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

Abstract

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.

Keywords: cell type; dopaminergic system; intersectional; molecular diversity; neuroanatomy; single-cell RNA-seq.

Figure 1.

Molecularly defined DA neuron subtypes. Our interpretation of putative DA neuron subtypes across several studies with their potential neuroanatomical locations in the adult mouse midbrain. Of note, the subclusters SN_4–4 (Th, C1ql3), SN_4–6 (Th, Cadm2), and SN_4–7 (Th, Nefl) from [18] are not mentioned, as we were unable to unambiguously locate these groups. In relation to [15], we have omitted neurons that have low Th and Dat expression (N-Dat^LOW, G-Dat^LOW). NT-Dat^LOW, defined by Npxh4, likely represents neurons in the rostral linear region, as depicted in that study. For discussion of results from a sixth related study, [17], please see main text; findings from this study have not been listed in this figure due to the limited information on clusters.