Abstract

Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders1 and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli2. Nuclei within the ventromedial hypothalamus3,4,5, extended amygdala6 and limbic7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour8. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF–lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF–lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF–lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF–lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

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Acknowledgements

This research was supported by US National Institutes of Health grants R01 MH090264, P50 MH096890 and P50 AT008661-01 (S.J.R.), R01 MH092306 (M.H.H.), T32 MH087004 (M.L.P., M.H. and M.F.), T32 MH096678 (M.L.P.), F30 MH100835 (M.H.), F31 MH105217 (M.L.P.), National Institute of General Medical Sciences 1FI2GM117583-01 (S.A.G.) and the Natural National Science Foundation of China 81200862 (H.Z.). We would like to thank K. Miczek and Y. Shaham for their input.

Author information

Author notes

    • Mitra Heshmati
    •  & Meghan Flanigan

    These authors contributed equally to this work.

Affiliations

  1. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Sam A. Golden
    • , Mitra Heshmati
    • , Meghan Flanigan
    • , Kevin Guise
    • , Madeline L. Pfau
    • , Hossein Aleyasin
    • , Caroline Menard
    • , Georgia E. Hodes
    • , Dana Bregman
    • , Lena Khibnik
    • , Jonathan Tai
    • , Nicole Rebusi
    • , Brian Krawitz
    • , Ming-Hu Han
    • , Matt L. Shapiro
    •  & Scott J. Russo
  2. Graduate Program in Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Sam A. Golden
    • , Mitra Heshmati
    • , Meghan Flanigan
    • , Kevin Guise
    • , Madeline L. Pfau
    •  & Brian Krawitz
  3. Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Palo Alto, California 94305, USA

    • Daniel J. Christoffel
    •  & Jessica J. Walsh
  4. Pharmacology and Systems Therapeutics and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Hongxing Zhang
    • , Dipesh Chaudhury
    •  & Ming-Hu Han

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Contributions

S.A.G. and S.J.R. designed and wrote the manuscript. S.A.G., D.J.C., M.H., C.M., J.J.W., M.L.P., N.R. H.A., G.E.H., M.F., D.B., L.K., J.T. and B.K. collected behavioural and immunohistochemistry data and aided in data analysis. H.Z., M.-H.H., D.C., K.G. and M.L.S. designed, carried out and analysed electrophysiological experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Scott J. Russo.

Reviewer Information Nature thanks O. Hikosaka and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature18601

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