Study Rationale: Parkinson’s disease (PD) begins decades before it compromises an individual’s ability to move about in the world and sleep through the night. Understanding how the dysfunction of brain circuits begins and then evolves to cause difficulty in moving and sleeping will allow us to diagnose PD earlier – increasing our chances of halting disease progression and our ability to better treat the disease once it appears.
Hypothesis: We hypothesize that progressive damage to dopamine-releasing neurons causes a staged disruption of neural circuits affecting larger and larger parts of the brain, ultimately leading to both the motor and sleep deficits characteristic of PD.
Study Design: Using newly developed preclinical models that faithfully reproduce the human staging of PD pathology in the basal ganglia, a brain region critical for motor control, we will employ the most advanced optical, electrophysiological and behavioral methods available to establish how altered activity in genetically defined brain circuits leads to an impaired ability to move and sleep soundly in PD. By examining how this brain circuitry changes over time, our studies should be able to pinpoint the most effective targets for new and more powerful therapeutic interventions for people with PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: Obtaining a better understanding of how the dysfunction of brain circuits evolves as PD progresses should allow earlier diagnosis – enhancing the potential benefit of disease-modifying therapies and providing better treatment strategies for later stage PD patients.
Next Steps for Development: A firmer grasp of the sequence of events leading to the circuit dysfunction underlying motor and sleep symptoms afflicting people with PD should allow the development and design of pharmacological and genetic therapies that target specifically these symptoms.