Circuit Mechanisms of Bradykinesia in Mouse Models of Parkinson’s Disease

PROJECT SUMMARY The degeneration of dopamine (DA) neurons within the basal ganglia (BG) causes Parkinson's disease (PD). One of its cardinal symptoms is the slowing of volitional movements of the hands, arms and/or legs, known as bradykinesia. Although much has been learned over the past several decades about the physiological consequences of DA neuron loss on the activity of neurons within the BG, much less in understood about how dysfunction of the BG ultimately impacts downstream brain regions to impair motor and cognitive abilities. Our long-term goal is to address this gap in knowledge in the hopes of identifying novel therapies to alleviate PD’s motor and non-motor symptoms. This exploratory R21 proposal represents the first step in this endeavor: it aims to distinguish the relative contribution of two main neural projections out of the BG – one feeding back to cortex via the thalamus vs. one feeding forward to brainstem nuclei – to bradykinesia. This proposal leverages a combination of imaging and optogenetic manipulations in mice performing a dexterous forelimb motor task before and after DA neuron lesions with 6-hydroxydopamine. Our experiments will test the hypothesis that bradykinesia results from impairments in BG feedback to cortex via thalamus by comparing and contrasting the activity of BG output neurons in the substantia nigra pars reticulata (SNr) that project to thalamus or brainstem using axonal Ca2+ photometry (Aim 1) and by testing the ability of BG efferents to restore vigorous forelimb movements using optogenetic manipulations (Aim 2). We will benchmark our findings to levodopa treatment to concentrate on therapeutically-effective pathways and validate them in a mouse genetic model of PD in which DA neurons degenerate progressively. Our findings will deepen our understanding of the mechanistic underpinnings of PD’s symptoms and stimulate investigations into novel, DA-independent therapeutic targets outside the BG to provide effective and continued symptomatic relief from motor impairments.