The midbrain dopamine (mDA) system is composed of molecularly and functionally distinct neuron subtypes that mediate specific behaviours and are linked to various brain diseases. Considerable progress has been made in identifying mDA neuron subtypes, and recent work has begun to unveil how these neuronal subtypes develop and organize into functional brain structures. This progress is important for further understanding the disparate physiological functions of mDA neurons and their selective vulnerability in disease, and will ultimately accelerate therapy development. This Review discusses recent advances in our understanding of molecularly defined mDA neuron subtypes and their circuits, ranging from early developmental events, such as neuron migration and axon guidance, to their wiring and function, and future implications for therapeutic strategies.
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The authors thank P. Lingor for input on the manuscript. Work on the dopamine system in the laboratory of the authors is supported by Stichting Parkinson Fonds, the Dutch Research Council (NWO; ALW-VICI 865.14.004) and the NWO Gravitation programme BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012) to R.J.P. The authors apologize to all investigators whose research could not be appropriately cited owing to space limitations.
The authors declare no competing interests.
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Neurotoxin that upon intracerebral injection causes rapid degeneration of the substantia nigra and parkinsonian symptoms, a method used for modelling (late-stage) Parkinson disease in animal models.
A toxic metabolite of 1-methyl-4-phenyl-1,2,3,5-tetrahydropyridine.
Radioactive thymidine analogue that is taken up when DNA is synthesized, used as a marker for cell proliferation.
A fused region-specific organoid used to model interactions between different tissue types or organs.
- Axon guidance
Process during which extrinsic molecules instruct the orientation of axonal growth through attraction and/or repulsion of the axon tip.
- Embryonic stem cells
(ES cells). Pluripotent stem cells derived from the inner cell mass of blastocyst-stage embryos.
A ventral organizer region along the midline of the neural tube that regulates neuronal differentiation and positioning.
- Genetic fate mapping
Genetic labelling of ancestor cells and their descendants to map the anatomical and cellular origin of cells of interest.
- Induced pluripotent stem cells
(iPS cells). Pluripotent stem cells that are generated through the reprogramming of somatic cells by expression of a set of transcription factors.
- Intersectional genetics
Selective targeting of cells by exploiting the combinatorial expression of two or more genes to express genetically encoded recombinases that results in the activation of proteins to label or manipulate cells.
- Laser capture microdissection
Laser- and microscope-assisted cutting that enables precise dissection of microregions within the tissue of interest.
- Lineage tracing
The identification of cellular progeny at subsequent developmental stages and processes by labelling an ancestor (progenitor) cell.
- Major histocompatibility complex
Cell surface proteins that present self-antigens to prevent an autoimmune response.
- Marginal zone
Cell-sparse, outermost zone of the neural tube or brain containing primarily axons and glial cells.
An undifferentiated precursor cell in the central nervous system that will eventually develop into a fully differentiated neural cell.
Stem cell-derived and self-assembled 3D cultures that represent key features of the represented organ.
- Radial glia-like cells
Cells that are positive for radial glia markers in single-cell RNA sequencing datasets.
- Radial migration
Migration of cells along radial glia fibres away from the ventricular zone.
Tagging of ribosomal subunits to enable immunopurification and downstream processing of ribosomes and attached mRNAs.
- Single-cell RNA sequencing
(scRNA-seq). Dissociation and isolation of individual cells followed by sequencing of the RNA transcriptome per cell.
- Single-nucleus RNA sequencing
(snRNA-seq). Dissociation and isolation of individual nuclei followed by sequencing of the RNA transcriptome per nucleus.
Processing of tissue sections on an indexed slide to label RNA transcripts so as to preserve their spatial origin.
- Spatial transcriptomics
Methods to assign cell types (based on mRNA readouts) to their anatomical location in tissue sections.
- Tangential migration
Migration of cells along the medial–lateral axis, parallel to the ventricular surface and orthogonal to radial glia fibres.
- Ventricular zone
A transient layer of tissue lining the ventricles of the central nervous system that contains neural stem cells.
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Garritsen, O., van Battum, E.Y., Grossouw, L.M. et al. Development, wiring and function of dopamine neuron subtypes. Nat Rev Neurosci 24, 134–152 (2023). https://doi.org/10.1038/s41583-022-00669-3