Study Rationale:
Dopamine is a critical signaling molecule in the brain for voluntary movement. Neurons that produce and release dopamine are lost in Parkinson’s disease leading to debilitating problems. Recent research has revealed different dopamine neuron subtypes that have different vulnerability to Parkinson’s. The release of dopamine from the ends of these neurons, termed axons, can be directly regulated by other signaling molecules, ‘neuromodulators’, and this regulation is very likely to differ between the distinct dopamine neuron subtypes. If we could identify how these mechanisms differ between vulnerable versus resistant subtypes we can understand whether this might contribute to differences in vulnerability and provide opportunities to refine treatments.
Hypothesis:
We hypothesize that distinct neuromodulator mechanisms will act directly on axons of vulnerable versus resistant dopamine neurons to differentially govern dopamine transmission.
Study Design:
This project will use state-of-the-art tools that measure dopamine axon activity and detect dopamine release to investigate how key modulatory mechanisms in the striatum regulate dopamine axons of vulnerable versus resistant molecular subtypes of dopamine neurons. The study will benefit from the leading expertise of both home and host laboratories. The mechanisms modulating striatal dopamine release from distinct dopamine neuron subtypes will first be established in the home lab in mouse brain slices, a preparation which facilitates mechanistic manipulations. Results from these experiments will inform the best candidates to explore to understand actions in intact brains of behaving mice in the host lab.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This study will address a critical knowledge gap in the Parkinson’s research field as to how distinct modulatory mechanisms may differentially regulate striatal axons of dopamine neurons that are vulnerable versus resistant to degeneration in Parkinson’s. This may inform the development of targeted and improved strategies to rescue DA dysfunction and offer new avenues for therapeutic benefit in Parkinson’s.
Next Steps for Development:
If successful, and this study points towards a specific mechanism that may differentially regulate axons of vulnerable dopamine neurons, the next steps would involve assessing potential differences in an animal model of PD, followed by identifying and testing a suitable drug to target this mechanism.