Neuron
Volume 88, Issue 4, 18 November 2015, Pages 774-791
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Article
Multi-Scale Molecular Deconstruction of the Serotonin Neuron System

https://doi.org/10.1016/j.neuron.2015.10.007Get rights and content
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Highlights

  • 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

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.

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