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Acute oxytocin improves memory and gaze following in male but not female nursery-reared infant macaques

Psychopharmacology volume 234, pages 497–506 (2017)Cite this article

Abstract

Rationale

Exogenous oxytocin administration is widely reported to improve social cognition in human and nonhuman primate adults. Risk factors of impaired social cognition, however, emerge in infancy. Early interventions—when plasticity is greatest—are critical to reverse negative outcomes.

Objective

We tested the hypothesis that oxytocin may exert similar positive effects on infant social cognition, as in adults. To test this idea, we assessed the effectiveness of acute, aerosolized oxytocin on two foundational social cognitive skills: working memory (i.e., ability to briefly hold and process information) and social gaze (i.e., tracking the direction of others’ gaze) in 1-month-old nursery-reared macaque monkeys (Macaca mulatta). We did not predict sex differences, but we included sex as a factor in our analyses to test whether our effects would be generalizable across both males and females.

Results

In a double-blind, placebo-controlled design, we found that females were more socially skilled at baseline compared to males, and that oxytocin improved working memory and gaze following, but only in males.

Conclusions

These sex differences, while unexpected, may be due to interactions with gonadal steroids and may be relevant to sexually dimorphic disorders of social cognition, such as male-biased autism spectrum disorder, for which oxytocin has been proposed as a potential treatment. In sum, we report the first evidence that oxytocin may influence primate infant cognitive abilities. Moreover, these behavioral effects appear sexually dimorphic, highlighting the importance of considering sex differences. Oxytocin effects observed in one sex may not be generalizable to the other sex.

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References

  • Aigner TG, Mitchell SJ, Aggleton JP, DeLong MR, Struble RG, Price DL, Wenk GL, Mishkin M (1987) Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert. Psychopharmacology 92:292–300

    CAS  Article  PubMed  Google Scholar 

  • Bachevalier J, Hagger C (1991) Sex differences in the development of learning abilities in primates. Psychoneuroendocrinology 16:177–188

    CAS  Article  PubMed  Google Scholar 

  • Bales KL, Carter CS (2003) Sex differences and developmental effects of oxytocin on aggression and social behavior in prairie voles (Microtus ochrogaster). Horm Behav 44:178–184

    CAS  Article  PubMed  Google Scholar 

  • Bayliss AP, Pellegrino GD, Tipper SP (2005) Sex differences in eye gaze and symbolic cueing of attention. Q J Exp Psychol 58:631–650

    Article  Google Scholar 

  • Brooks R, Meltzoff AN (2015) Connecting the dots from infancy to childhood: a longitudinal study connecting gaze following, language, and explicit theory of mind. J Exper Child Psychol 130:67–78

    Article  Google Scholar 

  • Campbell A, Ruffman T, Murray JE, Glue P (2014) Oxytocin improves emotion recognition for older males. Neurobiol Aging 35:2246–2248

    CAS  Article  PubMed  Google Scholar 

  • Carson DS, Berquist SW, Trujillo TH, Garner JP, Hannah SL, Hyde SA et al (2015) Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children. Mol Psychiatry 20:1085–1090

    CAS  Article  PubMed  Google Scholar 

  • Carter CS (2007) Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res 176:170–186

    CAS  Article  PubMed  Google Scholar 

  • Chang SW, Platt ML (2014) Oxytocin and social cognition in rhesus macaques: implications for understanding and treating human psychopathology. Brain Res 1580:57–68

    CAS  Article  PubMed  Google Scholar 

  • Charman T (2003) Why is joint attention a pivotal skill in autism? Philos Trans Roy Soc B Biol Sci 358:315–324

    Article  Google Scholar 

  • Charman T, Swettenham J, Baron-Cohen S, Cox A, Baird G, Drew A (1997) Infants with autism: an investigation of empathy, pretend play, joint attention, and imitation. Dev Psychol 33:781–789

    CAS  Article  PubMed  Google Scholar 

  • Choleris E, Gustafsson JA, Korach KS, Muglia LJ, Pfaff DW, Ogawa S (2003) An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-α and-β knockout mice. Proc Natl Acad Sci U S A 100:6192–6197

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Christov-Moore L, Simpson EA, Coudé G, Grigaityte K, Iacoboni M, Ferrari PF (2014) Empathy: gender effects in brain and behavior. Neurosci Biobehav Rev 46:604–627

    Article  PubMed  PubMed Central  Google Scholar 

  • Clark CL, St. John N, Pasca AM, Hyde SA, Hornbeak K, Abramova M et al (2013) Neonatal CSF oxytocin levels are associated with parent report of infant soothability and sociability. Psychoneuroendocrinology 38:1208–1212

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Connellan J, Baron-Cohen S, Wheelwright S, Batki A, Ahluwalia J (2000) Sex differences in human neonatal social perception. Infant Behav Dev 23:113–118

    Article  Google Scholar 

  • Corcoran CA, Pierre PJ, Haddad T, Bice C, Suomi SJ, Grant KA, Friedman DP, Bennett AJ (2012) Long-term effects of differential early rearing in rhesus macaques: behavioral reactivity in adulthood. Dev Psychobiol 54:546–555

    Article  PubMed  Google Scholar 

  • Cowan N, Fristoe NM, Elliott EM, Brunner RP, Saults JS (2006) Scope of attention, control of attention, and intelligence in children and adults. Mem Cogn 34:1754–1768

    Article  Google Scholar 

  • de Wilde A, Koot HM, van Lier PA (2016) Developmental links between children’s working memory and their social relations with teachers and peers in the early school years. J Abnorm Child Psychol 44:19–30

    Article  PubMed  Google Scholar 

  • Deaner RO, Shepherd SV, Platt ML (2007) Familiarity accentuates gaze cuing in women but not men. Biol Lett 3:65–68

    Article  Google Scholar 

  • Dettmer AM, Kaburu SSK, Simpson EA, Paukner A, Sclafani V, Byers KL, Murphy AM, Miller M, Marquez N, Miller GM, Suomi SJ, Ferrari PF (2016) Neonatal face-to-face interactions promote later social behaviour in infant rhesus monkeys. Nat Comm 7:11940

    CAS  Article  Google Scholar 

  • Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC (2007) Oxytocin improves “mind reading” in humans. Biol Psychiatry 61:731–733

    CAS  Article  PubMed  Google Scholar 

  • Ebitz RB, Watson KK, Platt ML (2013) Oxytocin blunts social vigilance in the rhesus macaque. Proc Natl Acad Sci U S A 110:11630–11635

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Emery NJ, Lorincz EN, Perrett DI, Oram MW, Baker CI (1997) Gaze following and joint attention in rhesus monkeys (Macaca mulatta). J Comp Psychol 111:286–293

    CAS  Article  PubMed  Google Scholar 

  • Feifel D, MacDonald K, McKinney R, Heisserer N, Serrano V (2011) A randomized, placebo-controlled investigation of intranasal oxytocin in patients with anxiety. Neuropsychopharmacology 36:S324–S449

    Article  Google Scholar 

  • Feng C, Hackett PD, DeMarco AC, Chen X, Stair S, Haroon E, Ditzen B, Pagnoni G, Rilling JK (2014) Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans. Brain Imaging Behav 9:754–764

    Article  Google Scholar 

  • Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT (2000) Social amnesia in mice lacking the oxytocin gene. Nat Genet 25:284–288

    CAS  Article  PubMed  Google Scholar 

  • Ferrari PF, Kohler E, Fogassi L, Gallese V (2000) The ability to follow eye gaze and its emergence during development in macaque monkeys. Proc Natl Acad Sci U S A 97:13997–14002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Freeman SM, Inoue K, Smith AL, Goodman MM, Young LJ (2014) The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta). Psychoneuroendocrinology 45:128–141

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Frischen A, Bayliss AP, Tipper SP (2007) Gaze cueing of attention: visual attention, social cognition, and individual differences. Psychol Bull 133:694–724

    Article  PubMed  PubMed Central  Google Scholar 

  • Gabor CS, Phan A, Clipperton-Allen AE, Kavaliers M, Choleris E (2012) Interplay of oxytocin, vasopressin, and sex hormones in the regulation of social recognition. Behav Neurosci 126:97–109

    CAS  Article  PubMed  Google Scholar 

  • Gao S, Becker B, Luo L, Geng Y, Zhao W, Yin Y et al (2016) Oxytocin, the peptide that bonds the sexes also divides them. Proc Natl Academ Sci USA 113:7650–7654

    Article  Google Scholar 

  • Gattass R, Desimone R (2014) Effect of microstimulation of the superior colliculus on visual space attention. J Cog Neurosci 26:1208–1219

    Article  Google Scholar 

  • Guastella AJ, MacLeod C (2012) A critical review of the influence of oxytocin nasal spray on social cognition in humans: evidence and future directions. Horm Behav 61:410–418

    Article  PubMed  Google Scholar 

  • Guastella AJ, Mitchell PB, Mathews F (2008) Oxytocin enhances the encoding of positive social memories in humans. Biol Psychiatry 64:256–258

    CAS  Article  PubMed  Google Scholar 

  • Hittelman JH, Dickes R (1979) Sex differences in neonatal eye contact time. Merrill Palmer Q Behav Dev 25:171–184

    Google Scholar 

  • Lefevre A, Sirigu A (2016) The two fold role of oxytocin in social developmental disorders: a cause and a remedy? Neurosci Biobehav Rev 63:168–176

    CAS  Article  PubMed  Google Scholar 

  • Liu N, Hadj-Bouziane F, Jones KB, Turchi JN, Averbeck BB, Ungerleider LG (2015) Oxytocin modulates fMRI responses to facial expression in macaques. Proc Natl Acad Sci U S A 112:E3123–E3130

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • MacDonald KS (2013) Sex, receptors, and attachment: a review of individual factors influencing response to oxytocin. Front Neurosci 6:194

    Article  PubMed  PubMed Central  Google Scholar 

  • Maroun M, Wagner S (2016) Oxytocin and memory of emotional stimuli: some dance to remember, some dance to forget. Biol Psychiatry 79:203–212

    CAS  Article  PubMed  Google Scholar 

  • McQuade JD, Murray-Close D, Shoulberg EK, Hoza B (2013) Working memory and social functioning in children. J Exper Child Psychol 115:422–435

    Article  Google Scholar 

  • Meltzoff AN, Kuhl PK, Movellan J, Sejnowski TJ (2009) Foundations for a new science of learning. Science 325:284–288

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Modi ME, Connor-Stroud F, Landgraf R, Young LJ, Parr LA (2014) Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 45:49–57

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Noland JS, Reznick JS, Stone WL, Walden T, Sheridan EH (2010) Better working memory for non-social targets in infant siblings of children with autism spectrum disorder. Dev Sci 13:244–251

    Article  PubMed  PubMed Central  Google Scholar 

  • Osofsky JD, O’Connell EJ (1977) Patterning of newborn behavior in an urban population. Child Dev 48:532–536

    Article  Google Scholar 

  • Parker KJ, Garner JP, Libove RA, Hyde SA, Hornbeak KB, Carson DS et al (2014) Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder. Proc Natl Acad Sci U S A 111:12258–12263

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Parr LA, Brooks JM, Jonesteller T, Moss S, Jordano JO, Heitz TR (2016) Effects of chronic oxytocin on attention to dynamic facial expressions in infant macaques. Psychoneuroendocrinology . doi:10.1016/j.psyneuen.2016.08.028Advance Online Publication

    PubMed  Google Scholar 

  • Phillips KA, Bales KL, Capitanio JP, Conley A, Czoty PW, ‘t Hart BA et al. (2014) Why primate models matter. Am J Primatol 76:801–827.

    Article  PubMed  PubMed Central  Google Scholar 

  • Putnam PT, Roman JM, Zimmerman PE, Gothard KM (2016) Oxytocin enhances gaze-following responses to videos of natural social behavior in adult male rhesus monkeys. Psychoneuroendocrinology 72:47–53

    CAS  Article  PubMed  Google Scholar 

  • Quintana DS, Woolley JD (2016) Intranasal oxytocin mechanisms can be better understood but its effects on social cognition and behavior are not to be sniffed at. Biol Psychiatry 79:e49–350

    CAS  Article  PubMed  Google Scholar 

  • Rault JL, Carter CS, Garner JP, Marchant-Forde JN, Richert BT, Lay DC Jr (2013) Repeated intranasal oxytocin administration in early life dysregulates the HPA axis and alters social behavior. Physiol Behav 112:40–48

    Article  PubMed  Google Scholar 

  • Rosati AG, Arre AM, Platt ML, Santos LR (2016) Rhesus monkeys show human-like changes in gaze following across the lifespan. Proc R Soc B 283:20160376

    Article  PubMed  Google Scholar 

  • Scaif M, Bruner JS (1975) The capacity for joint visual attention in the infant. Nature 253:265–266

    Article  Google Scholar 

  • Sclafani V, Paukner A, Suomi SJ, Ferrari PF (2015) Imitation promotes affiliation in infant macaques at risk for impaired social behaviors. Dev Sci 18:614–621

    Article  PubMed  Google Scholar 

  • Sclafani V, Del Rosso LA, Seil SK, Calonder LA, Madreid JE, Bone KJ, Sherr EH, Garner JP, Capitanio JP, Parker KJ (2016) Early predictors of impaired social functioning in male rhesus macaques (Macaca mulatta). PLOS ONE

  • Simpson EA, Sclafani V, Paukner A, Hamel AF, Novak MA, Meyer JS et al (2014) Inhaled oxytocin increases positive social behaviors in newborn macaques. Proc Natl Acad Sci U S A 111:6922–6927

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Simpson EA, Miller G, Ferrari PF, Suomi SJ, Paukner A (2016a) Neonatal imitation and early social experience predict gaze following abilities in infant macaques. Sci Rep 6:20233

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Simpson EA, Nicolini Y, Shetler M, Suomi SJ, Ferrari PF, Paukner A (2016b) Experience-independent sex differences in newborn macaques: females are more social than males. Sci Rep 6:19669

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Taylor AE, Lee HE, Buisman-Pijlman FT (2015) Oxytocin treatment in pediatric populations. Front Behav Neurosci 8:360

    Google Scholar 

  • Triesch J, Teuscher C, Deák GO, Carlson E (2006) Gaze following: why (not) learn it? Dev Sci 9:125–147

    Article  PubMed  Google Scholar 

  • Wass SV (2015) Applying cognitive training to target executive functions during early development. Child Neuropsychol 21:150–166

    Article  PubMed  Google Scholar 

  • Winslow JT, Noble PL, Lyons CK, Sterk SM, Insel TR (2003) Rearing effects on cerebrospinal fluid oxytocin concentration and social buffering in rhesus monkeys. Neuropsychopharmacology 28:910–918

    CAS  PubMed  Google Scholar 

  • Wurtz RH, Goldberg ME (1972) The primate superior colliculus and the shift of visual attention. Investig Ophthalmol 11:441–450

    CAS  Google Scholar 

  • Yoshida M, Takayanagi Y, Inoue K, Kimura T, Young LJ, Onaka T, Nishimori K (2009) Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J Neurosci 29:2259–2271

    CAS  Article  PubMed  Google Scholar 

  • Zik JB, Roberts DL (2015) The many faces of oxytocin: implications for psychiatry. Psychiatry Res 226:31–37

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank the staff and researchers in the Laboratory of Comparative Ethology for help with data collection, Paige Fairman for reliability coding, and Sarah E. Maylott for helpful comments. This work was supported by the National Institute of Child Health and Human Development, National Institutes of Health [P01HD064653 to P.F.F.], a James W. McLamore Provost Research Award in Social Sciences, University of Miami [to E.A.S.], and the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

Author contributions

EAS, AP, VS, and PFF designed the study. SJS provided critical resources. EAS coordinated the study and lead data collection. AP, VS, and SSKK assisted with data collection. EAS coded the videos, analyzed the data, and wrote the manuscript. All authors gave final approval.

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Affiliations

  1. Department of Psychology, University of Miami, 5665 Ponce De Leon Boulevard, Coral Gables, FL, 33124, USA

    Elizabeth A. Simpson

  2. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Poolesville, MD, USA

    Elizabeth A. Simpson, Annika Paukner, Valentina Sclafani, Stefano S. K. Kaburu & Stephen J. Suomi

  3. Dipartimento di Neuroscienze, Università di Parma, Parma, Italy

    Elizabeth A. Simpson, Valentina Sclafani, Stefano S. K. Kaburu & Pier F. Ferrari

  4. School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK

    Valentina Sclafani

  5. Department of Population Health and Reproduction, University of California, Davis, CA, USA

    Stefano S. K. Kaburu

  6. Institut des Sciences Cognitives Marc Jeannerod, CNRS / Université Claude Bernard Lyon, Lyon, France

    Pier F. Ferrari

Authors
  1. Elizabeth A. Simpson
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  2. Annika Paukner
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  3. Valentina Sclafani
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  4. Stefano S. K. Kaburu
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  5. Stephen J. Suomi
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  6. Pier F. Ferrari
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Corresponding author

Correspondence to Elizabeth A. Simpson.

Ethics declarations

The Eunice Kennedy Shriver National Institute of Child Health and Human Development Animal Care and Use Committee approved all procedures. The study was conducted in accordance with the Guide for the Care and Use of Laboratory Animals and Complied with the Animal Welfare Act.

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The authors declare that they have no conflicts of interest.

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Simpson, E.A., Paukner, A., Sclafani, V. et al. Acute oxytocin improves memory and gaze following in male but not female nursery-reared infant macaques. Psychopharmacology 234, 497–506 (2017). https://doi.org/10.1007/s00213-016-4480-x

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  • DOI: https://doi.org/10.1007/s00213-016-4480-x

Keywords

  • Infancy
  • Primate
  • Individual differences
  • Intranasal oxytocin
  • Cognitive
  • Development