Candidate: My long term goal is to become an independent investigator running an interdisciplinary and collaborative research team to understand the mechanisms underlying the effects of medications and drugs of abuse on intra/interconnected brain circuits . Specifically, my interests surround understanding how cholinergic interneurons (ChAT) regulate the activity of nicotinic acetylcholine receptors (nAChRs) in the local circuitry of the nucleus accumbens (NAc), thereby underlying sex differences in dopamine signaling associated with reward and motivated behavior. I have a strong background in electrophysiology and pharmacology, and propose to be trained in optogenetics, behavioral pharmacology, and in vivo fiber photometry to round out my training. This will provide me with the skills to produce high impact publications and successful R01 submissions. I received my PhD in April of 2017 and this is currently my third year of postdoctoral research training. Training: In addition to Dr. Calipari, I have an advisory committee of experts in academic research who will provide the necessary training and guidance to accomplish this proposal. Dr. Barnett, is the Vice-chair of and a Professor in the Department of Pharmacology and Dr. McCabe is the Director of the Office of Postdoctoral Affairs. Outside of the committee, we have identified, courses, seminars, and meetings to provide further technical training, presentation experience, responsible conduct in research, and the necessary skills (negotiations, tenure, laboratory management, etc.) to transition to independence. Research: Substance use disorder (SUD) is a chronic, recurring brain disease characterized by significant dysfunction in reward-seeking behavior. A large body of work has focused on understanding the neural mechanisms in the brain?s reward circuitry, yet these studies have overwhelmingly focused on male subjects. Epidemiological evidence shows that women represent a particularly susceptible population to SUD, yet the mechanisms in the brain that underlie sex differences in reward and motivation are largely unknown. The neural control of reward is dependent on dopamine release in the NAc that is subject to heavy modulation by ChAT signaling through nAChRs; a process that is essential to encoding information about environmental reward predictive cues. My preliminary data show fundamental sex differences in the regulation of dopamine release via nAChRs, yet to date, it is not known how this process occurs, what factors influence this effect, and how this relates to motivated behavior. The overall goal of this proposal is to define sex-specific circuit-based mechanisms governing sex differences in reward processing. By using voltammetry techniques along with pharmacology, behavioral analysis, and in vivo dopamine recording, I anticipate being able to expand our understanding of the sex differences in ChAT regulation of nAChR modulation of dopamine release underlying reward learning. The successful completion of this proposed project has the potential to inform the development of better and more effective pharmacotherapies to counter neurological disease states in women.
Epidemiological evidence shows that women represent a particularly vulnerable population in Substance Use Disorder, and preclinical studies have demonstrated a significant sex difference in reward processing and motivated behavior in female subjects. Acetylcholine released from cholinergic (ChAT) interneurons in the nucleus accumbens (NAc) acting through pentameric nicotinic acetylcholine receptors (nAChRs), is a potent regulator of dopamine release underlying reward processing in the NAc. In this proposal I will determine both the subunits of nAChRs modulating sex differences in reward processing and behavior as well as the circuit and cell-type specific regulation of dopamine release within the local NAc circuit by ChAT interneuron modulation of nAChR activity.