Distinct connectivity and functionality of aldehyde dehydrogenase 1a1-positive nigrostriatal dopaminergic neurons in motor learning
Open accessAbstract
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.
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ALDH1A1+ dopamine neurons of the substantia nigra pars compacta project prominently to the dorsal caudate putamen, with fibers being denser in rostral sections and less dense caudally.
“Prominent projections of ALDH1A1+ DA neurons of the SNc have been observed in the dorsal caudate putamen (CP; [20–22]), with fibers being more dense in rostral sections and less so in caudal regions.”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [22]
In the dorsal caudate putamen, ALDH1A1+ dopamine neurons preferentially innervate some mu-opioid receptor-positive patches, known as striosomes, although this preference is not exclusive.
“In the dorsal CP, these neurons preferentially innervate some μ-opioid receptor+ (MOR) patches (commonly known as striosomes), although this is not exclusive [20–22].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [22]
Otx2+, Aldh1a1+ dopamine neurons direct major projections to the medial shell of the nucleus accumbens and minor projections to the lateral septum.
“This population has been accessed using Aldh1a1 and NeuroD6 based drivers, and it appears to direct major projections to the medial shell of the ACB, and minor projections to the lateral septum [17,20,22,36].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [22]
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References 64 · Cited by 87
- Authors
- Wu, J., Kung, J., Dong, J., Chang, L., Xie, C., Habib, A., Hawes, S., Yang, N., Chen, V., Liu, Z., Evans, R., Liang, B., Sun, L., Ding, J., Yu, J., Saez-Atienzar, S., Tang, B., Khaliq, Z., Lin, D.-T., Le, W., & Cai, H.
- Affiliations
- National Institutes of Health (US)
- Beijing University of Chinese Medicine (CN)
- Central South University (CN)
- Dalian Medical University (CN)
- Corresponding author
- Cai, Huaibin
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 28
- Issue
- 5
- Pages
- 1167-1181.e7
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6741442
- OpenAlex
- W2965801756
- Cited by
- 87
- References
- 64
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 12 · 2023: 8 · 2022: 12 · 2021: 14 · 2020: 12 · 2019: 1
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Motor Control and Adaptation
- Keywords
- ALDH1A1, nigrostriatal dopaminergic neurons, dorsal striatum, medium spiny neurons, neuronal connectivity, motor skill learning, dopamine replacement therapy, Parkinson's disease, neuronal ablation, walking speed
- MeSH terms
- Aldehyde Dehydrogenase 1 Family, Animals, Corpus Striatum, Dopamine, Learning, Mice, Transgenic, Substantia Nigra, Retinal Dehydrogenase, Mice, Dopaminergic Neurons
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