title: Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling.
abstract: Effective approaches to neuropsychiatric disorders require detailed understanding of the cellular composition and circuitry of the complex mammalian brain. Here, we present a paradigm for deconstructing the diversity of neurons defined by a specific neurotransmitter using a microfluidic dynamic array to simultaneously evaluate the expression of 96 genes in single neurons. With this approach, we successfully identified multiple molecularly distinct dopamine neuron subtypes and localized them in the adult mouse brain. To validate the anatomical and functional correlates of molecular diversity, we provide evidence that one Vip+ subtype, located in the periaqueductal region, has a discrete projection field within the extended amygdala. Another Aldh1a1+ subtype, located in the substantia nigra, is especially vulnerable in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Overall, this rapid, cost-effective approach enables the identification and classification of multiple dopamine neuron subtypes, with distinct molecular, anatomical, and functional properties.
authors.affiliation: Department of Neurology and the Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Poulin
authors.affiliation: Department of Neurology and the Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, UK.
authors.forename: Janelle
authors.initials: J
authors.lastname: Drouin-Ouellet
authors.affiliation: Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Kwang-Youn A
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Centre de Recherche du CHU de Québec, Axe Neurosciences and Université Laval, Québec, QC G1V 4G2, Canada.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cicchetti
authors.affiliation: Department of Neurology and the Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: r-awatramani@northwestern.edu.
authors.forename: Rajeshwar B
authors.initials: RB
authors.lastname: Awatramani
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000375:Aging / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000145:classification / Q000166:cytology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D057166:High-Throughput Screening Assays; D008636:Mesencephalon / Q000166:cytology*; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000473:pathology
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine