Modulating the Oxytocin System During the Perinatal Period: A New Strategy for Neuroprotection of the Immature Brain?

Manuela Zinni, Marina Colella, Aline Rideau Batista Novais, Olivier Baud, Jérôme Mairesse, Manuela Zinni, Marina Colella, Aline Rideau Batista Novais, Olivier Baud, Jérôme Mairesse

Abstract

Oxytocin is a neurohypophysal hormone known for its activity during labor and its role in lactation. However, the function of oxytocin (OTX) goes far beyond the peripheral regulation of reproduction, and the central effects of OTX have been extensively investigated, since it has been recognized to influence the learning and memory processes. OTX has also prominent effects on social behavior, anxiety, and autism. Interaction between glucocorticoids, OTX, and maternal behavior may have long-term effects on the developmental program of the developing brain subjected to adverse events during pre and perinatal periods. OTX treatment in humans improves many aspects of social cognition and behavior. Its effects on the hypothalamic-pituitary-adrenal axis and inflammation appear to be of interest in neonates because these properties may confer benefits when the perinatal brain has been subjected to injury. Indeed, early life inflammation and abnormal adrenal response to stress have been associated with an abnormal white matter development. Recent investigations demonstrated that OTX is involved in the modulation of microglial reactivity in the developing brain. This review recapitulates state-of-the art data supporting the hypothesis that the OTX system could be considered as an innovative candidate for neuroprotection, especially in the immature brain.

Keywords: GABA; glucocorticosteroid; intra-uterine growth restriction; maternal behavior; microglia; neuro-inflammation; oxytocin; white matter brain injury.

Figures

Figure 1
Figure 1
Causal relationship between abnormal microglia activation and WMI in IUGR infants. IUGR, intrauterine growth restriction; WMI, white matter injury.
Figure 2
Figure 2
Bidirectional relationship between hypothalamic–pituitary–adrenal axis and oxytocin system. PVN, paraventricular nucleus; CRF, corticotropin releasing factor; ACTH, adrenocorticotropic hormone.

References

    1. Jarvis S, Glinianaia SV, Torrioli M-GG, Platt M-JJ, Miceli M, Jouk P-SS, et al. Cerebral palsy and intrauterine growth in single births: European collaborative study. Lancet (2003) 362(9390):1106–11.
    1. Regev RH, Lusky A, Dolfin T, Litmanovitz I, Arnon S, Reichman B, et al. Excess mortality and morbidity among small-for-gestational-age premature infants: a population-based study. J Pediatr (2003) 143(2):186–91.10.1067/S0022-3476(03)00181-1
    1. Nardozza LMM, Caetano ACR, Zamarian ACP, Mazzola JB, Silva CP, Marçal VMG, et al. Fetal growth restriction: current knowledge. Arch Gynecol Obstet (2017) 295(5):1061–77.10.1007/s00404-017-4341-9
    1. Katz J, Lee AC, Kozuki N, Lawn JE, Cousens S, Blencowe H, et al. Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis. Lancet (2013) 382(9890):417–25.10.1016/S0140-6736(13)60993-9
    1. Geva R, Eshel R, Leitner Y, Fattal-Valevski A, Harel S. Memory functions of children born with asymmetric intrauterine growth restriction. Brain Res (2006) 1117(1):186–94.10.1016/j.brainres.2006.08.004
    1. Korzeniewski SJ, Allred EN, Joseph RM, Heeren T, Kuban KCK, O’Shea TM, et al. Neurodevelopment at age 10 years of children born <28 weeks with fetal growth restriction. Pediatrics (2017) 140(5):e20170697.10.1542/peds.2017-0697
    1. Dubois J, Benders M, Borradori-Tolsa C, Cachia A, Lazeyras F, Ha-Vinh Leuchter R, et al. Primary cortical folding in the human newborn: an early marker of later functional development. Brain (2008) 131(Pt 8):2028–41.10.1093/brain/awn137
    1. Egaña-Ugrinovic G, Sanz-Cortes M, Figueras F, Couve-Perez C, Gratacós E. Fetal MRI insular cortical morphometry and its association with neurobehavior in late-onset small-for-gestational-age fetuses. Ultrasound Obstet Gynecol (2014) 44(3):322–9.10.1002/uog.13360
    1. Lodygensky GA, Seghier ML, Warfield SK, Tolsa CB, Sizonenko S, Lazeyras F, et al. Intrauterine growth restriction affects the preterm infant’s hippocampus. Pediatr Res (2008) 63(4):438–43.10.1203/PDR.0b013e318165c005
    1. Padilla N, Junqué C, Figueras F, Sanz-Cortes M, Bargalló N, Arranz A, et al. Differential vulnerability of gray matter and white matter to intrauterine growth restriction in preterm infants at 12 months corrected age. Brain Res (2014) 1545:1–11.10.1016/j.brainres.2013.12.007
    1. Tolsa CB, Zimine S, Warfield SK, Freschi M, Rossignol AS, Lazeyras F, et al. Early alteration of structural and functional brain development in premature infants born with intrauterine growth restriction. Pediatr Res (2004) 56(1):132–8.10.1203/01.PDR.0000128983.54614.7E
    1. Batalle D, Eixarch E, Figueras F, Muñoz-Moreno E, Bargallo N, Illa M, et al. Altered small-world topology of structural brain networks in infants with intrauterine growth restriction and its association with later neurodevelopmental outcome. Neuroimage (2012) 60(2):1352–66.10.1016/j.neuroimage.2012.01.059
    1. Fischi-Gómez E, Vasung L, Meskaldji D-E, Lazeyras F, Borradori-Tolsa C, Hagmann P, et al. Structural brain connectivity in school-age preterm infants provides evidence for impaired networks relevant for higher order cognitive skills and social cognition. Cereb Cortex (2015) 25(9):2793–805.10.1093/cercor/bhu073
    1. Jacobsson B, Ahlin K, Francis A, Hagberg G, Hagberg H, Gardosi J. Cerebral palsy and restricted growth status at birth: population-based case-control study. BJOG (2008) 115(10):1250–5.10.1111/j.1471-0528.2008.01827.x
    1. Blair E, Stanley F. Intrauterine growth and spastic cerebral palsy. Am J Obstet Gynecol (1990) 162(1):229–37.10.1016/0002-9378(90)90856-3
    1. Jacobsson B, Hagberg G. Antenatal risk factors for cerebral palsy. Best Pract Res Clin Obstet Gynaecol (2004) 18(3):425–36.10.1016/j.bpobgyn.2004.02.011
    1. MacLennan AH, Thompson SC, Gecz J. Cerebral palsy: causes, pathways, and the role of genetic variants. Am J Obstet Gynecol (2015) 213(6):779–88.10.1016/j.ajog.2015.05.034
    1. McIntyre S, Blair E, Badawi N, Keogh J, Nelson KB. Antecedents of cerebral palsy and perinatal death in term and late preterm singletons. Obstet Gynecol (2013) 122(4):869–77.10.1097/AOG.0b013e3182a265ab
    1. Wixey JA, Chand KK, Colditz PB, Bjorkman ST. Review: neuroinflammation in intrauterine growth restriction. Placenta (2017) 54:117–24.10.1016/j.placenta.2016.11.012
    1. Leviton A, Dammann O, Durum SK. The adaptive immune response in neonatal cerebral white matter damage. Ann Neurol (2005) 58(6):821–8.10.1002/ana.20662
    1. Rezaie P, Dean A. Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system. Neuropathology (2002) 22(3):106–32.10.1046/j.1440-1789.2002.00438.x
    1. Pham H, Duy AP, Pansiot J, Bollen B, Gallego J, Charriaut-Marlangue C, et al. Impact of inhaled nitric oxide on white matter damage in growth-restricted neonatal rats. Pediatr Res (2015) 77(4):563–9.10.1038/pr.2015.4
    1. Olivier P, Baud O, Bouslama M, Evrard P, Gressens P, Verney C. Moderate growth restriction: deleterious and protective effects on white matter damage. Neurobiol Dis (2007) 26(1):253–63.10.1016/j.nbd.2007.01.001
    1. Olivier P, Baud O, Evrard P, Gressens P, Verney C. Prenatal ischemia and white matter damage in rats. J Neuropathol Exp Neurol (2005) 64(11):998–1006.10.1097/01.jnen.0000187052.81889.57
    1. Campbell LR, Pang Y, Ojeda NB, Zheng B, Rhodes PG, Alexander BT. Intracerebral lipopolysaccharide induces neuroinflammatory change and augmented brain injury in growth-restricted neonatal rats. Pediatr Res (2012) 71(6):645–52.10.1038/pr.2012.26
    1. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature (2017) 541(7638):481–7.10.1038/nature21029
    1. Hanisch U-K, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci (2007) 10(11):1387–94.10.1038/nn1997
    1. Cunningham CL, Martinez-Cerdeno V, Noctor SC. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci (2013) 33(10):4216–33.10.1523/JNEUROSCI.3441-12.2013
    1. Squarzoni P, Oller G, Hoeffel G, Pont-Lezica L, Rostaing P, Low D, et al. Microglia modulate wiring of the embryonic forebrain. Cell Rep (2014) 8(5):1271–9.10.1016/j.celrep.2014.07.042
    1. Pont-Lezica L, Beumer W, Colasse S, Drexhage H, Versnel M, Bessis A. Microglia shape corpus callosum axon tract fasciculation: functional impact of prenatal inflammation. Eur J Neurosci (2014) 39(10):1551–7.10.1111/ejn.12508
    1. Kim H-J, Cho M-H, Shim WH, Kim JK, Jeon E-Y, Kim D-H, et al. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol Psychiatry (2017) 22(11):1576–84.10.1038/mp.2016.103
    1. Ben-Ari Y. Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders. Trends Neurosci (2008) 31(12):626–36.10.1016/j.tins.2008.09.002
    1. van Tilborg E, de Theije CGM, van Hal M, Wagenaar N, de Vries LS, Benders MJ, et al. Origin and dynamics of oligodendrocytes in the developing brain: implications for perinatal white matter injury. Glia (2018) 66(2):221–38.10.1002/glia.23256
    1. Volpe JJ, Kinney HC, Jensen FE, Rosenberg PA. Reprint of “The developing oligodendrocyte: key cellular target in brain injury in the premature infant”. Int J Dev Neurosci (2011) 29(6):565–82.10.1016/j.ijdevneu.2011.07.008
    1. Den Boon FS, Sarabdjitsingh RA. Circadian and ultradian patterns of HPA-axis activity in rodents: significance for brain functionality. Best Pract Res Clin Endocrinol Metab (2017) 31(5):445–57.10.1016/j.beem.2017.09.001
    1. Loram LC, Taylor FR, Strand KA, Frank MG, Sholar P, Harrison JA, et al. Prior exposure to glucocorticoids potentiates lipopolysaccharide induced mechanical allodynia and spinal neuroinflammation. Brain Behav Immun (2011) 25(7):1408–15.10.1016/j.bbi.2011.04.013
    1. Johnson JD, O’connor KA, Deak T, Stark M, Watkins LR, Maier SF. Prior stressor exposure sensitizes LPS-induced cytokine production. Brain Behav Immun (2002) 16(4):461–76.10.1006/brbi.2001.0638
    1. Yeager MP, Rassias AJ, Pioli PA, Beach ML, Wardwell K, Collins JE, et al. Pretreatment with stress cortisol enhances the human systemic inflammatory response to bacterial endotoxin. Crit Care Med (2009) 37(10):2727–32.10.1097/CCM.0b013e3181a592b3
    1. Meagher MW, Sieve AN, Johnson RR, Satterlee D, Belyavskyi M, Mi W, et al. Neonatal maternal separation alters immune, endocrine, and behavioral responses to acute Theiler’s virus infection in adult mice. Behav Genet (2010) 40(2):233–49.10.1007/s10519-010-9333-5
    1. Vanbesien-Mailliot CCAA, Wolowczuk I, Mairesse J, Viltart O, Delacre M, Khalife J, et al. Prenatal stress has pro-inflammatory consequences on the immune system in adult rats. Psychoneuroendocrinology (2007) 32(2):114–24.10.1016/j.psyneuen.2006.11.005
    1. Avitsur R, Hunzeker J, Sheridan JF. Role of early stress in the individual differences in host response to viral infection. Brain Behav Immun (2006) 20(4):339–48.10.1016/j.bbi.2005.09.006
    1. Gómez-González B, Escobar A. Prenatal stress alters microglial development and distribution in postnatal rat brain. Acta Neuropathol (2010) 119(3):303–15.10.1007/s00401-009-0590-4
    1. Roque A, Ochoa-Zarzosa A, Torner L. Maternal separation activates microglial cells and induces an inflammatory response in the hippocampus of male rat pups, independently of hypothalamic and peripheral cytokine levels. Brain Behav Immun (2016) 55:39–48.10.1016/j.bbi.2015.09.017
    1. Ślusarczyk J, Trojan E, Głombik K, Budziszewska B, Kubera M, Lasoń W, et al. Prenatal stress is a vulnerability factor for altered morphology and biological activity of microglia cells. Front Cell Neurosci (2015) 9:82.10.3389/fncel.2015.00082
    1. Diz-Chaves Y, Pernía O, Carrero P, Garcia-Segura LM. Prenatal stress causes alterations in the morphology of microglia and the inflammatory response of the hippocampus of adult female mice. J Neuroinflammation (2012) 9:1.10.1186/1742-2094-9-71
    1. Herman JP, McKlveen JM, Solomon MB, Carvalho-Netto E, Myers B. Neural regulation of the stress response: glucocorticoid feedback mechanisms. Biol Res (2012) 45(4):292–8.
    1. Sorrells SF, Sapolsky RM. An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun (2007) 21(3):259–72.10.1016/j.bbi.2006.11.006
    1. Zhang TY, Labonté B, Wen XL, Turecki G, Meaney MJ. Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology (2013) 38(1):111–23.10.1038/npp.2012.149
    1. Tyrka AR, Price LH, Marsit C, Walters OC, Carpenter LL. Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS One (2012) 7(1):e30148.10.1371/journal.pone.0030148
    1. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics (2008) 3(2):97–106.10.4161/epi.3.2.6034
    1. Zhu Y, Wang Y, Yao R, Hao T, Cao J, Huang H, et al. Enhanced neuroinflammation mediated by DNA methylation of the glucocorticoid receptor triggers cognitive dysfunction after sevoflurane anesthesia in adult rats subjected to maternal separation during the neonatal period. J Neuroinflammation (2017) 14(1):6.10.1186/s12974-016-0782-5
    1. Yoshida M, Takayanagi Y, Onaka T. The medial amygdala-medullary PrRP-synthesizing neuron pathway mediates neuroendocrine responses to contextual conditioned fear in male rodents. Endocrinology (2014) 155(8):2996–3004.10.1210/en.2013-1411
    1. Minhas S, Liu C, Galdamez J, So VM, Romeo RD. Stress-induced oxytocin release and oxytocin cell number and size in prepubertal and adult male and female rats. Gen Comp Endocrinol (2016) 234:103–9.10.1016/j.ygcen.2016.03.014
    1. Sanders G, Freilicher J, Lightman SL. Psychological stress of exposure to uncontrollable noise increases plasma oxytocin in high emotionality women. Psychoneuroendocrinology (1990) 15(1):47–58.10.1016/0306-4530(90)90046-C
    1. Windle RJ, Kershaw YM, Shanks N, Wood SA, Lightman SL, Ingram CD. Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity. J Neurosci (2004) 24(12):2974–82.10.1523/JNEUROSCI.3432-03.2004
    1. Windle RJ, Shanks N, Lightman SL, Ingram CD. Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology (1997) 138(7):2829–34.10.1210/endo.138.7.5255
    1. Jurek B, Slattery DA, Hiraoka Y, Liu Y, Nishimori K, Aguilera G, et al. Oxytocin regulates stress-induced Crf gene transcription through CREB-regulated transcription coactivator 3. J Neurosci (2015) 35(35):12248–60.10.1523/JNEUROSCI.1345-14.2015
    1. Neumann ID, Wigger A, Torner L, Holsboer F, Landgraf R. 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 (2001) 12(3):235–43.10.1046/j.1365-2826.2000.00442.x
    1. Ditzen B, Schaer M, Gabriel B, Bodenmann G, Ehlert U, Heinrichs M. Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biol Psychiatry (2009) 65(9):728–31.10.1016/j.biopsych.2008.10.011
    1. Page K, McCool WF, Guidera M. Examination of the pharmacology of oxytocin and clinical guidelines for use in labor. J Midwifery Womens Health (2017) 62(4):425–33.10.1111/jmwh.12610
    1. Karelina K, Stuller KA, Jarrett B, Zhang N, Wells J, Norman GJ, et al. Oxytocin mediates social neuroprotection after cerebral ischemia. Stroke (2011) 42(12):3606–11.10.1161/STROKEAHA.111.628008
    1. Amini-Khoei H, Mohammadi-Asl A, Amiri S, Hosseini M-J, Momeny M, Hassanipour M, et al. Oxytocin mitigated the depressive-like behaviors of maternal separation stress through modulating mitochondrial function and neuroinflammation. Prog Neuropsychopharmacol Biol Psychiatry (2017) 76(169–178):2017.10.1016/j.pnpbp.2017.02.022
    1. Yuan L, Liu S, Bai X, Gao Y, Liu G, Wang X, et al. Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. J Neuroinflammation (2016) 13(1):77.10.1186/s12974-016-0541-7
    1. Weil ZM, Norman GJ, Barker JM, Su AJ, Nelson RJ, Devries AC. Social isolation potentiates cell death and inflammatory responses after global ischemia. Mol Psychiatry (2008) 13(10):913–5.10.1038/mp.2008.70
    1. Busnelli M, Chini B. Molecular basis of oxytocin receptor signalling in the brain: what we know and what we need to know. Curr Top Behav Neurosci (2017).10.1007/7854_2017_6
    1. Liu H, Leak RK, Hu X. Neurotransmitter receptors on microglia. Stroke Vasc Neurol (2016) 1(2):52–8.10.1136/svn-2016-000012
    1. Leonzino M, Busnelli M, Antonucci F, Verderio C, Mazzanti M, Chini B. The timing of the excitatory-to-inhibitory GABA switch is regulated by the oxytocin receptor via KCC2. Cell Rep (2016) 15(1):96–103.10.1016/j.celrep.2016.03.013
    1. He Q, Nomura T, Xu J, Contractor A. The developmental switch in GABA polarity is delayed in fragile X mice. J Neurosci (2014) 34(2):446–50.10.1523/JNEUROSCI.4447-13.2014
    1. Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science (2014) 343(6171):675–9.10.1126/science.1247190
    1. Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hübner CA, Represa A, et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science (2006) 314(5806):1788–92.10.1126/science.1133212
    1. Valeeva G, Valiullina F, Khazipov R. Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro. Front Cell Neurosci (2013) 7:20.10.3389/fncel.2013.00020
    1. Curia G, Papouin T, Séguéla P, Avoli M. Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. Cereb Cortex (2009) 19(7):1515–20.10.1093/cercor/bhn159
    1. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev (2001) 81(2):629–83.10.1152/physrev.2001.81.2.629
    1. Malek A, Blann E, Mattison DR. Human placental transport of oxytocin. J Matern Fetal Med (1996) 5(5):245–55.10.1002/(SICI)1520-6661(199609/10)5:5<245::AID-MFM3>;2-H
    1. Pedersen C, Ascher J, Monroe Y, Prange A. Oxytocin induces maternal behavior in virgin female rats. Science (1982) 216(4546):648–50.10.1126/science.7071605
    1. Fahrbach SE, Morrell JI, Pfaff DW. Oxytocin induction of short-latency maternal behavior in nulliparous, estrogen-primed female rats. Horm Behav (1984) 18(3):267–86.10.1016/0018-506X(84)90016-3
    1. Shahrokh DK, Zhang T-Y, Diorio J, Gratton A, Meaney MJ. Oxytocin-dopamine interactions mediate variations in maternal behavior in the rat. Endocrinology (2010) 151(5):2276–86.10.1210/en.2009-1271
    1. Champagne F, Diorio J, Sharma S, Meaney MJ. Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. Proc Natl Acad Sci U S A (2001) 98(22):12736–41.10.1073/pnas.221224598
    1. Francis DD, Champagne FC, Meaney MJ. Variations in maternal behaviour are associated with differences in oxytocin receptor levels in the rat. J Neuroendocrinol (2000) 12(12):1145–8.10.1046/j.1365-2826.2000.00599.x
    1. Feldman R, Gordon I, Schneiderman I, Weisman O, Zagoory-Sharon O. Natural variations in maternal and paternal care are associated with systematic changes in oxytocin following parent-infant contact. Psychoneuroendocrinology (2010) 35:1133–41.10.1016/j.psyneuen.2010.01.013
    1. Feldman R, Weller A, Zagoory-Sharon O, Levine A. Evidence for a neuroendocrinological foundation of human affiliation. Psychol Sci (2007) 18(11):965–70.10.1111/j.1467-9280.2007.02010.x
    1. Gao Y, Raine A, Chan F, Venables PH, Mednick SA. Early maternal and paternal bonding, childhood physical abuse and adult psychopathic personality. Psychol Med (2010) 40(6):1007–16.10.1017/S0033291709991279
    1. Sylva K, Stein A, Leach P, Barnes J, Malmberg L-E. FCCC-team. Effects of early child-care on cognition, language, and task-related behaviours at 18 months: an English study. Br J Dev Psychol (2011) 29(Pt 1):18–45.10.1348/026151010X533229
    1. Bagot RC, Zhang T-Y, Wen X, Nguyen TTT, Nguyen H-B, Diorio J, et al. Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat. Proc Natl Acad Sci U S A (2012) 109(Suppl):17200–7.10.1073/pnas.1204599109
    1. Liu D, Diorio J, Day JC, Francis DD, Meaney MJ. Maternal care, hippocampal synaptogenesis and cognitive development inrats. Nat Neurosci (2000) 3(8):799–806.10.1038/77702
    1. Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM, Meaney MJ. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci U S A (1998) 95(9):5335–40.10.1073/pnas.95.9.5335
    1. Menard JL, Champagne DL, Meaney MJP. Variations of maternal care differentially influence “fear” reactivity and regional patterns of cFos immunoreactivity in response to the shock-probe burying test. Neuroscience (2004) 129(2):297–308.10.1016/j.neuroscience.2004.08.009
    1. Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science (1997) 277(5332):1659–62.10.1126/science.277.5332.1659

Source: PubMed

3
Subscribe