥用药物。这种个体差异性表明，神经生物学差异存在之前， 任何药物暴露，导致物种间的表型行为差异。在老鼠中， “目标追踪者”（GT）在结果被贬低时灵活地调整行为，与训练的程度无关。 易上瘾的“信号追踪者”（ST）无法调整他们的行为，并持续表现出增加的反应 尽管结果贬值，学习线索。我最近发现，ST大鼠的这种易变性只有在 有限的训练，因为它们在延长训练后变得行为灵活，类似于GT大鼠。这些瞬态 行为差异表明表型之间和跨 训练这个项目的长期目标是了解行为背后的神经生物学差异。 成瘾易感性表型的差异，以及这些行为和神经差异如何随着 训练我最近发现前岛叶皮层（aIC）和脑桥核核心之间的通讯 （NAcC）是必要的结果贬值，特别是在GT大鼠，但不是在ST大鼠。当前的目标 我们的建议是研究aIC神经元NAcC通路的激活、兴奋性和突触可塑性如何介导 跟踪和经验依赖的行为灵活性。我假设aIC的利用率增加， 与ST大鼠相比，GT大鼠中的信号通路在训练中调节行为灵活性。在目标1中，我将使用 特定途径化学遗传学测试aIC NAcC途径在结果中的必要性和充分性 在GT和ST大鼠的训练中贬值。在目标2中，我将使用离体电生理记录， 结合通路追踪和光遗传学来确定神经元内的兴奋性和突触差异。 结果评估后GT和ST大鼠之间的aIC-NAcC通路。在目标3中，我将使用体内 电生理学记录结合光遗传学测量aIC NAc C的实时活性 结果评估期间GT和ST通路。研究aIC NAcC通路如何介导 跟踪和经验依赖的行为灵活性的差异是必要的，以进一步了解我们的 神经生物学机制使个体在吸毒之前容易成瘾。 所提出的实验将促进我使用电生理技术和分析复杂的 数据集。该应用程序借鉴了马里兰州大学医学院教师的强大成瘾专业知识。 培养顺利完成拟培养计划的医学生。总之，我提出的目标沿着 我的部门强大的指导和协作性质确保了成功的发展， 独立科学家