Individual differences in cortical-striatal pathway utilization regulating flexibility

项目摘要 成瘾是一种多方面的慢性神经生物学疾病，只有15%-30%的人 滥用药物的实验。这种个体变异性表明神经生物学差异出现在 任何药物暴露，导致不同物种的表型行为差异。在大鼠身上，对成瘾有抵抗力 当结果贬值时，“目标追踪器”(GT)灵活地调整行为，而不受训练程度的影响。 容易上瘾的“信号跟踪者”(ST)无法调整自己的行为，并持续表现出更多的反应 学习到的线索，尽管结果贬值了。我最近发现，ST大鼠的这种僵化只有在 有限的训练，因为它们在延长训练后在行为上变得灵活，类似于GT大鼠。这些瞬变 行为差异表明表型和表型之间存在可分离的神经生物学机制 训练。这个项目的长期目标是了解潜在的神经生物学差异 成瘾易感性表型的差异，以及这些行为和神经差异如何随 训练。我最近发现前岛叶皮质(AIC)与伏隔核核心之间的联系 (NACC)对于结果贬值是必需的，特别是在GT大鼠中，但在ST大鼠中不是。当前的目标是 建议研究AICnacc通路的激活、兴奋性和突触可塑性是如何调节的 依赖跟踪和经验的行为灵活性。I假设提高了AICNAcc的利用率 与ST大鼠相比，GT大鼠在训练过程中调节行为灵活性的途径。在目标1中，我将使用 通路特异性化学遗传学检测AIC--NACC通路在结果中的必要性和充分性 GT和ST大鼠的跨训练贬值。在目标2中，我将使用体外电生理记录 结合路径跟踪和光遗传学来确定兴奋性和突触差异 GT和ST大鼠结局贬值后的AIC、、NACc通路。在《目标3》中，我将在体内使用 电生理记录与光遗传学相结合实时测量AIC神经元的活动 结果贬值时GT和ST的通路。研究AICNAcc通路是如何介导的 跟踪和经验依赖的行为灵活性的差异对于加深我们的理解是必要的 神经生物学机制，使个人在吸毒前容易上瘾。 建议的实验将促进我对电生理技术的使用和对复合体的分析 数据集。这个应用程序利用了马里兰大学学院教职员工强大的成瘾专业知识 医学，以促进成功完成拟议的培训计划。总而言之，我提出的目标以及 我的部门具有强大的导师和协作性质，确保成功地发展为 独立科学家。

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.