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Rapid nonapeptide synthesis during a critical period of development in the prairie vole: plasticity of the paraventricular nucleus of the hypothalamus


Vasopressin (VP) and oxytocin (OT) are involved in modulating basic physiology and numerous social behaviors. Although the anatomical distributions of nonapeptide neurons throughout development have been described, the functional roles of VP and OT neurons during development are surprisingly understudied, and it is unknown whether they exhibit functional changes throughout early development. We utilized an acute social isolation paradigm to determine if VP and OT neural responses in eight nonapeptide cell groups differ at three different stages of early development in prairie voles. We tested pups at ages that are representative of the three rapid growth stages of the developing brain: postnatal day (PND)2 (closed eyes; poor locomotion), PND9 (eye opening; locomotion; peak brain growth spurt), and PND21 (weaning). Neural responses were examined in pups that (1) were under normal family conditions with their parents and siblings, (2) were isolated from their parents and siblings and then reunited, and (3) were isolated from their parents and siblings. We found that VP and OT neural activity (as assessed via Fos co-localization) did not differ in response to social condition across development. However, remarkably rapid VP and OT synthesis in response to social isolation was observed only in the paraventricular nucleus of the hypothalamus (PVN) and only in PND9 pups. These results suggest that PVN nonapeptide neurons exhibit distinct cellular properties during a critical period of development, allowing nonapeptide neurons to rapidly upregulate peptide production in response to stressors on a much shorter timescale than has been observed in adult animals.

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  1. Ahern TH, Hammock EAD, Young LJ (2011) Parental division of labor, coordination, and the effects of family structure on parenting in monogamous prairie voles (Microtus ochrogaster). Dev Psychobiol 53(2):118–131. https://doi.org/10.1002/dev.20498

  2. Antoni FA (1993) Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Front Neuroendocrinol 14(2):76–122. https://doi.org/10.1006/frne.1993.1004

  3. Bamshad M, Novak MA, de Vries GJ (1994) Cohabitation alters vasopressin innervation and paternal behavior in prairie voles (Microtus ochrogaster). Physiol Behav 56(4):751–758

  4. Beurel E, Nemeroff CB (2014) Interaction of stress, corticotropin-releasing factor, arginine vasopressin and behaviour. Curr Top Behav Neurosci 18:67–80. https://doi.org/10.1007/7854_2014_306

  5. Bockhorst KH, Narayana PA, Liu R, Ahobila-Vijjula P, Ramu J (2008) Early postnatal development of rat brain: in vivo diffusion tensor imaging. J Neurosci Res 86:1520–1528. https://doi.org/10.1002/jnr.21607

  6. Boer GJ, Buijs RM, Swaab DF, De Vries GJ (1980) Vasopressin and the developing rat brain. Peptides 1:203–209

  7. Bosch OJ, Meddle SL, Beiderbeck DI, Douglas AJ, Neumann ID (2005) Brain oxytocin correlates with maternal aggression: link to anxiety. J Neurosci 25(29):6807–6815. https://doi.org/10.1523/JNEUROSCI.1342-05.2005

  8. Brown CH, Bains JS, Ludwig M, Stern JE (2013) Physiological regulation of magnocellular neurosecretory cell activity: integration of intrinsic, local and afferent mechanisms. J Neuroendocrinol 25(8):678–710. https://doi.org/10.1111/jne.12051

  9. Carter CS, Getz LL (1985) Social and hormonal determinants of reproductive patterns in the prairie vole. Neurobiology 18–36

  10. Cayetanot F, Bentivoglio M, Aujard F (2005) Arginine-vasopressin and vasointestinal polypeptide rhythms in the suprachiasmatic nucleus of the mouse lemur reveal aging-related alterations of circadian pacemaker neurons in a non-human primate. Eur J Neurosci 22(4):902–910. https://doi.org/10.1111/j.1460-9568.2005.04268.x

  11. Clancy B, Kersh B, Hyde J, Darlington RB, Anand KJ, Finlay BL (2007) Web-based method for translating neurodevelopment from laboratory species to humans. Neuroinfo 5(1):79–94

  12. Clutton-Brock TH (1991) The evolution of parental care. Princeton University Press 352. https://doi.org/10.1046/j.1420-9101.1992.5040719.x

  13. De Vries GJ, Panzica GC (2006) Sexual differentiation of central vasopressin and vasotocin systems in vertebrates: different mechanisms, similar endpoints. Neuroscience 138(3):947–955. https://doi.org/10.1016/j.neuroscience.2005.07.050

  14. Dean JM, Moravec MD, Grafe M, Abend N, Ren J, Gong X, Volpe JJ, Jensen FE, Hohimer AR, Back SA (2011) Strain-specific differences in perinatal rodent oligodendrocyte lineage progression and its correlation with human. Dev Neurosci 33(3–4):251–260. https://doi.org/10.1159/000327242

  15. Dekaban AS (1987) Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 4:345–356

  16. Dent GW, Okimoto DK, Smith MA, Levine S (2000) Stress-induced alterations in corticotropin-releasing hormone and vasopressin gene expression in the paraventricular nucleus during ontogeny. Neuroendocrinology 71(6):333–342

  17. DiBenedictis BT, Nussbaum ER, Cheung HK, Veenema AH (2017) Quantitative mapping reveals age and sex differences in vasopressin, but not oxytocin, immunoreactivity in the rat social behavior neural network. J Comp Neurol. https://doi.org/10.1002/cne.24216

  18. Engelmann M, Landgraf R, Wotjak CT (2004) The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited. Front Neuroendocrinol 25(3–4):132–149. https://doi.org/10.1016/j.yfrne.2004.09.001

  19. Ferguson AV, Latchford KJ, Samson WK (2008) The paraventricular nucleus of the hypothalamus - a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets 12(6):717–727. https://doi.org/10.1517/14728222.12.6.717

  20. Fitch HS (1957) Aspects of reproduction and development in the prairie vole. University of Kansas Publications, Museum of Natural History 10 (4):129–161

  21. Fox WM (1965) Reflex-ontogeny and behavioural development of the mouse. Anim Behav 13(2):234–241

  22. Getz LL, McGuire B, Pizzuto T, Hofmann JE, Frase B (1993) Social organization of the prairie vole (Microtus ochrogaster). J Mammal 74:44–58

  23. Gilles YD, Polston EK (2017) Effects of social deprivation on social and depressive-like behaviors and the numbers of oxytocin expressing neurons in rats. Behav Brain Res 328:28–38. https://doi.org/10.1016/j.bbr.2017.03.036

  24. Godefroy D, Dominici C, Hardin-Pouzet H, Anouar Y, Melik-Parsadaniantz S, Rostene W, Reaux-Le Goazigo A (2017) Three-dimensional distribution of tyrosine hydroxylase, vasopressin and oxytocin neurones in the transparent postnatal mouse brain. J Neuroendocrinol. https://doi.org/10.1111/jne.12551

  25. Goodson JL, Thompson RR (2010) Nonapeptide mechanisms of social cognition, behavior and species-specific social systems. Curr Opin Neurobiol 20(6):784–794. https://doi.org/10.1016/j.conb.2010.08.020

  26. Goodson JL, Wang Y (2006) Valence-sensitive neurons exhibit divergent functional profiles in gregarious and asocial species. Proc Natl Acad Sci USA 103(45):17013–17017. https://doi.org/10.1073/pnas.0606278103

  27. Goodson JL, Rinaldi J, Kelly AM (2009) Vasotocin neurons in the bed nucleus of the stria terminalis preferentially process social information and exhibit properties that dichotomize courting and non-courting phenotypes. Horm Behav 55(1):197–202. https://doi.org/10.1016/j.yhbeh.2008.10.007

  28. Gottlieb A, Keydar I, Epstein HT (1977) Rodent brain growth stages: an analytical review. Biol Neonate 32(3–4):166–176

  29. Grinevich V, Desarmenien MG, Chini B, Tauber M, Muscatelli F (2014) Ontogenesis of oxytocin pathways in the mammalian brain: late maturation and psychosocial disorders. Front Neuroanat 8:164. https://doi.org/10.3389/fnana.2014.00164

  30. Grippo AJ, Cushing BS, Carter CS (2007a) Depression-like behavior and stressor-induced neuroendocrine activation in female prairie voles exposed to chronic social isolation. Psychosom Med 69(2):149–157. https://doi.org/10.1097/PSY.0b013e31802f054b

  31. Grippo AJ, Gerena D, Huang J, Kumar N, Shah M, Ughreja R, Carter CS (2007b) Social isolation induces behavioral and neuroendocrine disturbances relevant to depression in female and male prairie voles. Psychoneuroendocrinol 32(8–10):966–980. https://doi.org/10.1016/j.psyneuen.2007.07.004

  32. Hammock EA (2015) Developmental perspectives on oxytocin and vasopressin. Neuropsychopharmacology 40(1):24–42. https://doi.org/10.1038/npp.2014.120

  33. Hoffman GE, Lyo D (2002) Anatomical markers of activity in neuroendocrine systems: are we all ‘fos-ed out’? J Neuroendocrinol 14(4):259–268

  34. Hoffman GE, Smith MS, Verbalis JG (1993) c-Fos and related immediate early gene products as markers of activity in neuroendocrine systems. Front Neuroendocrinol 14(3):173–213. https://doi.org/10.1006/frne.1993.1006

  35. Hull EM (2010) Male sexual behavior. Encycl Behav Neurosci Acad Press 154–162

  36. Kabelik D, Morrison JA, Goodson JL (2010) Cryptic regulation of vasotocin neuronal activity but not anatomy by sex steroids and social stimuli in opportunistic desert finches. Brain Behav Evol 75(1):71–84. https://doi.org/10.1159/000297522

  37. Kelly AM, Goodson JL (2014a) Personality is tightly coupled to vasopressin-oxytocin neuron activity in a gregarious finch. Front Behav Neurosci 8 (55). https://doi.org/10.3389/fnbeh.2014.00055

  38. Kelly AM, Goodson JL (2014b) Social functions of individual vasopressin-oxytocin cell groups in vertebrates: What do we really know? Front Neuroendocrinol 35(4):512–529. https://doi.org/10.1016/j.yfrne.2014.04.005

  39. Kelly AM, Hiura LC, Saunders AG, Ophir AG (2017) Oxytocin neurons exhibit extensive functional plasticity due to offspring age in mothers and fathers. Integr Comp Biol 57(3):603–618. https://doi.org/10.1093/icb/icx036

  40. Kelly AM, Saunders AG, Ophir AG (2018) Mechanistic substrates of a life history transition in male prairie voles: developmental plasticity in affiliation and aggression corresponds to nonapeptide neuronal function. Horm Behav 99:14–24. https://doi.org/10.1016/j.yhbeh.2018.01.006

  41. Kojima S, Stewart RA, Demas GE, Alberts JR (2012) Maternal contact differentially modulates central and peripheral oxytocin in rat pups during a brief regime of mother-pup interaction that induces a filial huddling preference. J Neuroendocrinol 24(5):831–840. https://doi.org/10.1111/j.1365-2826.2012.02280.x

  42. Krisch B (1980) Electron microscopic immunocytochemical investigation on the postnatal development of the vasopressin system in the rat. Cell Tissue Res 205:453–471

  43. Lagerspetz KYH (1966) Postnatal development of thermoregulation in laboratory mice. Helgol Mar Res 14(1):559–571

  44. Landgraf R, Neumann ID (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 25(3–4):150–176. https://doi.org/10.1016/J.Yfrne.2004.05.001

  45. Levine S (2002) Regulation of the hypothalamic-pituitary-adrenal axis in the neonatal rat: the role of maternal behavior. Neurotox Res 4(5–6):557–564. https://doi.org/10.1080/10298420290030569

  46. Li J, Li HX, Shou XJ, Xu XJ, Song TJ, Han SP, Zhang R, Han JS (2016) Effects of chronic restraint stress on social behaviors and the number of hypothalamic oxytocin neurons in male rats. Neuropeptides 60:21–28. https://doi.org/10.1016/j.npep.2016.08.011

  47. Lightman SL (2008) The neuroendocrinology of stress: a never ending story. J Neuroendocrinol 20(6):880–884. https://doi.org/10.1111/j.1365-2826.2008.01711.x

  48. Lodish H, Berk A, Kaiser CA, Krieger M, Scott MP, Bretscher A, Ploegh H, Matsudaira P (2007) Molecular Cell Biology, 6th edn. WH Freeman and Company, New York, NY

  49. Ludwig M, Leng G (2006) Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 7(2):126–136. https://doi.org/10.1038/nrn1845

  50. Ma XM, Levy A, Lightman SL (1997) Rapid changes in heteronuclear RNA for corticotrophin-releasing hormone and arginine vasopressin in response to acute stress. J Endocrinol 152(1):81–89

  51. Maier T, Guell M, Serrano L (2009) Correlation of mRNA and protein in complex biological samples. FEBS Lett 583(24):3966–3973. https://doi.org/10.1016/j.febslet.2009.10.036

  52. McGuire B, Lowell LL (1995) Communal nesting in prairie voles (Microtus ochrogaster)—an evaluation of costs and benefits based on patterns of dispersal and settlement. Can J Zool 73:383–391

  53. Mendonca R, Soares MC, Bshary R, Oliveira RF (2013) Arginine vasotocin neuronal phenotype and interspecific cooperative behaviour. Brain Behav Evol 82(3):166–176. https://doi.org/10.1159/000354784

  54. Neumann ID, Wigger A, Torner L, Holsboer F, Landgraf R (2000) Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: partial action within the paraventricular nucleus. J Neuroendocrinol 12(3):235–243

  55. Pan Y, Liu Y, Young KA, Zhang Z, Wang Z (2009) Post-weaning social isolation alters anxiety-related behavior and neurochemical gene expression in the brain of male prairie voles. Neurosci Lett 454(1):67–71. https://doi.org/10.1016/j.neulet.2009.02.064

  56. Qiu L, Zhu C, Wang X, Xu F, Eriksson PS, Nilsson M, Cooper-Kuhn CM, Kuhn HG, Blomgren K (2007) Less neurogenesis and inflammation in the immature than in the juvenile brain after cerebral hypoxia-ischemia. J Cereb Blood Flow Metab 27(4):785–794. https://doi.org/10.1038/sj.jcbfm.9600385

  57. Rabhi M, Ugrumov MV, Goncharevskaya OA, Bengelloun W, Calas A, Natchin YV (1996) Development of the hypothalamic vasopressin system and nephrons in Meriones shawi during ontogenesis. Anat Embryol (Berl) 193(3):281–296

  58. Rabhi M, Stoeckel ME, Calas A, Freund-Mercier MJ (1999) Historadioautographic localisation of oxytocin and vasopressin binding sites in the central nervous system of the merione (Meriones shawi). Brain Res Bull 48(2):147–163

  59. Rivalland ET, Clarke IJ, Turner AI, Pompolo S, Tilbrook AJ (2007) Isolation and restraint stress results in differential activation of corticotrophin-releasing hormone and arginine vasopressin neurons in sheep. Neuroscience 145(3):1048–1058. https://doi.org/10.1016/j.neuroscience.2006.12.045

  60. Robison WT, Myers MM, Hofer MA, Shair HN, Welch MG (2016) Prairie vole pups show potentiated isolation-induced vocalizations following isolation from their mother, but not their father. Dev Psychobiol 58(6):687–699. https://doi.org/10.1002/dev.21408

  61. Rood BD, De Vries GJ (2011) Vasopressin innervation of the mouse (Mus musculus) brain and spinal cord. J Comp Neurol 519(12):2434–2474. https://doi.org/10.1002/cne.22635

  62. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ (2013) Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106–107:1–16. https://doi.org/10.1016/j.pneurobio.2013.04.001

  63. Simerly RB, Swanson LW (1988) Projections of the medial preoptic nucleus: a Phaseolus vulgaris leucoagglutinin anterograde tract-tracing study in the rat. J Comp Neurol 270(2):209–242. https://doi.org/10.1002/cne.902700205

  64. Sivukhina EV, Jirikowski GF (2016) Magnocellular hypothalamic system and its interaction with the hypothalamo-pituitary-adrenal axis. Steroids 111:21–28. https://doi.org/10.1016/j.steroids.2016.01.008

  65. Smith JA, Pati D, Wang L, de Kloet AD, Frazier CJ, Krause EG (2015) Hydration and beyond: neuropeptides as mediators of hydromineral balance, anxiety and stress-responsiveness. Front Syst Neurosci 9:46. https://doi.org/10.3389/fnsys.2015.00046

  66. Smith CJ, Poehlmann ML, Li S, Ratnaseelan AM, Bredewold R, Veenema AH (2017) Age and sex differences in oxytocin and vasopressin V1a receptor bindign densities in the rat brain: focus on the social decision-making network. Brain Struct Funct 222(2):981–1006. https://doi.org/10.1007/s00429-016-1260-7

  67. Solomon NG (1991) Current indirect fitness benefits associated with philopatry in juvenile prairie voles. Behav Ecol Sociobiol 29(4):277–282. https://doi.org/10.1007/bf00163985

  68. Song Z, Tai F, Yu C, Wu R, Zhang X, Broders H, He F, Guo R (2010) Sexual or paternal experiences alter alloparental behavior and the central expression of ERalpha and OT in male mandarin voles (Microtus mandarinus). Behav Brain Res 214(2):290–300. https://doi.org/10.1016/j.bbr.2010.05.045

  69. Sperelakis N (2001) Cell physiology sourcebook: a molecular approach, 3rd edn. Academic Press, San Diego

  70. Steinman MQ, Laredo SA, Lopez EM, Manning CE, Hao RC, Doig IE, Campi KL, Flowers AE, Knight JK, Trainor BC (2015) Hypothalamic vasopressin systems are more sensitive to the long term effects of social defeat in males versus females. Psychoneuroendocrinol 51:122–134. https://doi.org/10.1016/j.psyneuen.2014.09.009

  71. Steinman MQ, Duque-Wilckens N, Greenberg GD, Hao R, Campi KL, Laredo SA, Laman-Maharg A, Manning CE, Doig IE, Lopez EM, Walch K, Bales KL, Trainor BC (2016) Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin. Biol Psychiatry 80(5):406–414. https://doi.org/10.1016/j.biopsych.2015.10.007

  72. Swaab DF, Ter Borg JP (1981) Development of peptidergic systems in the rat brain. Ciba Found Symp 86:271–294

  73. Swanson LW, Kuypers HG (1980) The paraventricular nucleus of the hypothalamus: cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde fluorescence double-labeling methods. J Comp Neurol 194(3):555–570. https://doi.org/10.1002/cne.901940306

  74. Swanson LW, Sawchenko PE (1980) Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms. Neuroendocrinology 31(6):410–417

  75. Swanson LW, Sawchenko PE (1983) Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6:269–324. https://doi.org/10.1146/annurev.ne.06.030183.001413

  76. Tamborski S, Mintz EM, Caldwell HK (2016) Sex differences in the embryonic development of the central oxytocin system in mice. J Neuroendocrinol. https://doi.org/10.1111/jne.12364

  77. Wang Z, Young LJ (1997) Ontogeny of oxytocin and vasopressin receptor binding in the lateral septum in prairie and montane voles. Brain Res Dev Brain Res 104(1–2):191–195

  78. Wang Z, Zhou L, Hulihan TJ, Insel TR (1996) Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: a quantitative comparative study. J Comp Neurol 366 (4):726–737. https://doi.org/10.1002/(SICI)1096-9861(19960318)366:4<726::AID-CNE11>3.0.CO;2-D

  79. Wang L, Zhang W, Wu R, Kong L, Feng W, Cao Y, Tai F, Zhang X (2014) Neuroendocrine responses to social isolation and paternal deprivation at different postnatal ages in mandarin voles. Dev Psychobiol 56(6):1214–1228. https://doi.org/10.1002/dev.21202

  80. Wigger A, Sanchez MM, Mathys KC, Ebner K, Frank E, Liu D, Kresse A, Neumann ID, Holsboer F, Plotsky PM, Landgraf R (2004) Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: critical role of vasopressin. Neuropsychopharmacology 29(1):1–14. https://doi.org/10.1038/sj.npp.1300290

  81. Williamson M, Viau V (2007) Androgen receptor expressing neurons that project to the paraventricular nucleus of the hypothalamus in the male rat. J Comp Neurol 503(6):717–740. https://doi.org/10.1002/cne.21411

  82. Williamson M, Viau V (2008) Selective contributions of the medial preoptic nucleus to testosterone-dependant regulation of the paraventricular nucleus of the hypothalamus and the HPA axis. Am J Physiol Regul Integr Comp Physiol 295(4):R1020–R1030. https://doi.org/10.1152/ajpregu.90389.2008

  83. Williamson M, Bingham B, Gray M, Innala L, Viau V (2010) The medial preoptic nucleus integrates the central influences of testosterone on the paraventricular nucleus of the hypothalamus and its extended circuitries. J Neurosci 30(35):11762–11770. https://doi.org/10.1523/JNEUROSCI.2852-10.2010

  84. Winkler DW (1987) A general model for parental care. Am Nat 103:526–543

  85. Yamamoto Y, Cushing BS, Kramer KM, Epperson PD, Hoffman GE, Carter CS (2004) Neonatal manipulations of oxytocin alter expression of oxytocin and vasopressin immunoreactive cells in the paraventricular nucleus of the hypothalamus in a gender-specific manner. Neuroscience 125(4):947–955. https://doi.org/10.1016/j.neuroscience.2004.02.028

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We are grateful for statistical help from the Statistics Consulting Center at Cornell University, to Chang Kim for assistance with PCR, and to Jeanne Powell for assistance with cell counts.

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Correspondence to Aubrey M. Kelly.

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The authors acknowledge the support from the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development HD081959 to AMK and HD079573 to AGO). The authors declare no competing financial interests and no conflicts of interest

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures were approved by and were in compliance with the Institutional Animal Care and Use Committee of Cornell University (2013-0102).

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Kelly, A.M., Hiura, L.C. & Ophir, A.G. Rapid nonapeptide synthesis during a critical period of development in the prairie vole: plasticity of the paraventricular nucleus of the hypothalamus. Brain Struct Funct 223, 2547–2560 (2018). https://doi.org/10.1007/s00429-018-1640-2

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  • Development
  • Vasopressin
  • Oxytocin
  • Critical period
  • Prairie vole
  • PVN