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Esr1+ cells in the ventromedial hypothalamus control female aggression

Nature Neuroscience volume 20, pages 15801590 (2017) | Download Citation

Abstract

As an essential means of resolving conflicts, aggression is expressed by both sexes but often at a higher level in males than in females. Recent studies suggest that cells in the ventrolateral part of the ventromedial hypothalamus (VMHvl) that express estrogen receptor-α (Esr1) and progesterone receptor are essential for male but not female mouse aggression. In contrast, here we show that VMHvlEsr1+ cells are indispensable for female aggression. This population was active when females attacked naturally. Inactivation of these cells reduced female aggression whereas their activation elicited attack. Additionally, we found that female VMHvl contains two anatomically distinguishable subdivisions that showed differential gene expression, projection and activation patterns after mating and fighting. These results support an essential role of the VMHvl in both male and female aggression and reveal the existence of two previously unappreciated subdivisions in the female VMHvl that are involved in distinct social behaviors.

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Acknowledgements

We thank D. Anderson (California Institute of Technology) for providing Esr1-2A-Cre mice and B. Lowell (Harvard Medical School) for providing Vglut2-ires-Cre and Vgat-ires-Cre mice and AAV-DIO-synaptophysin-mCherry for the pilot experiments. We thank R. Machold and M. Baek for technical support on in situ hybridization and RNA-seq, C. Loomis at the NYULMC Experimental Pathology Research Laboratory for help on laser capture microdissection, A. Heguy and Y. Zhang at the NYULMC Genome Technology Center for help on RNA-seq and T. Lhakhang at the NYULMC Bioinformatics Laboratory for help with sequence alignment. We thank A.L. Falkner, M. Halassa, G. Stuber and G. Suh for critical comments on the manuscript. This research was supported by a JSPS oversea fellowship (K.H.), Uehara postdoctoral fellowship (K.H.), National Natural Science Foundation of China 81471630 (J.Z.), NIH 1K99NS074077 (H.L.), NIH R21NS093987 (B.R.), NIH P01NS074972 (B.R.), NIH 1R01MH101377 (D. L.), NIH 1R21MH105774-01A1 (D. L.), the Mathers Foundation (D.L.), an Irma T. Hirschl Career Scientist Award (D.L.), a Sloan Research Fellowship (D.L.), a McKnight Scholar Award (D.L.), a Whitehall Fellowship (D.L.) and a Klingenstein Fellowship Award (D.L.).

Author information

Author notes

    • Koichi Hashikawa
    •  & Yoshiko Hashikawa

    These authors contributed equally to this work.

Affiliations

  1. Neuroscience Institute, New York University School of Medicine, New York, New York, USA.

    • Koichi Hashikawa
    • , Yoshiko Hashikawa
    • , Robin Tremblay
    • , James E Feng
    • , Alexander Sabol
    • , Bernardo Rudy
    •  & Dayu Lin
  2. Department of Physiology, Medical College of Xiamen University, Xiamen, Fujian, China.

    • Jiaxing Zhang
  3. Center for Neural Science, New York University, New York, New York, USA.

    • Walter T Piper
    •  & Dayu Lin
  4. Department of Brain and Cognitive Sciences, DGIST, Daegu, Korea.

    • Hyosang Lee
  5. Department of Psychiatry, New York University School of Medicine, New York, New York, USA.

    • Dayu Lin
  6. Emotional Brain Institute, New York University School of Medicine, New York, New York, USA.

    • Dayu Lin

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Contributions

D.L. supervised the project. D.L. and K.H. conceived the project, designed experiments and wrote the manuscript. K.H. and Y.H. conducted most experiments and analyzed data. R.T. conducted in vitro slice physiology. J.Z. conducted pilot pharmacological and c-Fos experiments. J.E.F. optimized in vivo single-unit recording. W.T.P. helped with pilot optogenetic experiments. A.S. helped with fiber photometry and optogenetic experiments. H.L. generated Esr1-2A-Cre mice. B.R. supervised slice physiology.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dayu Lin.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–15, Supplementary Tables 1 and 2, and Supplementary Note 1

  2. 2.

    Life Sciences Reporting Summary

  3. 3.

    Supplementary Dataset 1

  4. 4.

    Supplementary Dataset 2

Videos

  1. 1.

    The VMHvl Esr1+ population in a virgin SW female did not respond to an object.

    The GCaMP6f signal of Esr1+ neurons in the VMHvl of a female mouse was recorded using fiber photometry. There was little change in GCaMP6f signal when the female investigated a toy mouse.

  2. 2.

    The VMHvl Esr1+ population in a virgin female responded during aggressive encounters with a juvenile male mouse.

    GCaMP6f signal increased when the same female as shown in Supplementary Video 1 investigated or attacked a juvenile mouse.

  3. 3.

    The VMHvl Esr1+ population in a virgin SW female responded during a sexual interaction with an adult male mouse.

    GCaMP6f signal increased when the same female as shown in Supplementary Video 1 investigated or was engaged in sexual intercourse with an adult male mouse.

  4. 4.

    The VMHvl Esr1+ population in a lactating SW female responded during aggressive encounters with an adult male mouse.

    The GCaMP6f signal of Esr1+ neurons in the VMHvl of a lactating female mouse increased when the female attacked an adult male mouse.

  5. 5.

    Optogenetic activation of VMHvl Esr1+ neurons elicited social investigation of and attack on an adult female in a virgin SW female mouse.

    A SW female mouse that expressed ChR2 in Esr1+ neurons of the VMHvl was photostimulated through an optic fiber at 0.1, 0.4 or 1.5 mW, 20 Hz, 20-ms pulses. Light-induced behaviors progressed from investigation to attack as the light intensity increased.

  6. 6.

    Optogenetic activation of VMHvl Esr1+ neurons elicited mounting towards an adult female and an adult male in a virgin C57 female mouse.

    A C57 female mouse that expressed ChR2 in Esr1+ neurons of the VMHvl was photostimulated through an optic fiber at 20 Hz, 20 ms, 0.12 mW. The light induced mounting towards a female intruder, as well as a male intruder.

  7. 7.

    Optogenetic activation of VMHvl Esr1+ neurons elicited attack on an adult female in a lactating C57 female mouse.

    A lactating C57 female mouse (postpartum day 3) that expressed ChR2 in Esr1+ neurons of the VMHvl was photostimulated through an optic fiber at 20 Hz, 20 ms, 0.35 mW. Light induced an attack on a female intruder.

  8. 8.

    Fight and mate populations in the VMHvl of a female mouse are largely distinct.

    The 3D reconstruction of fighting- and mating-related populations in the VMHvl at all bregma levels of a female mouse used in a Fos catFISH experiment. Red, blue, and yellow dots indicate cells activated by fighting, mating and both, respectively.

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DOI

https://doi.org/10.1038/nn.4644

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