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

Abstract

SUMMARY 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.

Parkinson’s disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging

“…Rotarod motor skill learning test. As described previously [30], mice were placed onto a rotating rod with auto acceleration from 0 to 40 rpm in 5 min (Panlab). The length of time the mouse stayed on the rotating rod was recorded across 10 trials.…”

“…The length of time the mouse stayed on the rotating rod was recorded across 10 trials. Such experiments were performed on 6 continuous days [30].…”

“…Open-field velocity test by video-tracking. As described previously [30], video recording of each mouse was conducted using a LifeCam cinema webcam. For each trial, a white arena floor allowed for further analyses using EthoVision XT software package (Noldus IT), which detects the subjects against a monochrome background.…”

Functional dissection of basal ganglia inhibitory input onto SNc dopaminergic neurons

“…The SNc can be divided into a ventral tier that is positive for Aldh1a1 and a dorsal tier which is positive for calbindin (Gerfen et al, 1987;Kim et al, 2015;Poulin et al, 2018;Wu et al, 2019). We have previously shown that the ventral tier SNc neurons rebound more strongly from hyperpolarization due to their strong expression of T-type calcium channels and large Ih current .…”

“…Past studies have classified substantia nigra dopamine neurons subpopulations according to their projection targets (Farassat et al, 2019;Lerner et al, 2015;Schiemann et al, 2012), expression of neurochemical markers (La Manno et al, 2016;Poulin et al, 2018;Wu et al, 2019), and intrinsic membrane properties Neuhoff et al, 2002). Based on the anatomical results, Crittenden et al (2016) proposed that dopamine neuron clusters (in bouquets) may form specialized nigral compartments.…”