Molecular heterogeneity in the substantia nigra: A roadmap for understanding PD motor pathophysiology.

As the ability to capture single-cell expression profiles has grown in recent years, neuroscientists studying a wide gamut of brain regions have discovered remarkable heterogeneity within seemingly related populations (Saunders et al., 2018a; Zeisel et al., 2015). These "molecular subtypes" have been demonstrated even within brain nuclei expressing the same neurotransmitter (Saunders et al., 2018a; Poulin et al., 2020; Ren et al., 2019; Okaty et al., 2020). Recently, dopamine (DA) neurons of the substantia nigra pars compacta (SNc) and adjacent ventral tegmental area (VTA) have been revealed to be diverse not only when comparing between these two dopaminergic nuclei, but within them, and with the distribution of identified subtypes often agnostic to traditional neuroanatomical boundaries (Saunders et al., 2018a; Hook et al., 2018; Kramer et al., 2018; La Manno et al., 2016; Poulin et al., 2014; Tiklova et al., 2019; Poulin et al., 2018). Such molecularly defined subpopulations have been the subject of several recent studies. Investigations of these subtypes have ultimately unveiled many distinctive properties across several domains, such as their axonal projections and functional properties (Poulin et al., 2018; Wu et al., 2019; Pereira Luppi et al., 2021; Evans et al., 2017; Evans et al., 2020). These key differences between subtypes have begun to corroborate the biological relevance of DA neuron taxonomic schemes. We hypothesize that these putative molecular subtypes, with their distinctive circuits, could shed light on the wide variety of dopamine-related symptoms observed across several diseases including depression, chronic pain, addiction, and Parkinson's Disease. While it is difficult to reconcile how a single neurotransmitter can be involved in so many seemingly unrelated phenotypes, one solution could be the existence of several individual dopaminergic pathways serving different functions, with molecular subtypes serving as distinct nodes for these pathways. Indeed, this conceptual framework is already the dogma for anatomically distinct DA pathways, including the mesocortical, mesolimbic and mesostriatal pathways (Bjorklund & Dunnett, 2007). Here, we discuss our existing knowledge of DA neuron subtypes and attempt to provide a roadmap for how their distinctive properties can provide novel insights into the motor symptoms of Parkinson's disease (PD) (Fig. 1A). By exploring the differences between molecular subtypes and correlating this to their relative degeneration within the SNc, we may gain a deeper understanding of the cell-intrinsic mechanisms underlying why some DA neurons degenerate more than others in PD. Similarly, by mapping the inputs, projections, and functions of individual subtypes, we may better understand their individual roles in the circuit-level dysfunction of dopaminergic diseases.