Combinatorial Expression of Grp and Neurod6 Defines Dopamine Neuron Populations with Distinct Projection Patterns and Disease Vulnerability
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Abstract Midbrain dopamine neurons project to numerous targets throughout the brain to modulate various behaviors and brain states. Within this small population of neurons exists significant heterogeneity based on physiology, circuitry, and disease susceptibility. Recent studies have shown that dopamine neurons can be subdivided based on gene expression; however, the extent to which genetic markers represent functionally relevant dopaminergic subpopulations has not been fully explored. Here we performed single-cell RNA-sequencing of mouse dopamine neurons and validated studies showing that Neurod6 and Grp are selective markers for dopaminergic subpopulations. Using a combination of multiplex fluorescent in situ hybridization, retrograde labeling, and electrophysiology in mice of both sexes, we defined the anatomy, projection targets, physiological properties, and disease vulnerability of dopamine neurons based on Grp and/or Neurod6 expression. We found that the combinatorial expression of Grp and Neurod6 defines dopaminergic subpopulations with unique features. Grp + /Neurod6 + dopamine neurons reside in the ventromedial VTA, send projections to the medial shell of the nucleus accumbens, and have noncanonical physiological properties. Grp + /Neurod6- dopamine neurons are found in the VTA as well as in the ventromedial portion of the SNc, where they project selectively to the dorsomedial striatum. Grp-/Neurod6 + dopamine neurons represent a smaller VTA subpopulation, which is preferentially spared in a 6-OHDA model of Parkinson’s disease. Together, our work provides detailed characterization of Neurod6 and Grp expression in the midbrain and generates new insights into how these markers define functionally relevant dopaminergic subpopulations.
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The single-cell classification studies identified partially overlapping dopamine neuron subtypes, some of which were located in a manner agnostic to traditional anatomical boundaries.
“Although these studies differed significantly in their experimental parameters and analysis methods, they identified partially overlapping subtypes, some of which were located in a manner agnostic to traditional anatomical boundaries (SN, VTA, & RR).”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [17]
Molecular heterogeneity within the murine dopaminergic system has been investigated by at least six independent groups, all attempting to classify dopamine neurons based on gene expression.
“Molecular heterogeneity within the murine DAergic system has been investigated by at least six independent groups, all attempting to classify DA neurons based on gene expression [13–18].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [17]
The Aldh1a1+, Sox6+ dopamine neuron subtype also displays Aldh1a7 and Ndnf mRNA expression.
“These cells also display Aldh1a7 [14,17] and Ndnf [13,14] mRNA expression.”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [17]
Dopamine neurons labeled with Neurod6-Cre have a smaller Ih, more depolarized membrane potential, higher membrane resistance, less pronounced afterhyperpolarization, and shorter action potential height compared to substantia nigra pars compacta neurons.
“Physiologically, DA neurons labeled with Neurod6-Cre have a smaller Ih, more depolarized membrane potential, higher membrane resistance, less pronounced afterhyperpolarization, and shorter action potential height when compared to SNc neurons [17].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [17]
Otx2+, Aldh1a1+ dopamine neurons are located in the ventromedial ventral tegmental area.
“Otx2+, Aldh1a1+ DA neurons in the ventromedial VTA”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [17]
Sox6+, Aldh1a1- dopamine neurons lack Aldh1a1, Anxa1, and Aldh1a7 expression.
“In addition to lacking Aldh1a1 mRNA, they also do not express Anxa1 [14,17,18] and Aldh1a7 [14,17,18].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [17]
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 [17]
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References 58 · Cited by 70
- Authors
- Kramer, D. J., Risso, D., Kosillo, P., Ngai, J., & Bateup, H. S.
- Affiliations
- University of California, Berkeley (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Bateup, Helen S.
- Venue
- eNeuro
- Publisher
- Society for Neuroscience
- Published
- 2018-05
- Volume
- 5
- Issue
- 3
- Pages
- ENEURO.0152-18.2018
- ISSN
- 2373-2822 (ISSN-L)
- PMC
- PMC6104179
- OpenAlex
- W2803110575
- Cited by
- 70
- References
- 58
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 15 · 2023: 7 · 2022: 5 · 2021: 14 · 2020: 8 · 2019: 6
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- eNeuro (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- HHS | NIH | National Institute of Mental Health (U01MH105878)
- Alfred P. Sloan Foundation (FR-2015-65790)
- Brain and Behavior Research Foundation (25073)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopaminergic neurons, GRP, NeuroD6, ventral tegmental area, substantia nigra pars compacta, nucleus accumbens shell, dorsomedial striatum, 6-hydroxydopamine, neuronal heterogeneity, single-cell RNA sequencing, retrograde tracing, electrophysiology
- MeSH terms
- Animals, Female, Male, Mesencephalon, Mice, Inbred C57BL, Nerve Tissue Proteins, Neural Pathways, Nucleus Accumbens, In Situ Hybridization, Fluorescence, Sequence Analysis, RNA, Ventral Tegmental Area, Gastrin-Releasing Peptide, Basic Helix-Loop-Helix Proteins, Dopaminergic Neurons
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