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Imaging neuropeptide effects on human brain function

  • Arthur Lefevre
  • Rene Hurlemann
  • Valery Grinevich
Review

Abstract

The discovery of prosocial effects of oxytocin (OT) opened new directions for studying neuropeptide effects on the human brain. However, despite obvious effects of OT on neural responses as reported in numerous studies, other peptides have received less attention. Therefore, we will only briefly summarize evidence of OT effects on human functional magnetic resonance imaging (fMRI) and primarily focus on OT’s sister neuropeptide arginine-vasopressin by presenting our own coordinated-based activation likelihood estimation meta-analysis. In addition, we will recapitulate rather limited data on few other neuropeptides, including pharmacological and genetic fMRI studies. Finally, we will review experiments with external neuropeptide administration to patients afflicted with mental disorders, such as autism or schizophrenia. In conclusion, despite remaining uncertainty regarding the penetrance of exogenous neuropeptides through the blood-brain barrier, it is evident that neuropeptides simultaneously influence the activity of limbic and cortical areas, indicating that these systems have a good potential for therapeutic drug development. Hence, this calls for further systematic studies of a wide spectrum of known and less known neuropeptides to understand their normal function in the brain and, subsequently, to tackle their potential contribution for pathophysiological mechanisms of mental disorders.

Keywords

Neuropeptides Human fMRI ALE Oxytocin Vasopressin 

Notes

Funding information

Arthur Lefevre is a recipient of the Fyssen Research Foundation fellowship. The work was supported by the Chica and Heinz Schaller Research Foundation, Thyssen Foundation, SFB 1134 and 1158, DFG-ANR grant GR 3619/701 and Human Frontier Science Program to VG.

References

  1. Adrian TE, Allen JM, Bloom SR et al (1983) Neuropeptide Y distribution in human brain. Nature 306:584–586CrossRefPubMedGoogle Scholar
  2. Aoki Y, Watanabe T, Abe O et al (2014) Oxytocin’s neurochemical effects in the medial prefrontal cortex underlie recovery of task-specific brain activity in autism: a randomized controlled trial. Mol Psychiatry.  https://doi.org/10.1038/mp.2014.74
  3. Aspé-Sánchez M, Moreno M, Rivera MI et al (2015) Oxytocin and vasopressin receptor gene polymorphisms: role in social and psychiatric traits. Front Neurosci 9:510.  https://doi.org/10.3389/fnins.2015.00510 PubMedCrossRefGoogle Scholar
  4. Banerjee P, Joy KP, Chaube R (2016) Structural and functional diversity of nonapeptide hormones from an evolutionary perspective: a review. Gen Comp Endocrinol.  https://doi.org/10.1016/j.ygcen.2016.04.025
  5. Bartz JA, Zaki J, Bolger N, Ochsner KN (2011) Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci 15:301–309.  https://doi.org/10.1016/j.tics.2011.05.002 PubMedCrossRefGoogle Scholar
  6. Born J, Lange T, Kern W et al (2002) Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 5:514–516.  https://doi.org/10.1038/nn0602-849 CrossRefPubMedGoogle Scholar
  7. Borsook D, Upadhyay J, Klimas M et al (2012) Decision-making using fMRI in clinical drug development: revisiting NK-1 receptor antagonists for pain. Drug Discov Today 17:964–973.  https://doi.org/10.1016/j.drudis.2012.05.004 CrossRefPubMedGoogle Scholar
  8. Brunnlieb C, Münte TF, Krämer U et al (2013a) Vasopressin modulates neural responses during human reactive aggression. Soc Neurosci 8:148–164.  https://doi.org/10.1080/17470919.2013.763654 CrossRefPubMedGoogle Scholar
  9. Brunnlieb C, Münte TF, Tempelmann C, Heldmann M (2013b) Vasopressin modulates neural responses related to emotional stimuli in the right amygdala. Brain Res 1499:29–42.  https://doi.org/10.1016/j.brainres.2013.01.009 CrossRefPubMedGoogle Scholar
  10. Brunnlieb C, Nave G, Camerer CF et al (2016) Vasopressin increases human risky cooperative behavior. Proc Natl Acad Sci U S A 113:2051–2056.  https://doi.org/10.1073/pnas.1518825113 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Caldwell HK, Lee H-J, Macbeth AH, Young WS III (2008) Vasopressin: behavioral roles of an “original” neuropeptide. Prog Neurobiol 84:1–24.  https://doi.org/10.1016/j.pneurobio.2007.10.007 CrossRefPubMedGoogle Scholar
  12. Carter CS, Altemus M (1997) Integrative functions of lactational hormones in social behavior and stress management. Ann N Y Acad Sci 807:164–174CrossRefPubMedGoogle Scholar
  13. Chini B, Verhage M, Grinevich V (2017) The action radius of oxytocin release in the mammalian CNS: from single vesicles to behavior. Trends Pharmacol Sci.  https://doi.org/10.1016/j.tips.2017.08.005
  14. Choleris E, Devidze N, Kavaliers M, Pfaff DW (2008) Steroidal/neuropeptide interactions in hypothalamus and amygdala related to social anxiety. Prog Brain Res 170:291–303.  https://doi.org/10.1016/S0079-6123(08)00424-X CrossRefPubMedGoogle Scholar
  15. Contoreggi C (2015) Corticotropin releasing hormone and imaging, rethinking the stress axis. Nucl Med Biol 42:323–339.  https://doi.org/10.1016/j.nucmedbio.2014.11.008 CrossRefPubMedGoogle Scholar
  16. Dal Monte O, Noble PL, Turchi J et al (2014) CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One 9:e103677.  https://doi.org/10.1371/journal.pone.0103677 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Dannlowski U, Kugel H, Franke F et al (2011) Neuropeptide-S (NPS) receptor genotype modulates basolateral amygdala responsiveness to aversive stimuli. Neuropsychopharmacology 36:1879–1885.  https://doi.org/10.1038/npp.2011.73 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Domes G, Kumbier E, Heinrichs M, Herpertz SC (2013) Oxytocin promotes facial emotion recognition and amygdala reactivity in adults with Asperger syndrome. Neuropsychopharmacology.  https://doi.org/10.1038/npp.2013.254
  19. Domschke K, Akhrif A, Romanos M, et al (2017) Neuropeptide S receptor gene variation differentially modulates fronto-limbic effective connectivity in childhood and adolescence. Cereb Cortex N Y N 1991 27:554–566.  https://doi.org/10.1093/cercor/bhv259
  20. Domschke K, Reif A, Weber H et al (2011) Neuropeptide S receptor gene -- converging evidence for a role in panic disorder. Mol Psychiatry 16:938–948.  https://doi.org/10.1038/mp.2010.81 CrossRefPubMedGoogle Scholar
  21. Dumais KM, Veenema AH (2015) Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol.  https://doi.org/10.1016/j.yfrne.2015.04.003
  22. Eickhoff SB, Bzdok D, Laird AR et al (2012) Activation likelihood estimation meta-analysis revisited. NeuroImage 59:2349–2361.  https://doi.org/10.1016/j.neuroimage.2011.09.017 CrossRefPubMedGoogle Scholar
  23. Eser D, Leicht G, Lutz J et al (2009) Functional neuroanatomy of CCK-4-induced panic attacks in healthy volunteers. Hum Brain Mapp 30:511–522.  https://doi.org/10.1002/hbm.20522 CrossRefPubMedGoogle Scholar
  24. Febo M, Ferris CF (2014) Oxytocin and vasopressin modulation of the neural correlates of motivation and emotion: results from functional MRI studies in awake rats. Brain Res.  https://doi.org/10.1016/j.brainres.2014.01.019
  25. Feng C, DeMarco AC, Haroon E, Rilling JK (2015) Neuroticism modulates the effects of intranasal vasopressin treatment on the neural response to positive and negative social interactions. Neuropsychologia 73:108–115.  https://doi.org/10.1016/j.neuropsychologia.2015.05.004 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Francis SM, Kim S-J, Kistner-Griffin E et al (2016) ASD and genetic associations with receptors for oxytocin and vasopressin-AVPR1A, AVPR1B, and OXTR. Front Neurosci 10:516.  https://doi.org/10.3389/fnins.2016.00516 PubMedPubMedCentralCrossRefGoogle Scholar
  27. Freeman SM, Samineni S, Allen PC et al (2016) Plasma and CSF oxytocin levels after intranasal and intravenous oxytocin in awake macaques. Psychoneuroendocrinology 66:185–194.  https://doi.org/10.1016/j.psyneuen.2016.01.014 CrossRefPubMedGoogle Scholar
  28. Galbusera A, De Felice A, Girardi S et al (2017) Intranasal oxytocin and vasopressin modulate divergent brainwide functional substrates. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 42:1420–1434.  https://doi.org/10.1038/npp.2016.283 CrossRefGoogle Scholar
  29. Gordon I, Vander Wyk BC, Bennett RH et al (2013) Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci U S A.  https://doi.org/10.1073/pnas.1312857110
  30. Gozzi M, Dashow EM, Thurm A et al (2017) Effects of oxytocin and vasopressin on preferential brain responses to negative social feedback. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 42:1409–1419.  https://doi.org/10.1038/npp.2016.248 CrossRefGoogle Scholar
  31. Grund T, Goyon S, Li Y et al (2017) Neuropeptide S activates paraventricular oxytocin neurons to induce anxiolysis. J Neurosci.  https://doi.org/10.1523/JNEUROSCI.2161-17.2017
  32. Guastella AJ, Kenyon AR, Alvares GA et al (2010) Intranasal arginine vasopressin enhances the encoding of happy and angry faces in humans. Biol Psychiatry 67:1220–1222.  https://doi.org/10.1016/j.biopsych.2010.03.014 CrossRefPubMedGoogle Scholar
  33. Guhn A, Domschke K, Müller LD et al (2015) Neuropeptide S receptor gene variation and neural correlates of cognitive emotion regulation. Soc Cogn Affect Neurosci 10:1730–1737.  https://doi.org/10.1093/scan/nsv061 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Huber D, Veinante P, Stoop R (2005) Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308:245–248.  https://doi.org/10.1126/science.1105636 CrossRefPubMedGoogle Scholar
  35. Johnson ZV, Young LJ (2017) Oxytocin and vasopressin neural networks: implications for social behavioral diversity and translational neuroscience. Neurosci Biobehav Rev 76:87–98.  https://doi.org/10.1016/j.neubiorev.2017.01.034 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Laird AR, Eickhoff SB, Fox PM et al (2011) The BrainMap strategy for standardization, sharing, and meta-analysis of neuroimaging data. BMC Res Notes 4:349.  https://doi.org/10.1186/1756-0500-4-349 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lee MR, Scheidweiler KB, Diao XX et al (2017) Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol Psychiatry.  https://doi.org/10.1038/mp.2017.27
  38. Lee RJ, Coccaro EF, Cremers H et al (2013) A novel V1a receptor antagonist blocks vasopressin-induced changes in the CNS response to emotional stimuli: an fMRI study. Front Syst Neurosci 7:100.  https://doi.org/10.3389/fnsys.2013.00100 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Lefevre A, Mottolese R, Redouté J et al (2017) Oxytocin fails to recruit serotonergic neurotransmission in the autistic brain. Cereb Cortex N Y N 1991:1–10.  https://doi.org/10.1093/cercor/bhx272 CrossRefGoogle Scholar
  40. Lefevre A, Sirigu A (2016) The two fold role of oxytocin in social developmental disorders: a cause and a remedy? Neurosci Biobehav Rev.  https://doi.org/10.1016/j.neubiorev.2016.01.011
  41. Leng G, Ludwig M (2015) Intranasal oxytocin: myths and delusions. Biol Psychiatry  https://doi.org/10.1016/j.biopsych.2015.05.003
  42. Ludwig M, Leng G (2006) Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 7:126–136.  https://doi.org/10.1038/nrn1845 CrossRefPubMedGoogle Scholar
  43. McCall C, Singer T (2012) The animal and human neuroendocrinology of social cognition, motivation and behavior. Nat Neurosci 15:681–688.  https://doi.org/10.1038/nn.3084 CrossRefPubMedGoogle Scholar
  44. Mickey BJ, Zhou Z, Heitzeg MM et al (2011) Emotion processing, major depression, and functional genetic variation of neuropeptide Y. Arch Gen Psychiatry 68:158–166.  https://doi.org/10.1001/archgenpsychiatry.2010.197 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Modi ME, Connor-Stroud F, Landgraf R et al (2014) Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 45:49–57.  https://doi.org/10.1016/j.psyneuen.2014.02.011 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Modi ME, Inoue K, Barrett CE et al (2015) Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the prairie vole. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 40:1856–1865.  https://doi.org/10.1038/npp.2015.35 CrossRefGoogle Scholar
  47. Neumann ID, Maloumby R, Beiderbeck DI, et al (2013) Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology  https://doi.org/10.1016/j.psyneuen.2013.03.003
  48. Opmeer EM, Kortekaas R, van Tol M-J et al (2014) Interaction of neuropeptide Y genotype and childhood emotional maltreatment on brain activity during emotional processing. Soc Cogn Affect Neurosci 9:601–609.  https://doi.org/10.1093/scan/nst025 CrossRefPubMedGoogle Scholar
  49. Paiva L, Sabatier N, Leng G, Ludwig M (2017) Effect of melanotan-II on brain Fos immunoreactivity and oxytocin neuronal activity and secretion in rats. J Neuroendocrinol 29.  https://doi.org/10.1111/jne.12454
  50. Pape H-C, Jüngling K, Seidenbecher T et al (2010) Neuropeptide S: a transmitter system in the brain regulating fear and anxiety. Neuropharmacology 58:29–34.  https://doi.org/10.1016/j.neuropharm.2009.06.001 CrossRefPubMedGoogle Scholar
  51. Poisbeau P, Grinevich V, Charlet A (2017) Oxytocin signaling in pain: cellular, circuit, system, and behavioral levels. Curr Top Behav Neurosci  https://doi.org/10.1007/7854_2017_14
  52. Quintana DS, Alvares GA, Hickie IB, Guastella AJ (2014) Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model Neurosci Biobehav Rev  https://doi.org/10.1016/j.neubiorev.2014.12.011
  53. Raam T, McAvoy KM, Besnard A et al (2017) Hippocampal oxytocin receptors are necessary for discrimination of social stimuli. Nat Commun 8:2001.  https://doi.org/10.1038/s41467-017-02173-0 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Refojo D, Holsboer F (2009) CRH signaling. Molecular specificity for drug targeting in the CNS. Ann N Y Acad Sci 1179:106–119.  https://doi.org/10.1111/j.1749-6632.2009.04983.x CrossRefPubMedGoogle Scholar
  55. Rilling JK, DeMarco AC, Hackett PD et al (2013) Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology.  https://doi.org/10.1016/j.psyneuen.2013.09.022
  56. Rilling JK, DeMarco AC, Hackett PD et al (2012) Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 37:447–461.  https://doi.org/10.1016/j.psyneuen.2011.07.013 CrossRefPubMedGoogle Scholar
  57. Ruff CC, Fehr E (2014) The neurobiology of rewards and values in social decision making. Nat Rev Neurosci 15:549–562.  https://doi.org/10.1038/nrn3776 CrossRefPubMedGoogle Scholar
  58. Ruland T, Domschke K, Schütte V et al (2015) Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol 25:1677–1682.  https://doi.org/10.1016/j.euroneuro.2015.07.011 CrossRefGoogle Scholar
  59. Sabatier N, Caquineau C, Dayanithi G et al (2003) α-Melanocyte-stimulating hormone stimulates oxytocin release from the dendrites of hypothalamic neurons while inhibiting oxytocin release from their terminals in the neurohypophysis. J Neurosci 23:10351–10358CrossRefPubMedGoogle Scholar
  60. Sanders J, Nemeroff C (2016) The CRF system as a therapeutic target for neuropsychiatric disorders. Trends Pharmacol Sci 37:1045–1054.  https://doi.org/10.1016/j.tips.2016.09.004 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Schunck T, Erb G, Mathis A et al (2006) Functional magnetic resonance imaging characterization of CCK-4-induced panic attack and subsequent anticipatory anxiety. NeuroImage 31:1197–1208.  https://doi.org/10.1016/j.neuroimage.2006.01.035 CrossRefPubMedGoogle Scholar
  62. Smith AL, Freeman SM, Barnhart TE et al (2016a) Initial investigation of three selective and potent small molecule oxytocin receptor PET ligands in New World monkeys. Bioorg Med Chem Lett.  https://doi.org/10.1016/j.bmcl.2016.04.097
  63. Smith AS, Williams Avram SK, Cymerblit-Sabba A et al (2016b) Targeted activation of the hippocampal CA2 area strongly enhances social memory. Mol Psychiatry 21:1137–1144.  https://doi.org/10.1038/mp.2015.189 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Spengler FB, Schultz J, Scheele D et al (2017) Kinetics and dose dependency of intranasal oxytocin effects on amygdala reactivity. Biol Psychiatry.  https://doi.org/10.1016/j.biopsych.2017.04.015
  65. Stoop R (2014) Neuromodulation by oxytocin and vasopressin in the central nervous system as a basis for their rapid behavioral effects. Curr Opin Neurobiol 29C:187–193.  https://doi.org/10.1016/j.conb.2014.09.012 CrossRefGoogle Scholar
  66. Streit F, Haddad L, Paul T et al (2014) A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala. Stress Amst Neth 17:352–361.  https://doi.org/10.3109/10253890.2014.921903 CrossRefGoogle Scholar
  67. Striepens N, Kendrick KM, Hanking V, et al (2013) Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans, Sci Rep 3:.  https://doi.org/10.1038/srep03440
  68. Striepens N, Matusch A, Kendrick KM et al (2014) Oxytocin enhances attractiveness of unfamiliar female faces independent of the dopamine reward system. Psychoneuroendocrinology 39:74–87.  https://doi.org/10.1016/j.psyneuen.2013.09.026 CrossRefPubMedGoogle Scholar
  69. Tanaka A, Furubayashi T, Arai M et al (2018) Delivery of oxytocin to the brain for the treatment of autism spectrum disorder by nasal application. Mol Pharm 15:1105–1111.  https://doi.org/10.1021/acs.molpharmaceut.7b00991 CrossRefPubMedGoogle Scholar
  70. Turkeltaub PE, Eickhoff SB, Laird AR et al (2012) Minimizing within-experiment and within-group effects in activation likelihood estimation meta-analyses. Hum Brain Mapp 33:1–13.  https://doi.org/10.1002/hbm.21186 CrossRefPubMedGoogle Scholar
  71. Umbricht D, Del Valle RM, Hollander E et al (2017) A single dose, randomized, controlled proof-of-mechanism study of a novel vasopressin 1a receptor antagonist (RG7713) in high-functioning adults with autism spectrum disorder. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 42:1914–1923.  https://doi.org/10.1038/npp.2016.232 CrossRefGoogle Scholar
  72. van den Pol AN (2012) Neuropeptide transmission in brain circuits. Neuron 76:98–115.  https://doi.org/10.1016/j.neuron.2012.09.014 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Wang D, Yan X, Li M, Ma Y (2017) Neural substrates underlying the effects of oxytocin: a quantitative meta-analysis of pharmaco-imaging studies. Soc Cogn Affect Neurosci 12:1565–1573.  https://doi.org/10.1093/scan/nsx085 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Wang Y, Wang M, Yin S, et al (2015) NeuroPep: a comprehensive resource of neuropeptides Database J Biol Databases Curation 2015:bav038.  https://doi.org/10.1093/database/bav038
  75. Wigton R, Radua J, Allen P et al (2015) Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. J Psychiatry Neurosci JPN 40:E1–E22CrossRefPubMedGoogle Scholar
  76. Xu Y-L, Reinscheid RK, Huitron-Resendiz S et al (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43:487–497.  https://doi.org/10.1016/j.neuron.2004.08.005 CrossRefPubMedGoogle Scholar
  77. Zhou Z, Zhu G, Hariri AR et al (2008) Genetic variation in human NPY expression affects stress response and emotion. Nature 452:997–1001.  https://doi.org/10.1038/nature06858 CrossRefPubMedPubMedCentralGoogle Scholar
  78. Zink CF, Kempf L, Hakimi S et al (2011) Vasopressin modulates social recognition-related activity in the left temporoparietal junction in humans. Transl Psychiatry 1:e3.  https://doi.org/10.1038/tp.2011.2 CrossRefPubMedPubMedCentralGoogle Scholar
  79. Zink CF, Stein JL, Kempf L et al (2010) Vasopressin modulates medial prefrontal cortex-amygdala circuitry during emotion processing in humans. J Neurosci 30:7017–7022.  https://doi.org/10.1523/JNEUROSCI.4899-09.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Zwanzger P, Domschke K, Bradwejn J (2012) Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin. Depress Anxiety 29:762–774.  https://doi.org/10.1002/da.21919 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Schaller Research Group on NeuropeptidesGerman Cancer Research CenterHeidelbergGermany
  2. 2.Department of Psychiatry and Division of Medical PsychologyUniversity of BonnBonnGermany
  3. 3.Central Institute of Mental HealthMannheimGermany

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