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

• Published in: Cell Vol. 179; no. 3; pp. 713 - 728.e17
• Main Authors: Kim, Dong-Wook, Yao, Zizhen, Graybuck, Lucas T., Kim, Tae Kyung, Nguyen, Thuc Nghi, Smith, Kimberly A., Fong, Olivia, Yi, Lynn, Koulena, Noushin, Pierson, Nico, Shah, Sheel, Lo, Liching, Pool, Allan-Hermann, Oka, Yuki, Pachter, Lior, Cai, Long, Tasic, Bosiljka, Zeng, Hongkui, Anderson, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.10.2019
• Subjects: aggression; Animals; cell types; estrogen receptor; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; females; genes; hypothalamus; Hypothalamus - cytology; Hypothalamus - physiology; Male; males; mating; metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multivariate analysis; neurons; Neurons - classification; Neurons - metabolism; Neurons - physiology; sequence analysis; Sexual Behavior, Animal; sexual dimorphism; Single-Cell Analysis; single-cell RNA sequencing; Social Behavior; Transcriptome; transcriptomics; VMH; VMH; single-cell RNA sequencing; estrogen receptor; social behavior; cell types; metabolism; aggression; hypothalamus; sexual dimorphism; mating
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.09.020

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. [Display omitted] •SMART-seq and 10x platforms reveal 17 transcriptomic cell types (T-types) in VMHvl•Multiplexed smFISH confirms scRNA-seq and identifies T-types with A-P restrictions•Rare female- and male-specific T-types are found among the Esr1+ subclusters•Relatively few VMHvl T-types exhibit behavior-specific activation and connectivity Single-cell RNA sequencing of the mouse ventrolateral subdivision of the ventromedial hypothalamus, a brain region that contains ∼4,000 neurons and controls innate social behaviors including aggression and mounting, reveals several transcriptomic cell types that differ between males and females.