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Functional identification of an aggression locus in the mouse hypothalamus

Abstract

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.

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Figure 1: Fos catFISH analysis of cell activation during fighting versus mating.
Figure 2: Response patterns of a VMHvl neuron during social encounters.
Figure 3: Summary of cell responses in VMHvl during mating and fighting.
Figure 4: Optogenetic activation of VMHvl elicits attack in mice.
Figure 5: Reversible inhibition of natural aggression by genetic silencing of VMHvl

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Acknowledgements

We thank S. Ciocchi, S. Lin, Y. Ben-Shaul and A. Wang for advice on electrode and microdrive design; M. Gerfen and M. Vondrus for microdrive fabrication; M. P. Walsh, T. D. Heitzman and V. Rush for electronics support; A. Steele, R. Robbins, S. Ossorio, K. Gunapala, A. Paul, D. Oh, C. Kim and J. Nishiguchi for behaviour annotation and video scoring; H. Kim for technical assistance; W. E. Haubensak for teaching fibre-optic implant methods; J. T. Henderson for advice on stereotactic surgery; M. Kruk for advice on electrical stimulation experiments; K. Deisseroth for the Cre-dependent ChR2–EYFP AAV construct. M. Kruk, R. Mooney and R. Simerly for comments on the manuscripts; G. Mosconi for lab management and G. Mancuso for administrative support. This work was supported in part by the Weston-Havens Foundation and Jane Coffin Childs Foundation. D.J.A. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Contributions

D.L. designed, carried out and analyzed preliminary fos catFISH experiments and all other experiments, and co-wrote the manuscript; M.B. and E.L. performed additional fos catFISH experiments; P.D. and P.P. developed custom behaviour annotation software; H.L. performed some of the optogenetic experiments; D.J.A. conceived the project, suggested experiments, analysed data and co-wrote the manuscript.

Corresponding authors

Correspondence to Dayu Lin or David J. Anderson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-19 with legends, Supplementary Methods, Supplementary Footnotes 1-4 and additional references. (PDF 2917 kb)

Supplementary Movie 1

The sound in this movie corresponds to the response of a neuron recorded from a C57BL/6 male during investigation and attack of a BALB/c male. Viewers are kindly requested not to upload this movie to other publicly accessible sites. (MOV 11052 kb)

Supplementary Movie 2

The sound in this movie corresponds to the response of the same neuron shown in Supplementary Movie 1 during investigation and mounting of a C57BL/6 female. Viewers are kindly requested not to upload this movie to other publicly accessible sites. (MOV 13168 kb)

Supplementary Movie 3

The movie shows an attack towards a BALB/c female is induced by light stimulation of a C57BL/6 male mouse in the VMHvl region. Viewers are kindly requested not to upload this movie to other publicly accessible sites. (MOV 9764 kb)

Supplementary Movie 4

The movie shows an attack towards a glove, which is induced by stimulating VMHvl in a C57BL/6 male mouse. Viewers are kindly requested not to upload this movie to other publicly accessible sites. (MOV 9434 kb)

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Lin, D., Boyle, M., Dollar, P. et al. Functional identification of an aggression locus in the mouse hypothalamus. Nature 470, 221–226 (2011). https://doi.org/10.1038/nature09736

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