Physiological and Molecular Mechanisms of Mu Opioid Receptors in Motivation and Affect

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Project Summary: The primary goal of this training proposal is to understand, with mechanistic granularity, how mu opioid receptors (MORs) modulate motivated `wanting' versus affective `liking' in nucleus accumbens (NAc). During the proposed K99 training period, I will be trained in two in vivo physiology/imaging approaches (fiber photometry and 1-photon microscopy) and on intracellular/molecular effector systems. Additionally, I will actively participate in professional/career training opportunities and have frequent meetings with my mentoring committee to prepare to apply and succeed in an independent faculty position. The first research aim of my proposal seeks to understand the temporal dynamics and effects of endogenous MOR signaling in the DRNEnkNAc pathway. My previous postdoctoral research, using pharmacology, genetics, and optogenetics/chemogenetics, has identified the terminals of an enkephalinergic dorsal raphe nucleus projection to NAc as the site of MOR action for modulating food intake behaviors. To better understand how MOR signaling affects this pathway, I will use two in vivo imaging approaches, fiber photometry and microendoscopy, to determine how endogenous MOR signals shape neural circuit activity during motivated behaviors (Aim 1, K99). Additionally, because the roles of specific intracellular signaling cascades have not been well defined in brain reward circuits, I will manipulate G-protein and beta-arrestin signaling pathways to determine how each of them contributes to behavior (Aim 2, K99). During the K99 phase, I will also be preparing to lead my own research lab. I will actively participate in scientific society leadership positions (chairing symposia, steering committees), learn about how to direct a lab (budgeting and administrative tasks), and continue to further my scholarly knowledgebase (planned interactions with my mentor and committee members). For the R00 “independent” phase of my proposal, I propose to build on the mentored training above to examine what mechanisms and circuits underlie MOR-mediated affective `liking' in NAc (Aim 3). These studies are of interest because growing evidence suggests that though NAc MORs can robustly modulate both motivation and affect, they likely do so via different neural mechanisms. Understanding how these biopsychological systems are dissociable, even within a specific neurochemical class, has important implications for developing novel therapeutic drugs that are efficacious without also having a propensity for abuse. I will selectively disrupt or restore MOR function using multiple genetic mouse models and viral vector interventions, as well as record endogenous neuronal responses in vivo using microendoscopic approaches. I will perform these experiments while testing mice on the affective test reactivity (TR) test, which classifies and quantifies innate orofacial reactions to taste stimuli and has been used effectively for decades to measure the affective value of taste stimuli. The knowledge gained from these studies and mentorship opportunities will greatly facilitate the development of my own research program, preparing me for the next phase of my career.