Striatal Synaptic Plasticity in the Cognitive Aspects of Parkinsons Disease

Parkinson’s Disease (PD) has motor and nonmotor features. Amongst nonmotor symptoms, cognitive impairment drives disability and loss of quality of life. Even in early PD, deficits develop in executive function, which includes cognitive flexibility. These symptoms are rarely remediated by dopamine replacement therapy, and in fact, dopamine agonists can trigger impulse control disorder (ICD). ICD manifests as compulsive gambling, shopping, pornography use, or eating. While PD-related executive dysfunction and ICD are common, little is known about their cellular or circuit-level mechanisms. In this collaborative project, we will take advantage of our labs’ (1) optimized cognitive assays in Parkinsonian mice, (2) expertise in in vivo imaging, in vivo electrophysiology, and ex vivo electrophysiology to investigate the circuit- and synaptic-level mechanisms driving PD-related executive dysfunction and ICD. In Aim 1, we will determine the role of dynorphin – a neuropeptide specifically expressed in direct pathway spiny projection neurons (dSPNs) – in behavioral flexibility in mouse models of PD. In Aim 2, we will determine the role of prefrontal cortex- dorsomedial striatum inputs in the mouse model of PD/ICD. Lastly, in Aim 3, we will use in vivo 2-photon imaging and single-unit electrophysiology to identify the neuronal ensemble activity patterns and physiological signature of dysregulated executive function. Together, this integrative project will focus on striatal plasticity mechanisms underlying the cognitive dysfunction in PD. The insights from these studies will inform the development of treatments that alleviate cognitive-behavioral dysfunction in PD and ICD. 1 Project Number: 1R01NS148534-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Alexandra Nelson (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $595,208 | Activity Code: R01 | Study Section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11357011