Neurobiological investigation of delay discounting: role of prelimbic cortex -> nucleus accumbens circuit

项目摘要/摘要 延迟折扣是一种决策类型，在这种决策中，个人根据以下因素对奖励的价值进行折扣 接收的延迟量[1-4]。一般来说，当出现空头时，个人会等待更大的回报 延迟。然而，随着奖励延迟的增加，个体会将他们的偏好转向较小的， 即时奖励，在这种情况下，延迟贴现可作为冲动程度的度量[1，2，4]。重要的是 延迟折扣增加(冲动增加)是物质使用障碍的常见症状[5-8]。 像可卡因这样的滥用药物会降低个体转向小的、直接的回报的程度， 导致更冲动的行为[6，8，16-18]。因此，更多的冲动可能会促进选择 持续吸毒的短期奖励高于长期福利(例如，健康、工作、家庭) 戒毒。关键的是，这些发现在啮齿动物模型中得到了证实，因为先前接触可卡因 在涉及延迟、大小和延迟折扣的决策任务中增加冲动性[2，19， 20]。此外，在延迟折扣上存在性别差异，一些数据表明女性表现出 啮齿动物和人类在延迟折扣任务中的冲动增强(与雄性相比)[23-25] [21，22]。因此，理解延迟折扣行为的神经基础是至关重要的，并且 在这一过程中潜在的性别差异。在这方面，前皮质(PRL)和伏隔核 (NAC)与冲动行为和选择有关[26，27]，并代表延迟的关键神经回路 贴现行为。重要的是，PRL选择性地使NAC核心失效[28-32]。然而，没有研究表明 直接检测了雄性或雌性大鼠延迟贴现行为中PRL神经元的活动，或 如果PRL-NAC核心电路与此行为有因果关系。在本申请中提出了两个具体目标 来解决这些问题。Aim 1将使用多神经元记录方法来研究PRL中的神经元是如何 编码关于动物活跃时延迟折扣行为的重要特征的信息 执行既定的延迟折扣任务。目标2将在这项工作的基础上，使用光遗传工具 探讨PRL-NAC核心通路在延迟折扣行为中的潜在因果作用。总而言之， 这些研究将对PRL-NAC核心电路在延迟折扣中的功能作用提供关键的见解 跨性别的行为，为未来研究滥用药物如何改变奠定了基础 这一制度导致了不适应的决策行为。

Project Summary/Abstract Delay discounting is a type of decision-making in which individuals discount the value of a reward based on the amount of delay to its receipt [1-4]. Generally, individuals will wait for a larger reward when there is a short delay. However, as delay to reward increases, individuals will shift their preference toward the smaller, immediate reward and in this way, delay discounting serves as a measure of impulsivity [1, 2, 4]. Importantly, heightened delay discounting (increased impulsivity) is a common symptom of substance use disorders [5-8]. Drugs of abuse such as cocaine decrease the point at which individuals shift to the small, immediate reward, resulting in more impulsive behavior [6, 8, 16-18]. As such, increased impulsivity may promote the selection of short-term rewards of continued drug use over long-term benefits (e.g., health, jobs, family) associated with drug abstinence. Critically, these findings are corroborated in rodent models, as prior exposure to cocaine increases impulsivity during decision making tasks involving delay, magnitude, and delay discounting [2, 19, 20]. Further, gender differences exist in delay discounting, with some data indicating that females demonstrate heightened impulsivity (compared to males) during a delay discounting task in rodents [23-25], and in humans [21, 22]. As such, it is critical to understand the neural underpinnings of delay discounting behavior, and potential gender differences in this process. In this regard, the prelimbic cortex (PrL) and nucleus accumbens (NAc) are implicated in impulsive behavior and choice [26, 27] and represent a key neural circuit in delay discounting behavior. Importantly, the PrL selectively enervates the NAc core [28-32]. However, no studies have directly examined the activity of PrL neurons during delay discounting behavior in male or female rats, or if the PrL-NAc core circuit is causally linked to this behavior. Two specific aims are proposed in this application to address these topics. Aim 1 will use multi-neuron recording methods to examine how neurons in the PrL encode information about the important features of delay discounting behavior while animals are actively engaged in a well-established delay discounting task. Aim 2 will build upon that work and use optogenetic tools to investigate a potential causal role of the PrL-NAc core pathway in delay discounting behavior. Collectively, these studies will provide critical insight into the functional role of the PrL-NAc core circuit in delay discounting behavior across genders and set the foundation for future studies that can examine how drugs of abuse alter this system and contribute to maladaptive decision making behaviors.