B1 noradrenergic blockade in early withdrawal to reduce cocaine induced behavioral flexibility deficit

项目总结 平衡习惯和灵活的环境导航策略对于行为是必要的 这既是认知上有效的，也是适应变化的，也是破坏这种平衡的扰动 会导致严重的行为障碍。例如，滥用药物的患者 精神障碍通常很难改变他们的行为以应对不断变化的结果，导致 决策不力。在大鼠中，吸食可卡因的历史会削弱调节行为的能力 根据报酬贬值后的报酬预测线索，一种衡量灵活性的规范指标 行为(即，可卡因导致僵化的行为)。有趣的是，不同的纹状体底物 灵活的、目标导向的行为(伏隔核，NAC)和僵硬的习惯性行为是其基础 行为(背外侧纹状体，DLS)，以及NAC和DLS与它们之间的适当平衡 关联网络对于适应性(灵活)但高效(习惯性)行为至关重要。父辈 这一多样性补充剂奖考察了可卡因的历史如何提示平衡和改变 驱动灵活和僵化策略的神经网络信号。平衡这些因素 皮质下网络需要皮质输入。具体地说，要确定mPFC有多不同 亚区(前皮质，PRL；和下缘皮质，IL)不同地参与了柔韧 和僵化的战略。在这里，我们将重点阐明可卡因的历史是如何 导致不灵活的行为和异常的PRL和IL神经活性。我们认为早期的压力 戒断过程中可卡因自身诱发的行为灵活性障碍 行政管理。皮质酮治疗足以将行为转变为僵硬 策略，类似于我们所报道的可卡因历史。因为β-1拮抗剂可以 减少早期可卡因戒断症状，如焦虑升高和皮质酮，我们 假设这种治疗将恢复可卡因诱导的灵活行为缺陷。这 该项目将允许候选人学习新的技术(手术，自我管理，体内 电生理分析)，并准备继续我的研究生涯 研究生院。了解顽固行为背后的神经回路是如何神经的 这些区域的编码被药物使用改变将提供对新的和更多的关键洞察 药物滥用障碍患者治疗干预的选择性靶点。

PROJECT SUMMARY Balancing habitual and flexible strategies for navigating the environment is necessary for behavior that is both cognitively efficient yet 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. The parent award for this diversity supplement examines 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, to determine how distinct mPFC subregions (prelimbic cortex, PrL; and infralimbic cortex, IL) are differentially involved in flexible and inflexible strategies, respectively. Here, we will focus on elucidating how a history of cocaine leads to inflexible behavior and aberrant PrL and IL neural activity. We propose that early stress during withdrawal contributes to deficits in behavioral flexibility induced by cocaine self- administration. Corticosterone treatment is sufficient to shift behavior towards inflexible strategies, similar to what we have reported with a history of cocaine. Since β1 antagonism can reduce early cocaine withdrawal symptoms such as elevated anxiety and corticosterone, we hypothesize that this treatment will restore cocaine induced deficits in flexible behavior. This project will allow for the candidate to learn new techniques (surgeries, self-administration, in vivo electrophysiological analysis) and prepare for continuing my research career by applying to graduate school. Understanding the neural circuitry underlying inflexible behavior 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.