Make war not love: The neural substrate underlying a state-dependent switch in female social behavior
Female mice exhibit opposing social behaviors toward males depending on their reproductive state: virgins display sexual receptivity (lordosis behavior), while lactating mothers attack. How a change in reproductive state produces a qualitative switch in behavioral response to the same conspecific stimulus is unknown. Using single-cell RNA-seq, we identify two distinct subtypes of estrogen receptor-1-positive neurons in the ventrolateral subdivision of the female ventromedial hypothalamus (VMHvl) and demonstrate that they causally control sexual receptivity and aggressiveness in virgins and lactating mothers, respectively. Between- and within-subject bulk-calcium recordings from each subtype reveal that aggression-specific cells acquire an increased responsiveness to social cues during the transition from virginity to maternity, while the responsiveness of the mating-specific population appears unchanged. These results demonstrate that reproductive-state-dependent changes in the relative activity of transcriptomically distinct neural subtypes can underlie categorical switches in behavior associated with physiological state changes.
© 2021 The Author(s). Published by Elsevier Under a Creative Commons license - Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0). Received 27 July 2021, Revised 15 October 2021, Accepted 1 December 2021, Available online 3 January 2022. We thank Y. Huang for genotyping, G. Mancuso for administrative assistance, C. Chiu for lab management, E. Carcamo for mouse colony management, Caltech OLAR staff for animal care, and members of the Anderson Laboratory for helpful comments on this project. D.J.A. is an investigator of the Howard Hughes Medical Institute. This work was supported by NIH grants RO1 MH085082, MH070053, and U19 MH114830. Author contributions. M.L. and D.J.A. contributed to the study design. M.L. conducted all of the experiments, data analysis, and figure preparation. D.-W.K. and H. Z. helped with 10× Act-seq experiments and sequencing-data analysis. D.J.A. supervised the project. M.L. and D.J.A. wrote the manuscript. Declaration of interests. The authors declare no competing interests. D.J.A. is a member of the journal's advisory board. Data and code availability. • Single-cell RNA-seq data have been deposited at Mendeley Data: https://doi.org/10.17632/w25zm9cn6x.1 and are publicly available as of the date of publication. Neural manipulation and recording data reported in this paper is available from the lead contact upon request. • This paper does not report original code. • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
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