The Dual Role of Neural Activity in Parkinson's Disease

We will examine dopamine system compensation during the transition from presymptomatic to manifest (symptomatic) Parkinson’s disease, using a mouse model in which alpha-synuclein is virally overexpressed in dopamine neurons. We will use motor and cognitive behavioral assays and examine activity in the sensorimotor (dorsolateral, DLS) and associative (dorsomedial, DMS) striatum. We will record dopamine activity using GCaMP and dLight sensors, and we will examine adenosine and endocannabinoid activity using recently developed GRAB sensors for these molecules (Dong et al., 2021; Wu et al., 2020). Adenosine signaling may be of particular interest since istradefylline, an adenosine A2A receptor antagonist, is FDA-approved as an add-on for L-DOPA therapy to reduce “OFF” periods, but might have other protective roles in early disease progression. Adenosine homeostasis is thought to be disrupted in several neurodegenerative diseases, and is regulated at least in part by astrocytes (Boison et al., 2010). Finally, a novel aspect of this amendment would involve overexpressing alpha-synuclein specifically in DMS- or DLS-projecting dopamine neuron populations and using GCaMP to assess how these distinct dopamine circuits compensate for synuclein-induced impairment and eventual degeneration of specific pathways.