Dissecting neural circuits regulating sleep fragmentation in Parkinson’s disease

About This Grant

Project Summary/Abstract Parkinson’s disease (PD) is a common neurodegenerative disease affecting millions of people worldwide. PD is defined by its motor features (tremor, rigidity, and bradykinesia), but it also has prominent non-motor features, which can be disabling. Sleep disturbances are a common non-motor feature of PD that can dramatically affect patient quality of life. While there has been significant progress in our understanding of the neural circuitry driving motor features of PD, the circuits and mechanisms contributing to sleep disturbances in PD are poorly understood. The goal of this proposal is to use ex vivo and in vivo electrophysiologic techniques to dissect neural circuits driving sleep disturbances in a mouse model of PD. This proposal will focus on a brain region called the pedunculopontine nucleus (PPN), which links basal ganglia motor circuitry and brainstem sleep circuitry. Aim 1 will use brain slice electrophysiology to test how PPN neurons integrate basal ganglia inputs following loss of dopamine. Aim 2 will use in vivo electrophysiology and sleep recording to evaluate how PPN neuron firing changes across sleep-wake transitions after loss of dopamine. Together this work will make an important contribution to our understanding of how sleep circuitry is dysregulated in PD, which will aid in the development of targeted therapies to treat sleep disturbances in PD. As a clinician in Movement Disorders at UCSF, Dr. Marcott sees firsthand the struggles of patients living with PD. Under the mentorship of Drs. Alexandra Nelson and Ying-Hui Fu, Dr. Marcott will build on her previous experience using brain slice electrophysiology to study dopamine signaling in the basal ganglia and gain new skills for measuring in vivo brain activity across arousal states in parkinsonian mice. The work described in this proposal, including proposed experiments and career development plan, will support Dr. Marcott as she works to become an independent physician scientist studying sleep disturbances in PD.