Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin

Journal name:
Nature
Volume:
501,
Pages:
179–184
Date published:
DOI:
doi:10.1038/nature12518
Received
Accepted
Published online

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.

At a glance

Figures

  1. Oxytocin is required for social CPP.
    Figure 1: Oxytocin is required for social CPP.

    a–i, Protocol for social CPP (a). Experimental time course of intraperitoneal (i.p.) injections (b) and NAc reverse microdialysis (f) in social CPP. Individual (top) and average (bottom) responses in animals receiving intraperitoneal (i.p.) (c) or NAc (g) saline versus animals receiving i.p. (d) or NAc (h) OTR-A. For both i.p. and NAc delivery routes, saline- but not OTR-A-treated animals spend more time in social bedding cue following conditioning (n = 18 i.p. saline, n = 15 i.p. OTR-A; n = 9 NAc saline and n = 11 NAc OTR-A animals). Values below 900 indicate that subjects preferred isolate bedding; values above 900 indicate that subjects preferred social bedding. e, i, Comparisons between treatment (Rx) groups reveal significantly decreased normalized and subtracted social preference in both i.p. and NAc OTR-A-treated animals. Summary data are presented as mean±s.e.m. (*P<0.05, Student’s t-test). Each arrowhead indicates an application of saline or OTR-A.

  2. Oxytocin induces LTD in the NAc.
    Figure 2: Oxytocin induces LTD in the NAc.

    a–h, Representative traces (a, d, g, j), summary time course (b, e, h, k), and average post-treatment magnitude comparisons (c, f, i, l) reveal significant EPSC response depression in oxytocin-treated but not OTR-A-pre-incubated cells (a–c, n = 6 OT (oxytocin), n = 6 OT + OTR-A pre-incubation cells). OT-response depression is not reversed by post-induction OTR-A chase (df, n = 7 cells). The magnitude of OT-LTD is significantly increased in cells from isolation versus socially reared animals (g–i, isolate, n = 14, social n = 27 cells). The magnitude of EPSC OT-LTD is not different in D1 versus D2 MSNs (j-l, n = 9 D1, and n = 11 D2 cells). mq Representative miniature EPSC traces (m), cumulative probability (n, o), and average (p, q) comparisons reveal that miniature EPSC frequency (n, p), but not amplitude (o, q), is decreased in OT-treated versus control cells (control, n = 11, OT, n = 11 cells). r–t, Comparisons of representative traces (r) and average (s) paired-pulse ratios PPR (n = 6 cells) as well as average (t) coefficient of variance, CV (n = 32 cells) reveal significant increases following induction of OT-LTD. Summary data are presented as mean±s.e.m. (*P<0.05, Student’s t-test). Numbered traces (1, 2 and 3) were taken at the times indicated by numbers below the graphs.

  3. Presynaptic OTRs are required for social CPP.
    Figure 3: Presynaptic OTRs are required for social CPP.

    a–l, Experimental time course for sham (a), NAc AAV-Cre-eGFP injection showing AAV particle and spread of Cre-eGFP from injection site (e), and NAc RBV-Cre-eGFP injection showing RBV particle and spread of Cre-eGFP from injection site (i). Individual (top) and average (bottom) responses in wild-type (WT) (b, f, j), versus conditional OTR (cOTR) (c, g, k) animals receiving sham (b, c), NAc AAV-Cre-eGFP (f, g) or NAc-RbV-Cre-eGFP (j, k). WT animals, as well as sham and NAc AAV-Cre-eGFP-injected cOTR animals, but not cOTR animals injected with NAc RBV-Cre-eGFP, spend more time in the social bedding cue following conditioning (sham WT, n = 15, cOTR, n = 8; NAc AAV-Cre-eGFP WT, n = 15, cOTR, n = 19; NAc RBV-Cre-eGFP WT, n = 14, cOTR, n = 22 animals). d, h, l, Comparisons between WT and cOTR animals reveal normal social CPP in sham and NAc AAV-Cre-eGFP-injected animals, whereas in NAc RBV-Cre-eGFP-injected animals social CPP is significantly decreased in cOTR versus WT controls. Summary data are presented as mean±s.e.m. (*P<0.05, Student’s t-test).

  4. NAc OTRs in presynaptic terminals originating from the dorsal raphe nucleus are required for social CPP and OT-LTD.
    Figure 4: NAc OTRs in presynaptic terminals originating from the dorsal raphe nucleus are required for social CPP and OT-LTD.

    a, Experimental time course of dorsal raphe nucleus (dRph) AAV-Cre-eGFP injections in social CPP. b, c Individual (top) and average (bottom) comparisons reveal that dRph AAV-Cre-eGFP-injected WT (b), but not cOTR (c) animals spend significantly more time in the social bedding cue following conditioning (WT, n = 14, cOTR, n = 10 animals). d, Comparisons between dRph AAV-Cre-eGFP-injected groups reveal significantly decreased social CPP in cOTR animals compared to WT controls. e–g, Representative traces (e), summary time course (f) and average post-treatment magnitude comparisons (g) reveal absence of OT-LTD in EPSCs recorded from dRph AAV-Cre-eGFP-injected cOTR knockout versus pooled WT control animals (dRph AAV-Cre-eGFP-injected cOTR, n = 6 cells; pooled WT control, n = 30 cells). Summary data are presented as mean±s.e.m. (*P<0.05, Student’s t-test).

  5. OT-LTD in NAc requires 5HT1B receptors.
    Figure 5: OT-LTD in NAc requires 5HT1B receptors.

    a–i, Representative traces (a, d, g), summary time course (b, e, h) and average post-treatment magnitude comparisons (c, f, i) reveal that EPSC depression in cells treated with 5HTR1B agonist (CP-93129 dihydrochloride) is not augmented by subsequent application of OT (a–c, n = 5 cells); OT-LTD is significantly reduced in cells pre-treated with the 5HTR1b-antagonist (NAS-181) (d–f, control, n = 7, 5HTR1B antagonist, n = 7 cells); 5HTR1B-mediated LTD induced by application of CP-93129 is not affected by pharmacological blockade of OTRs (g–i, n = 5 cells). j–n Representative miniature EPSC traces (j), cumulative probability (k, l), and average (m, n) comparisons reveal miniature EPSC frequency (k, m), but not amplitude (l, n), is decreased in OT-treated cells versus cells treated with OT in the presence of NAS-181 (OT, n = 17, OT + 5HTR1b-A, n = 17 cells). Summary data are presented as mean±s.e.m. (*P<0.05, Student’s t-test).

  6. Social CPP requires NAc 5HT1B receptors.
    Figure 6: Social CPP requires NAc 5HT1B receptors.

    a, Experimental time course of NAc reverse microdialysis. b, c, Individual (top) and average (bottom) responses in animals receiving NAc saline (b) versus 5HTR1B antagonist (5HTR1B-A) (c). Saline-treated animals, but not 5HTR1B-A-treated animals, spend more time in social bedding cue following conditioning (NAc saline, n = 20, NAc 5HTR1B-A, n = 26 animals). d, Comparisons between treatment groups reveal significantly decreased normalized and subtracted social preference in NAc 5HTR1B-A-treated animals compared to saline controls. Summary data are presented as mean±s.e.m. (*P<0.05, Student’s t-test).

References

  1. Kelley, A. E. & Berridge, K. C. The neuroscience of natural rewards: relevance to addictive drugs. J. Neurosci. 22, 33063311 (2002)
  2. Insel, T. R. Is social attachment an addictive disorder? Physiol. Behav. 79, 351357 (2003)
  3. Shultz, S., Opie, C. & Atkinson, Q. D. Stepwise evolution of stable sociality in primates. Nature 479, 219222 (2011)
  4. Young, L. J. & Wang, Z. The neurobiology of pair bonding. Nature Neurosci. 7, 10481054 (2004)
  5. Lee, H.-J., Macbeth, A. H., Pagani, J. H. & Young, W. S. Oxytocin: the great facilitator of life. Prog. Neurobiol. 88, 127151 (2009)
  6. Ross, H. E. et al. Characterization of the oxytocin system regulating affliative behavior in female prairie voles. Neurosci. 162, 892903 (2009)
  7. Yamasue, H. et al. Integrative approaches utilizing oxytocin to enhance prosocial behavior: from animal and human social behavior to autistic social dysfunction. J. Neuroscience 32, 1410914117 (2012)
  8. Anderson, P. K. & Hill, J. Mus musculus: experimental induction of territory formation. Science 148, 17531755 (1965)
  9. Riedman, M. L. The evolution of alloparental care and adoption in mammals and birds. Q. Rev. Biol. 57, 405435 (1982)
  10. Holy, T. E. & Guo, Z. Ultrasonic songs of male mice. PLoS Biol. 3, e386 (2005)
  11. Panksepp, J. Behavior. Empathy and the laws of affect. Science 334, 13581359 (2011)
  12. Hodgson, S. R., Hofford, R. S., Roberts, K. W., Wellman, P. J. & Eitan, S. Socially induced morphine pseudosensitization in adolescent mice. Behav. Pharmacol. 21, 112120 (2010)
  13. Tzschentke, T. M. Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict. Biol. 12, 227462 (2007)
  14. Panksepp, J. B. & Lahvis, G. P. Social reward among juvenile mice. Genes Brain Behav. 6, 661671 (2007)
  15. Rosen, G. J., de Vries, G. J., Goldman, S. L., Goldman, B. D. & Forger, N. G. Distribution of oxytocin in the brain of a eusocial rodent. Neuroscience 155, 809817 (2008)
  16. Hermes, M. L., Buijs, R. M., Masson-Pévet, M. & Pévet, P. Oxytocinergic innervation of the brain of the garden dormouse (Eliomys quercinus L.). J. Comp. Neurol. 273, 252262 (1988)
  17. Phillipson, O. T. & Griffiths, A. C. The topographic order of inputs to nucleus accumbens in the rat. Neuroscience. 16, 275296 (1985)
  18. Brog, J. S., Ongse, A. S., Deutch, A. Y. & Zahm, D. S. The patterns of afferent innervation of the core and shell in the “accumbens” part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold. J. Comp. Neurol. 278, 255278 (1993)
  19. Knobloch, H. S. et al. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73, 553566 (2012)
  20. Lobo, M. K. & Nestler, E. J. The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons. Front. Neuroanat. 5, 41 (2011)
  21. Shuen, J. A., Chen, M., Gloss, B. & Calakos, N. Drd1a-tdTomato BAC transgenic mice for simultaneous visualization of medium spiny neurons in the direct and indirect pathways of the basal ganglia. J. Neurosci. 28, 26812685 (2008)
  22. Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917925 (2003)
  23. Yoshida, M. et al. Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J. Neurosci. 29, 22592271 (2009)
  24. Lee, H.-J., Caldwell, H. K., Macbeth, A. H., Tolu, S. G. & Young, W. S. A conditional knockout mouse line of the oxytocin receptor. Endocrinology 149, 32563263 (2008)
  25. Brunner, D., Buhot, M. C., Hen, R. & Hofer, M. Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice. Behav. Neurosci. 113, 587601 (1999)
  26. Furay, A. R., McDevitt, R. A., Miczek, K. A. & Neumaier, J. F. 5–HT1B mRNA expression after chronic social stress. Behav. Brain Res. 224, 350357 (2011)
  27. Orabona, G. M. et al. HTR1B and HTR2C in autism spectrum disorders in Brazilian families. Brain Res. 1250, 1419 (2009); erratum. 1264, 127 (2009)
  28. Mathur, B. N., Capik, N. A., Alvarez, V. A. & Lovinger, D. M. Serotonin induces long-term depression at corticostriatal synapses. J. Neurosci. 31, 74027411 (2011)
  29. Cui, G. et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494, 238242 (2013)
  30. Capper-Loup, C., Canales, J. J., Kadaba, N. & Graybiel, A. M. Concurrent activation of dopamine D1 and D2 receptors is required to evoke neural and behavioral phenotypes of cocaine sensitization. J. Neurosci. 22, 62186227 (2002)
  31. Nambu, A. Seven problems on the basal ganglia. Curr. Opin. Neurobiol. 18, 595604 (2008)
  32. Perreault, M. L., Hasbi, A., O’Dowd, B. F. & George, S. R. The dopamine d1-d2 receptor heteromer in striatal medium spiny neurons: evidence for a third distinct neuronal pathway in Basal Ganglia. Front. Neuroanat. 5, 31 (2011)
  33. Doya, K. Metalearning and neuromodulation. Neural Netw. 15, 495506 (2002)
  34. Nakamura, K., Matsumoto, M. & Hikosaka, O. Reward-dependent modulation of neuronal activity in the primate dorsal raphe nucleus. J. Neurosci. 28, 53315343 (2008)
  35. Tanaka, S. C. et al. Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops. Nature Neurosci. 7, 887893 (2004)
  36. Boureau, Y.-L. & Dayan, P. Opponency revisited: competition and cooperation between dopamine and serotonin. Neuropsychopharmacology 36, 7497 (2011)
  37. Silverman, J. L., Yang, M., Lord, C. & Crawley, J. N. Behavioural phenotyping assays for mouse models of autism. Nature Rev. Neurosci. 11, 490502 (2010)
  38. Panksepp, J. B. et al. Affiliative behavior, ultrasonic communication and social reward are influenced by genetic variation in adolescent mice. PLoS ONE 2, e351 (2007)
  39. Aronov, D., Andalman, A. S. & Fee, M. S. A specialized forebrain circuit for vocal babbling in the juvenile songbird. Science 320, 630634 (2008)
  40. Andalman, A. S. & Fee, M. S. A basal ganglia-forebrain circuit in the songbird biases motor output to avoid vocal errors. Proc. Natl Acad. Sci. USA 106, 1251812523 (2009)
  41. Mebatsion, T., Konig, M. & Conzelmann, K. K. Budding of rabies virus particles in the absence of the spike glycoprotein. Cell 84, 941951 (1996)
  42. Wickersham, I. R., Sullivan, H. A. & Seung, H. S. Production of glycoprotein-deleted rabies viruses for monosynaptic tracing and high-level gene expression in neurons. Nature Protocols 5, 595606 (2010)
  43. Wickersham, I. R., Finke, S., Conzelmann, K. & Callaway, E. M. Retrograde neuronal tracing with a deletion-mutant rabies virus. Nature Methods 4, 4749 (2007)
  44. Grimm, D. et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol. 82, 58875911 (2008)
  45. Lammel, S. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212217 (2012)
  46. Ben-Barak, Y., Russell, J., Whitnall, M., Ozato, K. & Gainer, H. Neurophysin in the hypothalamo-neurohypophysial system. I. Production and characterization of monoclonal antibodies. J. Neurosci. 5, 8197 (1985)
  47. Whitnall, M. H. Key. S., Ben-Barak, Y., Ozato, K. & Gainer, H. Neurophysin in the hypothalamo-neurohypophysial system. II. Immunocytochemical studies of the ontogeny of oxytocinergic and vasopressinergic neurons. J. Neurosci. 5, 98109 (1985)

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Author information

Affiliations

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

    • Gül Dölen,
    • Ayeh Darvishzadeh,
    • Kee Wui Huang &
    • Robert C. Malenka
  2. Present address: Department of Neuroscience, Johns Hopkins University, 855 North Wolfe Street, Baltimore, Maryland 21205, USA.

    • Gül Dölen

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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The authors declare no competing financial interests.

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Comments

  1. Report this comment #60050

    Peter Gibson said:

    The study by Dolen et al on social reward has involved a lot of work to explain autism and social dysfunction in humans. Possible much simpler explanations exist. The most obvious problem with such complex explanations is that, although not in themselves disputed, call into question how they relate to human behaviour. For example, any explanations for autism of whatever kind are circumspect. Although mouse model exist they may have little to do with clinical autism in humans. This point has been made repeatedly but seldom heeded. Again and again researches use such mechanisms to explain human behaviour. They appear to be a justification for the research.
    A problem is to know whether social behaviour actually exists. There is much evidence that suggests it does not. This is the thrust of the sociobiological argument. This, in essence, is that the survival of apparently social animals does not depend on cooperation or altruism. This behaviour may simply be herding instinct. It has obvious advantages to individual members to the herd but not to the herd. Member of the herd do not even have to belong to the same species.
    The mechanisms described in this study appear to be misplaced when it comes to human behaviour which in essence selfish. Social reward does not come into the equation. One can argue that the success of autism depends on manipulating the behaviour of parents for selfish reasons. Disorders such as depression are mechanistic and not behavioural as such. It is a problem of the individual and depends on levels of 5HT which are likely to be genetically determined. Depression can be relieved pharmaceutically. The concept of social behaviour in the honey bee has been borrowed from the sociological belief in human cooperation. However the triumph in the understanding of bee behaviour has been shown, in essence, the hive behaves as an individual. Members carry the same genes. Therefore any claims made in the name of social behaviour have to be very careful scrutinised.

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