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Published May 29, 2014 | Accepted Version + Supplemental Material
Journal Article Open

Scalable control of mounting and attack by Esr1^+ neurons in the ventromedial hypothalamus


Social behaviours, such as aggression or mating, proceed through a series of appetitive and consummatory phases that are associated with increasing levels of arousal. How such escalation is encoded in the brain, and linked to behavioural action selection, remains an unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male–male and male–female social encounters. Non-cell-type-specific optogenetic activation of this region elicited attack behaviour, but not mounting. We have identified a subset of VMHvl neurons marked by the oestrogen receptor 1 (Esr1), and investigated their role in male social behaviour. Optogenetic manipulations indicated that Esr1^+ (but not Esr1^−) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behaviour. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behaviour, rather than attack, towards both males and females, as well as sniffing and close investigation. Increasing photostimulation intensity could promote a transition from close investigation and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1^+ neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1^+ neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population.

Additional Information

© 2014 Macmillan Publishers Limited. All rights reserved. Received 04 September 2013. Accepted 21 February 2014. Published online 16 April 2014. We thank C. Park for behavioural scoring, R. Robertson for behavioural scoring and MATLAB programming, L. Lo for testing Cre-mediated recombination in Esr1cre/1 male mice, C. Chiu and X. Wang for histology, M. McCardle for genotyping, J. S. Chang for technical assistance, S. Pease for generation of knock-in mice, H. Cai for training in slice electrophysiology, A. Wong for assistance with two-photon imaging, K. Deisseroth and J. Harris for AAV constructs, E. Boyden for advice on ferrule fibre fabrication, D. Lin and M. Boyle for their contributions to early stages of this project, W. Hong and R. Axel for comments on the manuscript, C. Chiu for laboratory management and G. Mancuso for administrative assistance. D.J.A. is an Investigator of the Howard Hughes Medical Institute and a Paul G. Allen Distinguished Investigator. This work was supported in part by NIH grant no. R01MH070053, and grants from the Gordon Moore Foundation and Ellison Medical Research Foundation. H.L. was supported by the NIH Pathway to Independence Award 1K99NS074077. T.E.A. was supported by NIH NRSA postdoctoral fellowship grant 1F32HD055198-01 and a Beckman Fellowship. Author Contributions H.L. characterized Esr1cre mice, designed and performed optogenetic behavioural experiments and co-wrote the manuscript; D.-W.K. performed slice electrophysiology and imaging experiments; R.R. performed in vivo electrophysiology; T.E.A. generated the Esr1cre targeting construct and AAV vectors; A.C. carried out some behavioural experiments; L.M. and H.Z. performed in situ hybridization experiments; D.J.A. supervised experiments and co-wrote the manuscript.

Attached Files

Accepted Version - nihms576781.pdf

Supplemental Material - nature13169-s1.pdf

Supplemental Material - nature13169-sv1.mp4

Supplemental Material - nature13169-sv10.mp4

Supplemental Material - nature13169-sv2.mp4

Supplemental Material - nature13169-sv3.mp4

Supplemental Material - nature13169-sv4.mp4

Supplemental Material - nature13169-sv5.mp4

Supplemental Material - nature13169-sv6.mp4

Supplemental Material - nature13169-sv7.mp4

Supplemental Material - nature13169-sv8.mp4

Supplemental Material - nature13169-sv9.mp4


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August 20, 2023
October 26, 2023