Investigating the role of prefrontal cortex circuits in opioid-induced risk-taking behavior

研究前额皮质回路在阿片类药物诱发的冒险行为中的作用

• 批准号: 10389524
• 负责人: Cana Quave
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389524
• 关键词: Address; Affect; Affective; Animals; Area; Attention; Awareness; Behavior; Behavioral; Biological; Brain; Cessation of life; Choice Behavior; Clinical; Conflict (Psychology); Cues; Decision Making; Development; Drug usage; Drug user; Electrophysiology (science); Emotional; Executive Dysfunction; Exposure to; Felis catus; Female; Fentanyl; Food; Fostering; Fright; Goals; Health; Human; Impairment; Individual; Intake; Investigation; Knowledge; Light; Link; Medial; Mental disorders; Modeling; Motivation; Negative Reinforcements; Neurons; Nucleus Accumbens; Odors; Opiate Addiction; Opioid; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Population; Positive Reinforcements; Prefrontal Cortex; Process; Public Health; Rattus; Research; Rewards; Risk; Risk Behaviors; Risk-Taking; Rodent; Rodent Model; Role; Stimulus; Structure; Structure of paraventricular nucleus of thalamus; Substance Use Disorder; Synaptic plasticity; Techniques; Technology; Testing; Time; Transcranial magnetic stimulation; United States; approach avoidance behavior; avoidance behavior; base; behavioral phenotyping; cognitive function; conditioned place preference; conditioning; drug reward; experimental study; in vivo; individual variation; male; motivated behavior; neural circuit; neural patterning; neuromechanism; novel; novel strategies; novel therapeutics; opioid exposure; opioid misuse; opioid use; opioid use disorder; opioid withdrawal; optogenetics; preference; relating to nervous system; response; substance use; synthetic opioid; tool

Project Summary Despite the widely publicized risks of non-medical opioid use, opioid misuse continues to be a serious health problem affecting a significant parcel of the population in the United States. While opioid use disorder has been linked to abnormal risk-related decision making, the causal mechanisms underlying this relationship remain unclear. Both human and animal studies suggest that aberrant activity in the brain's prefrontal cortex (PFC) may contribute to the risky choice behavior induced by repeated opioid exposure. Particularly, the prelimbic subregion (PL) of the PFC has been implicated in both the rewarding effects and the subsequent behavioral changes induced by opioids. Previous neuroanatomical studies have shown that PL neurons send dense projections to the nucleus accumbens (NAc), a region implicated in behavioral motivation and maladaptive opioid seeking. Additionally, the PL projects densely to the paraventricular nucleus of the thalamus (PVT), a region involved in behavioral conflict and the negative emotional aspects of opioid withdrawal. However, how opioids alter the function of these two distinct PL pathways to elicit risky drug seeking remains unexplored. I will address this question by using a novel model of opioid-induced risk-taking behavior in which rats will be exposed to a conflict between seeking opioids and avoiding a fearful stimulus. In Aim 1, I will investigate individual variabilities in risky decision making and determine which behaviors predict risky choice during a conflict situation. In Aim 2, I will combine optogenetic and electrophysiological techniques to record the activity of PL neurons that project to either the NAc (PL-NAc) or the PVT (PL-PVT) during the conflict test. Finally, in Aim 3, I will establish the role of PL-NAc and PL-PVT projections in opioid-induced risk taking by using optogenetics to either inhibit or excite these circuits during conflict and characterize the resultant behavior. This project will allow me to uncover the PFC underpinnings of opioid-induced risky decision making, which may help us to understand how repeated opioid exposure affects motivated behaviors in humans.

项目概要 尽管非医疗阿片类药物使用的风险已被广泛宣传，但阿片类药物滥用仍然是一个严重的健康问题 影响美国很大一部分人口的问题。虽然阿片类药物使用障碍已 与异常的风险相关决策有关，这种关系背后的因果机制仍然存在 不清楚。人类和动物研究表明，大脑前额皮质 (PFC) 的异常活动可能会导致 导致反复接触阿片类药物引起的危险选择行为。特别是前边缘分区 PFC 的 (PL) 与奖励效应和随后的行为变化有关 由阿片类药物诱发。先前的神经解剖学研究表明，PL 神经元向 伏核（NAc），一个与行为动机和适应不良的阿片类药物寻求有关的区域。 此外，PL 密集投射到丘脑室旁核 (PVT)，该区域参与 行为冲突和阿片类药物戒断的负面情绪方面。然而，阿片类药物如何改变 这两种不同的 PL 途径在引发危险药物寻求方面的功能仍有待探索。我会解决这个问题 通过使用阿片类药物诱导的冒险行为的新模型来回答这个问题，在该模型中，老鼠将面临冲突 在寻求阿片类药物和避免可怕的刺激之间。在目标 1 中，我将调查风险的个体差异 决策并确定哪些行为预示着冲突情况下的危险选择。在目标 2 中，我将 结合光遗传学和电生理学技术来记录 PL 神经元的活动，这些神经元投射到 冲突测试期间的 NAc (PL-NAc) 或 PVT (PL-PVT)。最后，在目标 3 中，我将建立以下角色： 通过使用光遗传学抑制或激发阿片类药物诱导的冒险行为中的 PL-NAc 和 PL-PVT 预测 这些电路在冲突期间并表征由此产生的行为。这个项目将让我发现 PFC 是阿片类药物引起的风险决策的基础，这可能有助于我们了解如何重复 阿片类药物暴露会影响人类的动机行为。