Ahsan Habib, United States of America
National Institute on Aging, National Institutes of Health, USA NeurogeneticsAuthor Of 1 Presentation
FUNCTION AND REGULATION OF ALDH1A1-POSITIVE NIGROSTRIATAL DOPAMINERGIC NEURONS IN MOTOR CONTROL AND PARKINSON'S DISEASE
Abstract
Aims
To understand the function and regulation of aldehyde dehydrogenase 1a1 (ALDH1A1)-positive nigrostriatal dopaminergic neurons (ALDH1A1+ nDANs), which display the most profound loss in Parkinson's disease (PD).
Methods
Using custom-built ALDH1A1-CreERT2 knock-in mice, we selectively ablated the ALDH1A1+ nDANs and tested for any PD-related motor and non-motor phenotypes. We then determined the connectivity of these neurons and examined the impact of different presynaptic inputs on the function of these neurons. We further performed live imaging of dopamine release in behaving mice to correlate neuron activity with different behavioral modalities.
Results
We presented the first whole-brain circuit map of ALDH1A1+ nDANs and revealed an essential physiological function of these neurons in regulating the vigor of movement during the acquisition of motor skills. We found that the ALDH1A1+ nDAN-ablated mice moved less often at high walking-speed and completely lost the ability to improve the vigor of movement during the motor skill learning task. Dopamine replacement therapy, routinely used to treat PD patients was effective to restore walking speed, but it failed to rescue motor learning impairments. Live imaging studies further revealed a close correlation of dopamine release with the motor performance during the acquisition phase of motor learning.
Conclusions
This study underscores the importance of intact brain circuit, which allows the ALDH1A1+ nDAN to integrate diverse presynaptic inputs and produce timely and dynamic dopamine release in the motor learning process.