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

项目摘要 尽管非医用阿片类药物使用的风险被广泛宣传，但阿片类药物滥用仍然是一种严重的健康问题。 影响到美国相当一部分人口的问题。虽然阿片类药物使用障碍一直是 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。人类和动物的研究都表明，大脑前额叶皮质(PFC)的异常活动可能 导致反复接触阿片类药物而导致的危险选择行为。特别是，初步分区域 PFC的(PL)与奖赏效应和随后的行为变化有关 阿片类药物引起的。以前的神经解剖学研究表明，PL神经元向 伏隔核(NAC)，这是一个与行为动机和不适应阿片类药物寻找有关的区域。 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，阿片类药物是如何改变 这两个不同的PL通路在引发危险药物寻求方面的功能仍未被探索。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提出问题，在该模型中，大鼠将暴露在冲突中 在寻求阿片类药物和避免可怕的刺激之间。在目标1中，我将研究Risk 作出决策，并确定哪些行为预测在冲突情况下的风险选择。在《目标2》中，我会 结合光遗传学和电生理学技术记录投射到 冲突测试期间的NAC(PL-NAC)或PVT(PL-PVT)。最后，在目标3中，我将确立 光遗传学抑制或兴奋阿片类药物诱导的冒险行为中PL-NAC和PL-PVT的投射 这些电路在冲突期间并表征了所产生的行为。这个项目将让我发现 PFC是阿片类药物诱导的危险决策的基础，这可能有助于我们理解如何重复 阿片类药物的暴露会影响人类的动机行为。

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.