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

项目摘要 尽管广泛宣传非医疗类阿片使用的风险，但类阿片滥用仍然是一个严重的健康问题， 这个问题影响了美国相当一部分人口。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，大脑前额叶皮层（PFC）的异常活动可能 与阿片类药物重复暴露诱发的风险选择行为有关。特别是前边缘区 (PL)前额叶皮层的活动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神经元发送密集的投射， 丘脑核（NAc），一个涉及行为动机和适应不良的阿片类药物寻求的区域。 此外，PL密集地投射到丘脑的室旁核（PVT），这是一个涉及与丘脑相关的区域。 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 这两个不同的PL途径的功能，以引起危险的药物寻求仍然没有探索。我会解决这个问题 问题通过使用阿片类药物诱导的冒险行为的新模型，其中大鼠将暴露于冲突 寻求阿片类药物和避免恐惧刺激之间的关系。在目标1中，我将研究风险的个体差异， 决策制定，并确定哪些行为预测冲突情况下的风险选择。在目标2中，我将 联合收割机光遗传学和电生理学技术记录PL神经元的活动， 冲突测试期间的NAc（PL-NAc）或PVT（PL-PVT）。最后，在目标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行为中的PL-NAc和PL-PVT投射 这些电路在冲突期间，并表征结果的行为。这个项目将让我揭开 PFC是阿片类药物诱导的风险决策的基础，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.