NEURAL CIRCUITRY MEDIATING BEHAVIORAL FLEXIBILITY

项目摘要/摘要 平衡习惯和灵活的环境导航策略对于两者都是必要的行为 在认知上高效并适应变化，而扰乱这种平衡的扰动可能会导致显著的 行为障碍。例如，患有药物滥用障碍的患者通常很难改变 他们对不断变化的结果做出反应的行为，导致糟糕的决策。在老鼠身上，有一段历史 可卡因削弱了调整行为的能力，使其远离奖励贬值后的奖励预测线索，a 灵活行为的规范衡量标准(即，可卡因导致不灵活的行为)。有趣的是，不同的纹状体 底物是灵活的、目标导向的行为(伏隔核，NAC)和僵硬的习惯性行为的基础 行为(背外侧纹状体，DLS)，以及NAC和DLS及其相关区域之间的适当平衡 网络对于适应性(灵活)但高效(习惯性)行为至关重要。因此，当前应用程序将 研究可卡因的历史如何提示平衡和改变驱动灵活的神经网络信号 和僵化的策略。平衡这些皮质下网络需要大脑皮层的输入。具体地说，不同的 MPFC亚区(前皮质，PRL；和下缘皮质，IL)不同地参与了灵活和 分别是僵化的战略。因此，为了更全面地描述可卡因的历史如何导致持久 行为障碍，我提出了4个具体目标来检查可卡因历史或影响的具体影响 对推动灵活性的网络进行特定的操作。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(局部场势)在学习过程中奖励预测性线索 和灵活的行为。在目标2中，我将确定初级皮层(PRL)对NAC核心的输入是否具有因果关系 与NAC中的灵活行为及其神经编码有关。在目标3中，我将独立决定如何 可卡因的病史改变了IL和DLS细胞的激活和网络动力学，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IL是否对黑质(主要输入 DLS)通路与DLS中的灵活行为和神经编码有因果关系。加在一起，这些 具体目标将描述两个并行电路之间的平衡(一个涉及PRL和NAC，另一个 涉及IL和DLS)在行为灵活性中的作用，并确定可卡因的历史如何改变这种平衡 朝向僵化的(习惯性的)电路和行为。了解灵活VS背后的神经电路 习惯性行为和这些区域的神经编码如何因药物使用而改变将提供关键的洞察力 为药物滥用障碍患者的治疗干预提供新的、更具选择性的靶点。

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.