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Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin

Nature volume 501, pages 179–184 (2013)Cite this article

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Abstract

Social behaviours in species as diverse as honey bees and humans promote group survival but often come at some cost to the individual. Although reinforcement of adaptive social interactions is ostensibly required for the evolutionary persistence of these behaviours, the neural mechanisms by which social reward is encoded by the brain are largely unknown. Here we demonstrate that in mice oxytocin acts as a social reinforcement signal within the nucleus accumbens core, where it elicits a presynaptically expressed long-term depression of excitatory synaptic transmission in medium spiny neurons. Although the nucleus accumbens receives oxytocin-receptor-containing inputs from several brain regions, genetic deletion of these receptors specifically from dorsal raphe nucleus, which provides serotonergic (5-hydroxytryptamine; 5-HT) innervation to the nucleus accumbens, abolishes the reinforcing properties of social interaction. Furthermore, oxytocin-induced synaptic plasticity requires activation of nucleus accumbens 5-HT1B receptors, the blockade of which prevents social reward. These results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of oxytocin and 5-HT in the nucleus accumbens, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism.

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Figure 1: Oxytocin is required for social CPP.
Figure 2: Oxytocin induces LTD in the NAc.
Figure 3: Presynaptic OTRs are required for social CPP.
Figure 4: NAc OTRs in presynaptic terminals originating from the dorsal raphe nucleus are required for social CPP and OT-LTD.
Figure 5: OT-LTD in NAc requires 5HT1B receptors.
Figure 6: Social CPP requires NAc 5HT1B receptors.

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Acknowledgements

We thank members of the Malenka laboratory for comments; A. Andalman, W. Xu, B.K. Lim and T. Sudhof for technical advice; and the SIM1 Animal Care facility for husbandry support. The OT-neurophysin antibody was a gift of H. Gainer. OTR-Venus reporter mice were a gift of L. J. Young. D1-TdTomato BAC transgenic mice were provided by N. Calakos. The rabies virus complementary DNA plasmid and viral component-expressing plasmids were gifts from K. Conzelmann and I. Wickersham. HHK-B19G cells were a gift from E. Callaway. AAVs were produced by the Stanford NGVVC (supported by National Institutes of Health grant NIH NS069375). The AAV-DJ helper plasmid was a gift from M. Kay. This work was supported by funding from the Simons Foundation Autism Research Initiative (R.C.M.), N.I.H. (R.C.M.), and a Berry Foundation Postdoctoral Fellowship (G.D.)

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  1. Gül Dölen

    Present address: Present address: Department of Neuroscience, Johns Hopkins University, 855 North Wolfe Street, Baltimore, Maryland 21205, USA.,

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  1. Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University School of Medicine, 265 Campus Drive, Stanford, 94305, California, USA

    Gül Dölen, Ayeh Darvishzadeh, Kee Wui Huang & Robert C. Malenka

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Contributions

G.D. and R.C.M. designed the study, interpreted results and wrote the paper. G.D. performed behavioural experiments, electrophysiology, and confocal microscopy. G.D., A.D. and K.W.H. performed stereotaxic injections and immunohistochemistry. K.W.H. generated RBV viruses. All authors edited the paper.

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Correspondence to Robert C. Malenka.

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Dölen, G., Darvishzadeh, A., Huang, K. et al. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501, 179–184 (2013). https://doi.org/10.1038/nature12518

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