NEURAL CIRCUITRY MEDIATING BEHAVIORAL FLEXIBILITY

神经回路调节行为灵活性

• 批准号: 10363725
• 负责人: Elizabeth A West
• 金额: $ 24.84万
• 依托单位: ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363725
• 关键词: Abstinence; Association Learning; Automobile Driving; Behavior; Behavioral; Cells; Cocaine; Cognitive; Corpus striatum structure; Cues; Decision Making; Disease; Dorsal; Drug Addiction; Drug usage; Electrophysiology (science); Environment; Equilibrium; Foundations; Goals; Habits; Impairment; Lateral; Learning; Link; Measures; Medial; Mediating; Mentors; Nature; Neurons; Nucleus Accumbens; Outcome; Pathway interactions; Patients; Performance; Phase; Prefrontal Cortex; Rattus; Recording of previous events; Response to stimulus physiology; Rewards; Signal Transduction; Substance abuse problem; Substantia nigra structure; Therapeutic Intervention; Training; addiction; behavioral impairment; career; cocaine use; cognitive function; flexibility; insight; neural circuit; neural network; optogenetics; reinforcer; relating to nervous system; response; targeted treatment

Project Summary/Abstract Balancing habitual and flexible strategies for navigating the environment is necessary for behavior that is both cognitively efficient and adaptive to change, and perturbations that disrupt this balance can result in significant behavioral impairments. For example, patients with substance abuse disorders often have difficulty altering their behavior to respond to changing outcomes, leading to poor decision-making. In the rat, a history of cocaine impairs the ability to adjust behavior away from reward-predictive cues following reward devaluation, a canonical measure of flexible behavior (i.e., cocaine leads to inflexible behavior). Interestingly, different striatal substrates underlie flexible, goal-directed behaviors (nucleus accumbens, NAc) and inflexible, habitual behaviors (dorsal lateral striatum, DLS), and proper balance between the NAc and DLS and their associated networks is critical for adaptive (flexible) but efficient (habitual) behavior. Thus, the current application will examine how a history of cocaine tips that balance and alters the neural network signaling that drives flexible and inflexible strategies. Balancing these subcortical networks requires cortical input. Specifically, distinct mPFC subregions (prelimbic cortex, PrL; and infralimbic cortex, IL) are differentially involved in flexible and inflexible strategies, respectively. Thus, to more fully characterize how a history of cocaine results in lasting behavioral impairments, I propose 4 specific aims to examine specific effects of a history of cocaine or effects of specific manipulations to networks driving flexibility. In aim 1, I will determine how a history of cocaine alters PrL and NAc cell firing and network dynamics (local field potentials) to reward predictive cues during learning and flexible behavior. In aim 2, I will determine if prelimbic cortical (PrL) inputs to the NAc core are causally linked to both flexible behavior and its neural encoding in the NAc. In aim 3, I will independently determine how a history of cocaine alters IL and DLS cell firing and network dynamics to reward predictive cues during learning and flexible behavior. Finally, in aim 4, I will determine if the IL to substania nigra (the primary input into DLS) pathway is causally linked to flexible behavior and neural encoding in the DLS. Together, these specific aims will characterize the balance between two parallel circuits (one involving PrL and NAc, and one involving IL and DLS) in behavioral flexibility and determine how a history of cocaine shifts this balance towards inflexible (habitual) circuitry and behavior. Understanding the neural circuitry underlying flexible vs habitual behavior and how neural encoding in these regions is altered by drug use will provide critical insight into new and more selective targets for therapeutic intervention for patients with substance abuse disorders.

项目总结/摘要 平衡习惯和灵活的策略来导航环境是必要的行为， 认知效率和适应变化，扰乱这种平衡的扰动可能导致重大的 行为障碍例如，患有物质滥用障碍的患者通常难以改变 他们的行为来应对不断变化的结果，导致决策失误。在大鼠中， 可卡因损害了在奖励贬值后调整行为远离奖励预测线索的能力， 柔性行为的规范度量（即，可卡因导致不灵活的行为）。有趣的是， 基底是灵活的、目标导向的行为（核神经元，NAc）和不灵活的、习惯性的行为（核神经元，NAc）的基础。 行为（背侧纹状体，DLS），以及NAc和DLS之间的适当平衡及其相关 网络对于适应性（灵活）但有效（习惯性）的行为至关重要。因此，当前应用程序将 研究可卡因的历史是如何平衡和改变神经网络信号的， 不灵活的战略。平衡这些皮层下网络需要皮层输入。具体来说， mPFC亚区（前边缘皮质，PrL;和下边缘皮质，IL）在灵活性和 不灵活的策略。因此，为了更充分地描述可卡因史如何导致持久的 行为障碍，我提出了4个具体目标，以检查可卡因或影响的历史的具体影响 对网络的特定操作，从而提高灵活性。在目标1中，我将确定可卡因的历史如何改变 PrL和NAc细胞放电和网络动力学（局部场电位）在学习过程中奖励预测线索 灵活的行为。在目标2中，我将确定前边缘皮层（PrL）对NAc核心的输入是否是因果关系， 与灵活的行为及其在NAc中的神经编码有关。在目标3中，我将独立决定如何 可卡因的历史改变了IL和DLS细胞的放电和网络动力学，以奖励预测线索， 学习和灵活的行为。最后，在目标4中，我将确定白细胞介素是否进入黑质（主要输入 进入DLS）通路与DLS中的灵活行为和神经编码有因果关系。所有这些 具体的目标将描述两个平行电路之间的平衡（一个涉及PrL和NAc，另一个涉及PrL和NAc） 包括IL和DLS）在行为灵活性中的作用，并确定可卡因史如何改变这种平衡 不灵活的（习惯性的）电路和行为。理解灵活与 习惯性行为以及这些区域的神经编码是如何被药物使用改变的， 为药物滥用障碍患者的治疗干预提供新的和更具选择性的目标。