Dopamine is an important chemical messenger in the brain, which modulates movement, reward, motivation, and memory. Different populations of neurons can produce and release dopamine in the brain and regulate different behaviors. Here we focus our discussion on a small but distinct group of dopamine-producing neurons, which display the most profound loss in the ventral substantia nigra pas compacta of patients with Parkinson’s disease. This group of dopaminergic neurons can be readily identified by a selective expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and accounts for 70% of total nigrostriatal dopaminergic neurons in both human and mouse brains. Recently, we presented the first whole-brain circuit map of these ALDH1A1-positive dopaminergic neurons and reveal an essential physiological function of these neurons in regulating the vigor of movement during the acquisition of motor skills. In this review, we first summarize previous findings of ALDH1A1-positive nigrostriatal dopaminergic neurons and their connectivity and functionality, and then provide perspectives on how the activity of ALDH1A1-positive nigrostriatal dopaminergic neurons is regulated through integrating diverse presynaptic inputs and its implications for potential Parkinson’s disease treatment.

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Parkinson's disease (PD), the most common degenerative movement disorder, is clinically manifested with various motor and non-motor symptoms. Degeneration of midbrain substantia nigra pas compacta (SNc) dopaminergic neurons (DANs) is generally attributed to the motor syndrome. The underlying neuronal mechanisms of non-motor syndrome are largely unexplored. Besides SNc, midbrain ventral tegmental area (VTA) DANs also produce and release dopamine and modulate movement, reward, motivation, and memory. Degeneration of VTA DANs also occurs in postmortem brains of PD patients, implying an involvement of VTA DANs in PD-associated non-motor symptoms. However, it remains to be established that there is a distinct segregation of different SNc and VTA DAN subtypes in regulating different motor and non-motor functions, and that different DAN subpopulations are differentially affected by normal ageing or PD. Traditionally, the distinction among different DAN subtypes was mainly based on the location of cell bodies and axon terminals. With the recent advance of single cell RNA sequencing technology, DANs can be readily classified based on unique gene expression profiles. A combination of specific anatomic and molecular markers shows great promise to facilitate the identification of DAN subpopulations corresponding to different behavior modules under normal and disease conditions. In this review,

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