Review
Classification of Midbrain Dopamine Neurons Using Single-Cell Gene Expression Profiling Approaches

https://doi.org/10.1016/j.tins.2020.01.004Get rights and content

Highlights

  • Emerging literature has identified molecularly distinct midbrain dopamine (DA) neuron subtypes but their number, location, and defining markers are currently debated.

  • Based on available studies, we propose seven putative DA neuron subtypes and elaborate on their characteristic features.

  • We provide a common framework for understanding DA neuron diversity, and this will hopefully facilitate the study of DA neurons in a subtype-specific manner.

Dysfunctional dopamine (DA) signaling has been associated with a broad spectrum of neuropsychiatric disorders, prompting investigations into how midbrain DA neuron heterogeneity may underpin this variety of behavioral symptoms. Emerging literature indeed points to functional heterogeneity even within anatomically defined DA clusters. Recognizing the need for a systematic classification scheme, several groups have used single-cell profiling to catalog DA neurons based on their gene expression profiles. We aim here not only to synthesize points of congruence but also to highlight key differences between the molecular classification schemes derived from these studies. In doing so, we hope to provide a common framework that will facilitate investigations into the functions of DA neuron subtypes in the healthy and diseased brain.

Section snippets

Heterogeneity within the DA Midbrain System

Since their discovery, neurotransmitters and their associated molecular machineries have been used to differentiate one type of neuron from another. This trend has been reinforced by thousands of neuropharmacological studies which have linked diverse behaviors, mental states, or diseases to specific neurotransmitter systems. Too often, however, neuronal populations possessing a common neurotransmitter were assumed to be homogeneous, even though they differed significantly based on morphological

Defining DA Neuron Subtypes Based on Their Molecular Profiles

It is generally agreed that groups of neurons that possess a core number of distinctly expressed genes can be classified as the same cell type [10., 11., 12.]. However, classifying neurons into subtypes is no easy task, particularly when the types are closely related. In the case of midbrain DA neurons, all display a typical neuron molecular signature in addition to expressing genes necessary for the synthesis, packaging, and release of DA (Box 2). Superimposed on this generic midbrain DA

Generating Midbrain DA Neuron Diversity during Embryonic Development

The embryonic primordium of midbrain DA neurons is well defined. These neurons originate from the mesodiencephalic FP, a region at the ventral midline defined by the mRNA expression of Shh+ and Foxa2+ [67., 68., 69., 70., 71., 72., 73.]. The boundaries of this primordium have been well defined by transcription factor expression. The caudal extent is defined by the Otx2/Gbx2 boundary coincident with the morphological midbrain–hindbrain boundary [74]. The rostral extent is defined by the En1/Dbx1

Concluding Remarks and Future Perspectives

Single-cell gene expression profiling has enabled progress in defining DA neuron subtypes, thus revising traditional anatomically based classification schemes. Parsing midbrain DA subtypes is a challenging endeavor because these neurons all share a common developmental origin in the FP and share the expression of many terminal selector genes and their downstream cascades. Nonetheless, although single-cell studies have discrepancies in resulting subtypes, these studies have begun to provide a

Acknowledgments

R.A. is supported by National Institutes of Health (NIH) grants R01NS096240, R01MH110556, and P50 DA044121. J-F.P. is supported by the Healthy Brains, Healthy Lives (HBHL) program/Canada First Research Excellence Fund (CFREF).

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