PROJECT ABSTRACT Opioid Use Disorder (OUD) is a complex medical condition characterized by compulsive and maladaptive use of opioid substances, including prescribed pharmaceuticals (such as oxycodone) and illegal agents (such as heroin). It causes physiological, psychological, and sociological effects, including tolerance, withdrawal symptoms, relapse, and impaired daily functioning. Managing opioid use disorder (OUD) involves addressing withdrawal symptoms and relapse risks during abstinence, which can vary throughout different stages of recovery. During the initial phase of opioid withdrawal, individuals often encounter the most severe and debilitating symptoms. These symptoms typically peak within the first few days of refraining from drug use and gradually subside with prolonged abstinence. Nevertheless, the most significant challenge during this critical stage of recovery is the sustained risk of relapse, even after the initial withdrawal symptoms have abated. This risk is further amplified by external cues that can trigger intense cravings and the compulsion to seek drugs. Hence, it is imperative to acquire a comprehensive comprehension of the neural mechanisms that underlie relapse during early and prolonged abstinence from opioid use. Rodent studies suggest that glutamatergic projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) are involved in the expression of negative affective states and relapse after abstinence. Both PVT and NAc are heterogeneous and complex brain regions with diverse sets of cell types, functional connections, unique subregions, and neurotransmitter systems. Opponent roles of anterior/posterior PVT subregions, and D1- and D2-medium spiny neuron activity, has been found for approach/appetitive and avoidance/aversive behaviors. This research project addresses the critical question of how the PVT interacts with the NAc to modulate withdrawal symptoms during early abstinence and prolonged abstinence on the vulnerability to relapse. This project is an essential step towards my goal of becoming an independent researcher. Through the K99/R00 grant, I'll have the opportunity to improve my understanding and abilities in advanced neuroscientific methodologies, which will lay the groundwork for my research program focused on addiction neuroscience. The knowledge and data I gather during the K99 phase will be a solid foundation for a successful transition to the R00 phase, which will help me expand my research in this field. Additionally, this work will reveal the complex PVT-NAc neural mechanisms governing relapsing behaviors, which could lead to innovative strategies for addiction treatment and prevention.

PROJECT NARRATIVE This K99/R00 proposal incorporates innovative optogenetics and fiber photometry techniques to investigate alterations in synaptic plasticity and circuit dynamics during oxycodone use (self-administration), abstinence, and relapse. Specifically, the ultimate goal is to advance our mechanistic understanding of opioid use disorders, including differences between sexes.