Abstract
Parkinson's disease causes the most profound lossofthe 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.
Highlights
The nigrostriatal dopaminergic neurons are heterogenous and can be categorized into subpopulations based on location, gene expression profiles, electrophysiological properties, morphology, projection pattern, physiological functions, and vulnerabilities to diseases (Beier et al, 2015; Lammel et al, 2011, 2012; Lerner et al, 2015; Menegas et al, 2015, 2018; Yang et al, 2013)
Uneven Distribution of aldehyde dehydrogenase 1A1 (ALDH1A1)+ DANs in Different Midbrain Dopaminergic Subregions Midbrain dopaminergic neurons can be divided into three main subgroups, retrorubral field (RRF, A8), substantia nigra pars compacta (SNc) (A9), and ventral tegmental area (VTA, A10), in human and rodents (Bentivoglio and Morelli, 2005; Vogt Weisenhorn et al, 2016)
We found that ALDH1A1+ DANs in clusters 1–4 projected more restrictively to the dorsolateral striatum (DLS) in the intermediate caudate-putamen nuclei (CP), whereas ALDH1A1+ DANs in cluster 5 and 6 projected more heavily to the rostral striatum, including both CP and ventral striatum (VS) (Figure 2C)
Summary
The nigrostriatal dopaminergic neurons (nDANs) are heterogenous and can be categorized into subpopulations based on location, gene expression profiles, electrophysiological properties, morphology, projection pattern, physiological functions, and vulnerabilities to diseases (Beier et al, 2015; Lammel et al, 2011, 2012; Lerner et al, 2015; Menegas et al, 2015, 2018; Yang et al, 2013). In the postmortem brains of PD patients, the most profound loss of nDANs was observed in the ventral tier of substantia nigra pars compacta (SNc) (Fearnley and Lees, 1991; Kordower et al, 2013). These ventral nDANs can be molecularly defined by the selective expression of aldehyde dehydrogenase 1A1 (ALDH1A1) (Cai et al, 2014; Liu et al, 2014). Little is known about which brain regions send afferents to ALDH1A1+ nDANs or about which specific motor or non-motor functions ALDH1A1+ nDANs regulate
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