title: Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.
abstract: Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance.
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Okaty
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Freret
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Rood
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Rachael D
authors.initials: RD
authors.lastname: Brust
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Hennessy
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: deBairos
authors.affiliation: Psychology Department, University of Toronto, 100 St. George Street, Toronto ON, M5S 3G3, Canada.
authors.forename: Jun Chul
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Department of Psychology, University of Memphis, 400 Innovation Drive, Memphis, TN 38152, USA.
authors.forename: Melloni N
authors.initials: MN
authors.lastname: Cook
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: dymecki@genetics.med.harvard.edu.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Dymecki
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology*; D055724:Electrophysiological Phenomena; D020869:Gene Expression Profiling; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017423:Sequence Analysis, RNA; D059326:Serotonergic Neurons / Q000145:classification* / Q000166:cytology / Q000378:metabolism