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

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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.