Striatal Mu Opioid Receptor Containing Neurons in L-DOPA induced dyskinesia

/Abstract: Candidate: My goal is to become an independent investigator running a multidisciplinary, translational, systems neuroscience lab which investigates mechanisms underlying specific symptoms of movement disorders and designs translational strategies. My lab will use electrophysiology and optical neuroscience techniques paired with behavior to investigate how cellular ensembles and circuits contribute to movement disorders symptoms. I have a strong background in behavioral neuropharmacology and electrophysiology. I propose to learn optical neuroscience techniques including 1-photon in vivo calcium imaging and data analysis methods which use computational neuroscience and machine learning to analyze behavior. This will allow me to make inferences about the role of specific neurons and circuits in motor symptoms and to have the necessary skills to produce high-impact publications and successful R01 submissions. I received my PhD in June 2020. After receiving an extension due to major medical issues, this is my last eligibility cycle for the K99/R00. Training: In addition to my mentor Dr. Moehle, and co-mentor Dr. Wesson, I have assembled an advisory committee of experts in opioid pharmacology and electrophysiology, Dr. Varga, and in using machine learning strategies and analyzing large datasets, Dr. Vaillancourt. This committee will provide training and guidance to accomplish this proposal. I have also identified both local and external courses, seminars, and meetings which will provide technical training, presentation experience, responsible conduct in research, and necessary skills (offer negotiations, tenure, lab management, etc.) to facilitate my transition to independence. Research: After chronic L-DOPA treatment, up to 90 percent of Parkinson’s disease patients will develop debilitating abnormal, involuntary movements called L-DOPA-induced dyskinesia (LID). The mechanisms behind LID development are not understood. A common single nucleotide polymorphism in the mu opioid receptor (MOR) gene, OPRM1 increases susceptibility to LID. The mechanisms whereby OPRM1 variants increase LID susceptibility and how MOR+ spiny projection neurons (SPNs) contribute to LID is unknown. My underlying hypothesis is that striatal MOR+ neurons cause LID through increased dSPN activity. In AIM1 I will use fiber photometry and machine learning methods in a mouse expressing an equivalent Oprm1 variant to understand the mechanism by which this Oprm1 variant influences neural activity and specific LID behaviors. In AIM2 I will chemogenetically stimulate or inhibit MOR+ dSPN and iSPNs to determine the effects of MOR+ SPNs on LID behavior and striatal cellular ensemble activity as determined by 1-photon calcium imaging. In AIM3A, I will test the physiological changes occurring in MOR+ and MOR- dSPNs and iSPNs over the course of chronic L-DOPA treatment. In AIM3B I will test how MOR+ vs. MOR- dSPN ensembles are involved in LID using 1P calcium imaging with chemogenetic excitation and inhibition. Project Number: 1K99NS142560-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Nicole Chambers | Institution: UNIVERSITY OF FLORIDA, GAINESVILLE, FL | Award Amount: $114,102 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 CN-V (91)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371349