Distinct Connectivity and Functionality of Aldehyde Dehydrogenase 1a1-Positive Nigrostriatal Dopaminergic Neurons in Motor Learning

Parkinson's disease causes the most profound loss of the aldehyde dehydrogenase 1A1-positive (ALDH1A1⁺) nigrostriatal dopaminergic neuron (nDAN) subpopulation. The connectivity and functionality of ALDH1A1⁺ nDANs, however, remain poorly understood. Here, we show in rodent brains that ALDH1A1⁺ nDANs project predominantly to the rostral dorsal striatum, from which they also receive most monosynaptic inputs, indicating extensive reciprocal innervations with the striatal spiny projection neurons (SPNs). Functionally, genetic ablation of ALDH1A1⁺ nDANs causes severe impairments in motor skill learning, along with a reduction in high-speed walking. While dopamine replacement therapy accelerated walking speed, it failed to improve motor skill learning in ALDH1A1⁺ nDAN-ablated mice. Altogether, our study provides a comprehensive whole-brain connectivity map and reveals a key physiological function of ALDH1A1⁺ nDANs in motor skill acquisition, suggesting the motor learning processes require ALDH1A1⁺ nDANs to integrate diverse presynaptic inputs and supply dopamine with dynamic precision. Wu et al. show that aldehyde dehydrogenase 1A1-positive nigrostriatal dopaminergic neurons, which display the most profound degeneration in Parkinson's disease, are essential in the acquisition of skilled movements in rodent models. The proper synaptic inputs to these neurons are critical for providing the timely dopamine release required in the learning process.