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

Kim, Dong-Wook and Yao, Zizhen and Graybuck, Lucas T. and Kim, Tae Kyung and Nguyen, Thuc Nghi and Smith, Kimberly A. and Fong, Olivia and Yi, Lynn and Koulena, Noushin and Pierson, Nico and Shah, Sheel and Lo, Liching and Pool, Allan-Hermann and Oka, Yuki and Pachter, Lior and Cai, Long and Tasic, Bosiljka and Zeng, Hongkui and Anderson, David J. (2019) Multimodal Analysis of Cell Types in a Hypothalamic Node Controlling Social Behavior. Cell, 179 (3). pp. 713-728. ISSN 0092-8674. PMCID PMC7534821. https://resolver.caltech.edu/CaltechAUTHORS:20191017-094121433

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2019.09.020DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534821PubMed CentralArticle
ORCID:
AuthorORCID
Kim, Dong-Wook0000-0002-5497-5853
Yao, Zizhen0000-0002-9361-5607
Graybuck, Lucas T.0000-0002-8814-6818
Yi, Lynn0000-0003-4575-0158
Koulena, Noushin0000-0002-9419-5712
Pool, Allan-Hermann0000-0002-0811-9861
Pachter, Lior0000-0002-9164-6231
Cai, Long0000-0002-7154-5361
Tasic, Bosiljka0000-0002-6861-4506
Zeng, Hongkui0000-0002-0326-5878
Anderson, David J.0000-0001-6175-3872
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.
Group:Tianqiao and Chrissy Chen Institute for Neuroscience
Funders:
Funding AgencyGrant Number
NIHU01MH105982
NIHU19MH114830
NIHMH070053
NIHTR01 OD024686
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:hypothalamus; cell types; VMH; estrogen receptor; social behavior; single-cell RNA sequencing; aggression; mating; sexual dimorphism; metabolism
Issue or Number:3
PubMed Central ID:PMC7534821
Record Number:CaltechAUTHORS:20191017-094121433
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191017-094121433
Official Citation:Dong-Wook Kim, Zizhen Yao, Lucas T. Graybuck, Tae Kyung Kim, Thuc Nghi Nguyen, Kimberly A. Smith, Olivia Fong, Lynn Yi, Noushin Koulena, Nico Pierson, Sheel Shah, Liching Lo, Allan-Hermann Pool, Yuki Oka, Lior Pachter, Long Cai, Bosiljka Tasic, Hongkui Zeng, David J. Anderson, Multimodal Analysis of Cell Types in a Hypothalamic Node Controlling Social Behavior, Cell, Volume 179, Issue 3, 2019, Pages 713-728.e17, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2019.09.020. (http://www.sciencedirect.com/science/article/pii/S0092867419310712)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99325
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:19 Oct 2019 04:38
Last Modified:07 Oct 2020 16:00

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