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: 10557087
• 负责人: Cana Quave
• 金额: $ 3.52万
• 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/10557087
• 关键词: 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; Link; Medial; Mental disorders; Modeling; Morphine; Motivation; Negative Reinforcements; Neuroanatomy; Neurons; Nucleus Accumbens; Odors; Opiate Addiction; Opioid; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Population; Positive Reinforcements; Prefrontal Cortex; Process; Public Health; Rattus; Relapse; Research; Rewards; Risk; Risk Behaviors; Risk Reduction; Risk Taking; Rodent; Rodent Model; Role; Stimulus; Structure; Structure of paraventricular nucleus of thalamus; Substance Use Disorder; Synaptic plasticity; Techniques; Technology; Testing; Transcranial magnetic stimulation; United States; addiction; approach avoidance behavior; avoidance behavior; behavior prediction; behavioral phenotyping; cognitive function; conditioned place preference; conditioning; drug reward; experimental study; fentanyl use; in vivo; individual variation; male; motivated behavior; neural; neural circuit; neural patterning; neuromechanism; novel; novel strategies; novel therapeutics; opioid exposure; opioid misuse; opioid use; opioid use disorder; opioid withdrawal; optogenetics; preference; 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.

项目摘要 尽管非医疗阿片类药物使用的风险广泛，但阿片类药物滥用仍然是一种严重的健康状况 影响美国大量人口的问题。虽然阿片类药物使用障碍 与异常与风险相关的决策有关，这种关系的因果机制仍然存在 不清楚。人类和动物研究都表明，大脑前额叶皮层（PFC）的异常活性可能 有助于反复暴露阿片类药物引起的危险选择行为。特别是预次子区域 PFC的（PL）与奖励效应和随后的行为变化有关 由阿片类药物诱导。以前的神经解剖学研究表明，PL神经元将密集的投影发送给 伏隔核（NAC），该区域涉及行为动机和适应不良的阿片类药物。 另外，PL密集地向丘脑（PVT）的室室核密集地投射 行为冲突和阿片类药物戒断的负面情绪方面。但是，阿片类药物如何改变 这两种不同的PL途径的功能仍未得到探索。我将解决这个问题 通过使用阿片类药物引起的冒险行为的新型模型，其中大鼠暴露于冲突 在寻求阿片类药物和避免可怕的刺激之间。在AIM 1中，我将调查风险的个别变异性 决策并确定哪些行为可以预测冲突情况下的冒险选择。在AIM 2中，我会 结合光遗传学和电生理技术，以记录投影到的PL神经元的活性 冲突测试期间NAC（PL-NAC）或PVT（PL-PVT）。最后，在AIM 3中，我将确定 通过使用光遗传学抑制或激发阿片类药物诱导的风险的PL-NAC和PL-PVT投影 冲突期间的这些电路并表征了由此产生的行为。这个项目将使我发现 PFC的基础阿片类药物引起的风险决策制定，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。