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Published October 17, 2019 | Accepted Version + Supplemental Material
Journal Article Open

Multimodal Analysis of Cell Types in a Hypothalamic Node Controlling Social Behavior


The ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) contains ∼4,000 neurons that project to multiple targets and control innate social behaviors including aggression and mounting. However, the number of cell types in VMHvl and their relationship to connectivity and behavioral function are unknown. We performed single-cell RNA sequencing using two independent platforms—SMART-seq (∼4,500 neurons) and 10x (∼78,000 neurons)—and investigated correspondence between transcriptomic identity and axonal projections or behavioral activation, respectively. Canonical correlation analysis (CCA) identified 17 transcriptomic types (T-types), including several sexually dimorphic clusters, the majority of which were validated by seqFISH. Immediate early gene analysis identified T-types exhibiting preferential responses to intruder males versus females but only rare examples of behavior-specific activation. Unexpectedly, many VMHvl T-types comprise a mixed population of neurons with different projection target preferences. Overall our analysis revealed that, surprisingly, few VMHvl T-types exhibit a clear correspondence with behavior-specific activation and connectivity.

Additional Information

© 2019 Elsevier Inc. Received 15 January 2019, Revised 28 July 2019, Accepted 20 September 2019, Available online 17 October 2019. We thank A. Jones and C. Koch for support at the Allen Institute for Brain Sciences during the writing of this manuscript, J.-S. Chang for cell counting, Y. Huang for genotyping, G. Mancuso for administrative assistance, C. Chiu for lab management, S. Diamond for assistance with FACS, the Single Cell Profiling and Engineering Center (SPEC) in the Beckman Institute at Caltech for initial help for 10x scRNA-seq experiments, S. Pease for assistance with transgenic mouse strains, J. Costanza for mouse colony management, members of the Anderson laboratory for helpful comments on this project, and an anonymous reviewer for suggesting social fear testing in group-housed mice. This work was supported by US National Institutes of Health (NIH) BRAIN Initiative grants U01MH105982 and U19MH114830 to H.Z. and D.J.A. and NIH grants MH070053 and TR01 OD024686 to D.J.A. and L.C., respectively. D.-W.K. was supported by a Howard Hughes Medical Institute International Student Research Fellowship. D.J.A. is an investigator of the Howard Hughes Medical Institute. Author Contributions: D.-W.K., B.T., H.Z., and D.J.A. contributed to the study design. D.-W.K. performed most of the experiments. T.K.K. and K.A.S. prepared sequencing libraries for SMART-seq scRNA-seq. L.T.G and O.F. contributed data visualization. D.-W.K. and T.N.N performed Retro-seq experiments. D.-W.K., Z.Y, L.T.G, L.Y., and L.P. analyzed the scRNA-seq data. D.-W.K. and N.K. performed seqFISH experiments. D.-W.K., N.P., S.S., and L.C. analyzed the seqFISH data. D.-W.K. and L.L. performed retrograde labeling with c-fos immunohistochemistry experiments. A.-H.P. and Y.O. developed the tissue preparation protocols for 10x Act-seq. D.J.A. supervised the project. D.-W.K. and D.J.A. wrote the manuscript with contributions from B.T. and H.Z. All authors discussed and commented on the manuscript. The authors declare no competing interests.

Attached Files

Accepted Version - nihms-1629366.pdf

Supplemental Material - 1-s2.0-S0092867419310712-mmc1.xlsx

Supplemental Material - 1-s2.0-S0092867419310712-mmc2.xlsx

Supplemental Material - 1-s2.0-S0092867419310712-mmc3.xlsx


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