Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins

Milagros Pereira Luppi, Maite Azcorra, Giuliana Caronia-Brown, Jean Francois Poulin, Zachary Gaertner, Serafin Gatica, Oscar Andrés Moreno-Ramos, Navid Nouri, Marilyn Dubois, Yongchao C. Ma, Charu Ramakrishnan, Lief Fenno, Yoon Seok Kim, Karl Deisseroth, Francesca Cicchetti, Daniel A. Dombeck*, Rajeshwar Awatramani

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Dopamine (DA) neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease, while those in the dorsal tier are relatively spared. Defining the molecular, functional, and developmental characteristics of each SNc tier is crucial to understand their distinct susceptibility. We demonstrate that Sox6 expression distinguishes ventrally and dorsally biased DA neuron populations in the SNc. The Sox6+ population in the ventral SNc includes an Aldh1a1+ subset and is enriched in gene pathways that underpin vulnerability. Sox6+ neurons project to the dorsal striatum and show activity correlated with acceleration. Sox6 neurons project to the medial, ventral, and caudal striatum and respond to rewards. Moreover, we show that this adult division is encoded early in development. Overall, our work demonstrates a dual origin of the SNc that results in DA neuron cohorts with distinct molecular profiles, projections, and functions.

Original languageEnglish (US)
Article number109975
JournalCell reports
Volume37
Issue number6
DOIs
StatePublished - Nov 9 2021

Keywords

  • Aldh1a1
  • Calb1
  • Parkinson's
  • Sox6
  • dopamine
  • dorsal SNc
  • fate map
  • selective vulnerability
  • ventral SNc

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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