Multi-Scale Molecular Deconstruction of the Serotonin Neuron System

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 variati...

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Bibliographic Details
Published in:	Neuron (Cambridge, Mass.) Vol. 88; no. 4; pp. 774 - 791
Main Authors:	Okaty, Benjamin W., Freret, Morgan E., Rood, Benjamin D., Brust, Rachael D., Hennessy, Morgan L., deBairos, Danielle, Kim, Jun Chul, Cook, Melloni N., Dymecki, Susan M.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 18-11-2015 Elsevier Limited
Subjects:	Animals Behavior Brain - cytology Data analysis Electrophysiological Phenomena Experiments Gene expression Gene Expression Profiling Genomes Grants Histology Mice Mice, Knockout Neurons Phenotype Sequence Analysis, RNA Serotonergic Neurons - classification Serotonergic Neurons - cytology Serotonergic Neurons - metabolism
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Summary:	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. •5HT neuron RNA-seq across anatomy and sublineage at population and single-cell scales•Unbiased analyses identify 5HT neuron subtypes and organizing principles•Differential gene expression predicts subtype-specific functions and disease associations•In vitro drug responses, sensorimotor gating, and behaviors map to distinct subtypes Serotonergic neurons are often considered a single neuron type; however, examples of diversity suggest otherwise. Okaty and Freret et al. use intersectional genetics, RNA-seq, and subtype-specific manipulations to reveal a functional organization rooted in sublineage and anatomy and comprised of neuron subtypes highly diverse at the molecular and functional levels.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally
ISSN:	0896-6273 1097-4199
DOI:	10.1016/j.neuron.2015.10.007