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

Lee, Hyosang and Kim, Dong-Wook and Remedios, Ryan and Anthony, Todd E. and Chang, Angela and Madisen, Linda and Zeng, Hongkui and Anderson, David J. (2014) Scalable control of mounting and attack by Esr1^+ neurons in the ventromedial hypothalamus. Nature, 509 (7502). pp. 627-632. ISSN 0028-0836. PMCID PMC4069208. http://resolver.caltech.edu/CaltechAUTHORS:20140422-111238454

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[img] Video (MPEG) (Video 5: Optogenetic activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse evokes aggressive sniffing towards a castrated BALB/c male intruder) - Supplemental Material
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[img] Video (MPEG) (Video 8: Activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse shifts behavioral responses from mounting, to a mixture of mounting and attack, to attack towards an unreceptive intact BALB/c female intruder as the photostimulation intensity is incre) - Supplemental Material
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[img] Video (MPEG) (Video 9: Activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse shifts behavioral responses from mounting, to a mixed behavior of mounting and attack, to attack towards a castrated BALB/c male intruder as the photostimulation intensity is increased) - Supplemental Material
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[img] Video (MPEG) (Video 10: Optogenetic activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse at intermediate photostimulation intensities evokes repeated, interspersed attempts at mounting and attack towards an unreceptive intact BALB/c female intruder) - Supplemental Material
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Abstract

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.


Item Type:Article
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http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13169.htmlPublisherArticle
http://dx.doi.org/10.1038/nature13169DOIArticle
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13169.html#supplementary-informationPublisherSupplementary information
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069208/PubMed CentralArticle
http://rdcu.be/cmpKPublisherFree ReadCube access
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.
Funders:
Funding AgencyGrant Number
NIHR01MH070053
Gordon Moore FoundationUNSPECIFIED
Ellison Medical Research FoundationUNSPECIFIED
NIH Pathway to Independence Award1K99NS074077
NIH NRSA postdoctoral fellowship grant1F32HD055198-01
Arnold and Mabel Beckman FoundationUNSPECIFIED
PubMed Central ID:PMC4069208
Record Number:CaltechAUTHORS:20140422-111238454
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20140422-111238454
Official Citation:Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus Hyosang Lee, Dong-Wook Kim, Ryan Remedios, Todd E. Anthony, Angela Chang + et al. Nature 509, 627–632 (29 May 2014) doi:10.1038/nature13169
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:45114
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:22 Apr 2014 20:28
Last Modified:19 Mar 2015 23:57

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