Project Summary / Abstract Parkinson disease (PD) is the second most common neurodegenerative disease, leading to disability and death for individuals, and significant costs for caregivers and society. Cognitive impairment is a common cause of functional impairment in PD and a central feature of the related disorder Dementia with Lewy Bodies (DLB). To date, there are no disease-modifying therapies to prevent the development or progression of these symptoms. In both PD and DLB, intraneuronal inclusions of the protein alpha-synuclein (α-syn) in limbic and cortical regions correlates with cortical hypometabolism, hallucinations, and progression to dementia, suggesting a central role for α-syn in cognitive impairment. However, the specific effects and mechanisms by which α-syn pathology impacts the function of cortical neurons and circuits remain unknown. In addition, the cortex exhibits regional vulnerability, both to the deposition of α-syn and to the degree of functional impairment, for unknown reasons. Thus, major gaps remain in our understanding of how cortical circuits become dysfunctional in PD and DLB and how specific features of cortical circuits impact the spread and accumulation of α-syn. Here, Dr. Zeiger will lead a research group to test the hypothesis that a reciprocal relationship exists between α-syn pathology and neuronal activity, such that cortical α-syn accumulation directly disrupts neuronal activity, and conversely, that changes in neuronal activity influence the progression of α-syn pathology. In Aim 1, Dr. Zeiger’s group will use a novel model system in a mouse model of PD to directly define how α-syn impacts the function of different disease-relevant cortical circuits. Innovative longitudinal two-photon imaging methods will be used to simultaneously monitor neuronal activity and the accumulation of α-syn inclusions with single-cell resolution. This will then be correlated with behavioral studies to better understand how α-syn-mediated circuit dysfunction leads to cognitive and motor symptoms. The impact of co-existing Alzheimer’s disease amyloid-beta pathology on α-syn-mediated circuit dysfunction will also be tested. In Aim 2, Dr. Zeiger’s group will test the hypothesis that changes in activity can increase or decrease the accumulation of α-syn in the cortex. Advanced transgenic mouse lines and viral tools will be used to specifically manipulate the activity of different components of corticostriatal circuits to define how the activity of specific sub-populations of neurons contribute to the progression of PD pathology. Together, these studies will uncover basic mechanisms about how cortical circuits are affected in PD and DLB. This information is also of great importance for future translational studies aiming to use therapeutic neuromodulation to treat symptoms arising from cortical circuit dysfunction or potentially even slow disease progression in PD and DLB.