Function and Regulation of ALDH1A1-Positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson's Disease

Abstract

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.

Keywords: ALDH1A1; Parkinson’s disease; connectivity; dopamine; motor learning; substantia nigra.

FIGURE 1

Distinct molecular signature of ALDH1A1⁺ nDANs. (A) Correlation of Aldh1a1 expression with a selective set of genes in mature mouse DANs from a single cell RNA sequencing study (La Manno et al., 2016). (B) In situ hybridization of Aldh1a1 and correlated genes in the SNc of adult mouse brains (Allen Brain Atlas).

FIGURE 2

Electrophysiological characteristics of ALDH1A1⁺ nDANs. (A) Two-photon image of a ALDH1A1⁺ nDAN. (B) Average calcium transient (above) and action potential (below) shape during tonic firing for a ALDH1A1⁺ nDAN. (C) Hyperpolarization-dependent after depolarizations (above) and corresponding dendritic calcium transients (below) for a ALDH1A1⁺ nDAN. (D) Amplitude of the calcium transient from a potential of −80 mV graphed by the area under the curve (AUC) for the corresponding low-threshold depolarization. Calb^–, Calbindin-negative population (data re-graphed from Evans et al., 2017, (D), adult heated calbindin-negative population).

FIGURE 3

Distinct electrophysiology, connectivity, and functionality of ALDH1A1⁺ nDANs. (A) Rebound activity of ALDH1A1⁺ nDANs following dSPN inhibition. (B) Major inhibitory and excitatory presynaptic inputs to the ALDH1A1⁺ nDANs. (C) A critical involvement of ALDH1A1⁺ nDANs in regulating the vigor of movement during the acquisition of motor skills.