Projection-specific signals of dopamine neurons in health and Parkinson’s disease

Midbrain dopamine neurons have fundamental roles in reward learning and movement control, and their dysfunction is associated with various disorders in particular Parkinson’s disease. Recent studies have shown substantial diversity in the activity of these neurons depending on where in the striatum their axons project. In our recent experiments we recorded the activity of dopamine axonal terminals while systematically manipulating stimuli, actions and rewards in a precise behavioural task. While the activity of dopamine projections to ventral regions of striatum mainly reflected rewards, dopamine axonal projections to dorsal striatum encoded contralateral stimuli and actions with negligible representation of reward value. These findings raise the questions of whether dopamine signals across striatum encode specific aspects of associations between stimuli, actions and rewards during learning, and whether these anatomically-specific dopamine signals are impaired during Parkinson’s disease. This project will address these questions using a combination of imaging, computational and behavioural experiments in healthy mice as well as mouse models of Parkinson’s disease. In Oxford University (Lak lab), we will use recent genetically–encoded dopamine sensors in combination with fiber photometry to monitor the dynamics of dopamine signals across the striatum while healthy mice perform a learning task guided by sensory stimuli and rewards. These results will provide a foundation for examining these dopamine signals during Parkinson’s disease, which will be performed at NIH (Cui lab). Using MitoPark mouse line (with progressive and robust phynotype of Parkinson’s disease), we will examine the dynamics of striatal dopamine signals using photometry during learning tasks established in healthy mice in Oxford. In analysing the data, we will use learning models to relate dopamine signals with normative computational models of decision making and learning. The project is primarily experimental in nature but will provide an opportunity to develop computational skills. The project will provide fundamental insights into behaviourally-relevant computations that dopamine signals across the striatum encode, and will uncover how these neuronal computations change during Parkinson’s disease. For further information visit: https://www.niehs.nih.gov/research/atniehs/labs/ln/pi/iv/index.cfm and www.laklab.org

*This project is available for the 2021 Oxford-NIH Pilot Programme*