Journal
NEURON
Volume 88, Issue 4, Pages 774-791Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2015.10.007
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Funding
- NIH [P01 HD036379, R01 DA034022]
- Harvard Stem Cell Institute Seed Grant
- NARSAD Distinguished Investigator Grant from the Brain and Behavior Foundation
- Blavatnik Biomedical Accelerator at Harvard University Pilot Award
- American SIDS Institute research grant
- NIGMS [T32GM007753]
- [R21 MH083613]
- [R21 DA023643]
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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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