Abstract
Rationale
Early life stress has been implicated in many psychiatric disorders ranging from depression to anxiety. Maternal separation in rodents is a well-studied model of early life stress. However, stress during this critical period also induces alterations in many systems throughout the body. Thus, a variety of other disorders that are associated with adverse early life events are often comorbid with psychiatric illnesses, suggesting a common underlying aetiology. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is thought to involve a dysfunctional interaction between the brain and the gut. Essential aspects of the brain–gut axis include spinal pathways, the hypothalamic pituitary adrenal axis, the immune system, as well as the enteric microbiota. Accumulating evidence suggest that stress, especially in early life, is a predisposing factor to IBS.
Objective
The objective of this review was to assess and compile the most relevant data on early life stress and alterations at all levels of the brain gut axis.
Results
In this review, we describe the components of the brain–gut axis individually and how they are altered by maternal separation. The separated phenotype is characterised by alterations of the intestinal barrier function, altered balance in enteric microflora, exaggerated stress response and visceral hypersensitivity, which are all evident in IBS.
Conclusion
Thus, maternally separated animals are an excellent model of brain–gut axis dysfunction for the study of disorders such as IBS and for the development of novel therapeutic interventions.
Similar content being viewed by others
References
Aisa B, Tordera R, Lasheras B, Del Rio J, Ramirez MJ (2008) Effects of maternal separation on hypothalamic–pituitary–adrenal responses, cognition and vulnerability to stress in adult female rats. Neuroscience 154:1218–1226
Aisa B, Gil-Bea FJ, Marcos B, Tordera R, Lasheras B, Del Rio J, Ramirez MJ (2009) Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: involvement of the HPA axis. Psychoneuroendocrinology 34:1495–1505
Al-Chaer ED, Kawasaki M, Pasricha PJ (2000) A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 119:1276–1285
Arborelius L, Eklund MB (2007) Both long and brief maternal separation produces persistent changes in tissue levels of brain monoamines in middle-aged female rats. Neuroscience 145:738–750
Arias C, Solari AC, Mlewski EC, Miller S, Haymal B, Spear NE, Molina JC (2010) Social isolation and stress related hormones modulate the stimulating effect of ethanol in preweanling rats. Behav Brain Res 211:64–70
Avitsur R, Sheridan JF (2009) Neonatal stress modulates sickness behavior. Brain Behav Immun 23:977–985
Bailey MT, Coe CL (1999) Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol 35:146–155
Bale TL, Picetti R, Contarino A, Koob GF, Vale WW, Lee KF (2002) Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci 22:193–199
Ballard RA, Ballard PL, Granberg JP, Sniderman S (1979) Prenatal administration of betamethasone for prevention of respiratory distress syndrome. J Pediatr 94:97–101
Banihashemi L, Rinaman L (2010) Repeated brief postnatal maternal separation enhances hypothalamic gastric autonomic circuits in juvenile rats. Neuroscience 165:265–277
Barna I, Balint E, Baranyi J, Bakos N, Makara GB, Haller J (2003) Gender-specific effect of maternal deprivation on anxiety and corticotropin-releasing hormone mRNA expression in rats. Brain Res Bull 62:85–91
Barreau F, Cartier C, Ferrier L, Fioramonti J, Bueno L (2004a) Nerve growth factor mediates alterations of colonic sensitivity and mucosal barrier induced by neonatal stress in rats. Gastroenterology 127:524–534
Barreau F, Ferrier L, Fioramonti J, Bueno L (2004b) Neonatal maternal deprivation triggers long term alterations in colonic epithelial barrier and mucosal immunity in rats. Gut 53:501–506
Barreau F, Cartier C, Leveque M, Ferrier L, Moriez R, Laroute V, Rosztoczy A, Fioramonti J, Bueno L (2007a) Pathways involved in gut mucosal barrier dysfunction induced in adult rats by maternal deprivation: corticotrophin-releasing factor and nerve growth factor interplay. J Physiol 580:347–356
Barreau F, Ferrier L, Fioramonti J, Bueno L (2007b) New insights in the etiology and pathophysiology of irritable bowel syndrome: contribution of neonatal stress models. Pediatr Res 62:240–245
Barreau F, Salvador-Cartier C, Houdeau E, Bueno L, Fioramonti J (2008) Long-term alterations of colonic nerve–mast cell interactions induced by neonatal maternal deprivation in rats. Gut 57:582–590
Biagini G, Pich EM, Carani C, Marrama P, Agnati LF (1998) Postnatal maternal separation during the stress hyporesponsive period enhances the adrenocortical response to novelty in adult rats by affecting feedback regulation in the CA1 hippocampal field. Int J Dev Neurosci 16:187–197
Bian ZX, Zhang M, Han QB, Xu HX, Sung JJ (2010) Analgesic effects of JCM-16021 on neonatal maternal separation-induced visceral pain in rats. World J Gastroenterol 16:837–845
Blanchard EB, Lackner JM, Jaccard J, Rowell D, Carosella AM, Powell C, Sanders K, Krasner S, Kuhn E (2008) The role of stress in symptom exacerbation among IBS patients. J Psychosom Res 64:119–28
Boasen JF, McPherson RJ, Hays SL, Juul SE, Gleason CA (2009) Neonatal stress or morphine treatment alters adult mouse conditioned place preference. Neonatology 95:230–239
Bolton TB, Prestwich SA, Zholos AV, Gordienko DV (1999) Excitation–contraction coupling in gastrointestinal and other smooth muscles. Annu Rev Physiol 61:85–115
Bonaz B, Sabate JM (2009) Brain–gut axis dysfunction. Gastroentérol Clin Biol 33(Suppl 1):S48–S58
Bravo JA, Dinan TG, Cryan JF (2010) Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders. Int J Neuropsychopharmacol (in press)
Bredy TW, Grant RJ, Champagne DL, Meaney MJ (2003) Maternal care influences neuronal survival in the hippocampus of the rat. Eur J Neurosci 18:2903–2909
Cain KC, Jarrett ME, Burr RL, Rosen S, Hertig VL, Heitkemper MM (2009) Gender differences in gastrointestinal, psychological, and somatic symptoms in irritable bowel syndrome. Dig Dis Sci 54:1542–1549
Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM, Meaney MJ (1998) Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci USA 95:5335–5340
Caldji C, Diorio J, Meaney MJ (2000a) Variations in maternal care in infancy regulate the development of stress reactivity. Biol Psychiatry 48:1164–1174
Caldji C, Francis D, Sharma S, Plotsky PM, Meaney MJ (2000b) The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Neuropsychopharmacology 22:219–229
Caldji C, Diorio J, Anisman H, Meaney MJ (2004) Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice. Neuropsychopharmacology 29:1344–1352
Camilleri M, Andrews CN, Bharucha AE, Carlson PJ, Ferber I, Stephens D, Smyrk TC, Urrutia R, Aerssens J, Thielemans L, Gohlmann H, van den Wyngaert I, Coulie B (2007) Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome. Gastroenterology 132:17–25
Carrera O, Cerrato M, Sanchez A, Gutierrez E (2009) Long maternal separation has protective effects in rats exposed to activity-based anorexia. Dev Psychobiol 51:616–624
Cellek S, Thangiah R, Bassil AK, Campbell CA, Gray KM, Stretton JL, Lalude O, Vivekanandan S, Wheeldon A, Winchester WJ, Sanger GJ, Schemann M, Lee K (2007) Demonstration of functional neuronal beta3-adrenoceptors within the enteric nervous system. Gastroenterology 133:175–183
Chaloner A, Rao A, Al-Chaer ED, Greenwood-Van Meerveld B (2010) Importance of neural mechanisms in colonic mucosal and muscular dysfunction in adult rats following neonatal colonic irritation. Int J Dev Neurosci 28:99–103
Champagne FA, Francis DD, Mar A, Meaney MJ (2003) Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol Behav 79:359–371
Chung EK, Zhang X, Li Z, Zhang H, Xu H, Bian Z (2007a) Neonatal maternal separation enhances central sensitivity to noxious colorectal distention in rat. Brain Res 1153:68–77
Chung EK, Zhang XJ, Xu HX, Sung JJ, Bian ZX (2007b) Visceral hyperalgesia induced by neonatal maternal separation is associated with nerve growth factor-mediated central neuronal plasticity in rat spinal cord. Neuroscience 149:685–695
Chung EK, Bian ZX, Xu HX, Sung JJ (2009) Neonatal maternal separation increases brain-derived neurotrophic factor and tyrosine kinase receptor B expression in the descending pain modulatory system. Neurosignals 17:213–221
Cirulli F, Berry A, Alleva E (2003) Early disruption of the mother–infant relationship: effects on brain plasticity and implications for psychopathology. Neurosci Biobehav Rev 27:73–82
Collins SM, Bercik P (2009) The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 136:2003–2014
Cotella EM, Lascano IM, Levin GM, Suarez MM (2009) Amitriptyline treatment under chronic stress conditions: effect on circulating catecholamines and anxiety in early maternally separated rats. Int J Neurosci 119:664–680
Coutinho SV, Plotsky PM, Sablad M, Miller JC, Zhou H, Bayati AI, McRoberts JA, Mayer EA (2002) Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am J Physiol Gastrointest Liver Physiol 282:G307–G316
Cremon C, Gargano L, Morselli-Labate AM, Santini D, Cogliandro RF, De Giorgio R, Stanghellini V, Corinaldesi R, Barbara G (2009) Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol 104:392–400
Crowell MD, Shetzline MA, Moses PL, Mawe GM, Talley NJ (2004) Enterochromaffin cells and 5-HT signaling in the pathophysiology of disorders of gastrointestinal function. Curr Opin Investig Drugs 5:55–60
Cruz FC, Quadros IM, Planeta Cda S, Miczek KA (2008) Maternal separation stress in male mice: long-term increases in alcohol intake. Psychopharmacology 201:459–468
Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790
Daniels WM, Pietersen CY, Carstens ME, Stein DJ (2004) Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metab Brain Dis 19:3–14
de Kloet ER, Sibug RM, Helmerhorst FM, Schmidt MV (2005) Stress, genes and the mechanism of programming the brain for later life. Neurosci Biobehav Rev 29:271–281
De Wied D, Diamant M, Fodor M (1993) Central nervous system effects of the neurohypophyseal hormones and related peptides. Front Neuroendocrinol 14:251–302
Delvaux M (2004) Alterations of sensori-motor functions of the digestive tract in the pathophysiology of irritable bowel syndrome. Best Pract Res Clin Gastroenterol 18:747–771
Desbonnet L, Garrett L, Daly E, McDermott KW, Dinan TG (2008) Sexually dimorphic effects of maternal separation stress on corticotrophin-releasing factor and vasopressin systems in the adult rat brain. Int J Dev Neurosci 26:259–268
Dinan TG, Quigley EM, Ahmed SM, Scully P, O’Brien S, O’Mahony L, O’Mahony S, Shanahan F, Keeling PW (2006) Hypothalamic–pituitary–gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology 130:304–311
Dinan TG, Cryan J, Shanahan F, Keeling PW, Quigley EM (2010) IBS: an epigenetic perspective. Nat Rev Gastroenterol Hepatol 7(8):465–471 (Epub 29 Jun 2010)
Doupe AJ, Landis SC, Patterson PH (1985) Environmental influences in the development of neural crest derivatives: glucocorticoids, growth factors, and chromaffin cell plasticity. J Neurosci 5:2119–2142
Drake MJ, Fowler CJ, Griffiths D, Mayer E, Paton JF, Birder L (2010) Neural control of the lower urinary and gastrointestinal tracts: supraspinal CNS mechanisms. Neurourol Urodyn 29:119–127
Drossman DA, Morris CB, Schneck S, Hu YJ, Norton NJ, Norton WF, Weinland SR, Dalton C, Leserman J, Bangdiwala SI (2009) International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J Clin Gastroenterol 43:541–550
Dunlop SP, Coleman NS, Blackshaw E, Perkins AC, Singh G, Marsden CA, Spiller RC (2005) Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol 3:349–357
Eklund MB, Johansson LM, Uvnas-Moberg K, Arborelius L (2009) Differential effects of repeated long and brief maternal separation on behaviour and neuroendocrine parameters in Wistar dams. Behav Brain Res 203:69–75
Estienne M, Claustre J, Clain-Gardechaux G, Paquet A, Tache Y, Fioramonti J, Plaisancie P (2010) Maternal deprivation alters epithelial secretory cell lineages in rat duodenum: role of CRF-related peptides. Gut 59:744–751
Farhadi A, Fields JZ, Keshavarzian A (2007) Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: stress, intestinal hyperpermeability and inflammation. World J Gastroenterol 13:3027–3030
Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi P (2009) Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 58:367–378
Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J (2010) Mood and gut feelings. Brain Behav Immun 24:9–16
Foscolo DR, Foscolo RB, Marubayashi U, Reis AM, Coimbra CC (2008) Neonatal maternal separation affects endocrine and metabolic stress responses to ether exposure but not to restraint exposure in adult rats. Metab Brain Dis 23:375–385
Francis D, Diorio J, Liu D, Meaney MJ (1999a) Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 286:1155–1158
Francis DD, Champagne FA, Liu D, Meaney MJ (1999b) Maternal care, gene expression, and the development of individual differences in stress reactivity. Ann NY Acad Sci 896:66–84
Gaman A, Kuo B (2008) Neuromodulatory processes of the brain–gut axis. Neuromodulation 11:249–259
Garcia-Rodenas CL, Bergonzelli GE, Nutten S, Schumann A, Cherbut C, Turini M, Ornstein K, Rochat F, Corthesy-Theulaz I (2006) Nutritional approach to restore impaired intestinal barrier function and growth after neonatal stress in rats. J Pediatr Gastroenterol Nutr 43:16–24
Gardner KL, Hale MW, Lightman SL, Plotsky PM, Lowry CA (2009) Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression. Brain Res 1305:47–63
Gareau MG, Jury J, Yang PC, MacQueen G, Perdue MH (2006) Neonatal maternal separation causes colonic dysfunction in rat pups including impaired host resistance. Pediatr Res 59:83–88
Gareau MG, Jury J, MacQueen G, Sherman PM, Perdue MH (2007a) Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut 56:1522–1528
Gareau MG, Jury J, Perdue MH (2007b) Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability. Am J Physiol Gastrointest Liver Physiol 293:G198–G203
Gaykema RP, Goehler LE, Lyte M (2004) Brain response to cecal infection with Campylobacter jejuni: analysis with Fos immunohistochemistry. Brain Behav Immun 18:238–245
Gebhart GF (2004) Descending modulation of pain. Neurosci Biobehav Rev 27:729–737
Gershon MD (1999) Review article: roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther 13(Suppl 2):15–30
Gershon M, Kirchgessner AL, Wade PR (1994) Functional anatomy of the enteric nervous system. In: Johnson LR (ed) Physiology of the gastrointestinal tract. Raven, New York, pp 381–422
Gibney SM, Gosselin RD, Dinan TG, Cryan JF (2009) Assessment of cortico-limbic activation following colorectal distension in the rat; influence of genetics and early life stress. Gastroenterology 136:W2037
Goehler LE, Lyte M, Gaykema RP (2007) Infection-induced viscerosensory signals from the gut enhance anxiety: implications for psychoneuroimmunology. Brain Behav Immun 21:721–726
Goehler LE, Park SM, Opitz N, Lyte M, Gaykema RP (2008) Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav Immun 22:354–366
Gosselin RD, O’Connor RM, Tramullas M, Julio-Pieper M, Dinan TG, Cryan JF (2010) Riluzole normalizes early-life stress-induced visceral hypersensitivity in rats: role of spinal glutamate reuptake mechanisms. Gastroenterology 138:2418–2425
Greenwood-Van Meerveld B, Johnson AC, Cochrane S, Schulkin J, Myers DA (2005) Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic hypersensitivity in rats. Neurogastroenterol Motil 17:415–422
Gubernick DJ, Alberts JR (1983) Maternal licking of young: resource exchange and proximate controls. Physiol Behav 31:593–601
Gue M, Del Rio-Lacheze C, Eutamene H, Theodorou V, Fioramonti J, Bueno L (1997) Stress-induced visceral hypersensitivity to rectal distension in rats: role of CRF and mast cells. Neurogastroenterol Motil 9:271–279
Gunnar MR, Donzella B (2002) Social regulation of the cortisol levels in early human development. Psychoneuroendocrinology 27:199–220
Haulica I, Bild W, Boisteanu D, Ionita T, Mihaila C (2002) Actual data concerning the brain–immune system interface. Roum Arch Microbiol Immunol 61:141–157
Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49:1023–1039
Holmes A, Lachowicz JE, Sibley DR (2004) Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes. Neuropharmacology 47:1117–1134
Holmes A, le Guisquet AM, Vogel E, Millstein RA, Leman S, Belzung C (2005) Early life genetic, epigenetic and environmental factors shaping emotionality in rodents. Neurosci Biobehav Rev 29:1335–1346
Huang CC, Liang YC, Hsu KS (2001) Characterization of the mechanism underlying the reversal of long term potentiation by low frequency stimulation at hippocampal CA1 synapses. J Biol Chem 276:48108–48117
Huot RL, Thrivikraman KV, Meaney MJ, Plotsky PM (2001) Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment. Psychopharmacology 158:366–373
Huot RL, Plotsky PM, Lenox RH, McNamara RK (2002) Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats. Brain Res 950:52–63
Huot RL, Gonzalez ME, Ladd CO, Thrivikraman KV, Plotsky PM (2004) Foster litters prevent hypothalamic–pituitary–adrenal axis sensitization mediated by neonatal maternal separation. Psychoneuroendocrinology 29:279–289
Hyland NP, Julio-Pieper M, O’Mahony SM, Bulmer DC, Lee K, Quigley EM, Dinan TG, Cryan JF (2009) A distinct subset of submucosal mast cells undergoes hyperplasia following neonatal maternal separation: a role in visceral hypersensitivity? Gut 58:1029–1030, author reply 1030–1031
Johnson AC, Myers B, Lazovic J, Towner R, Greenwood-Van Meerveld B (2010) Brain activation in response to visceral stimulation in rats with amygdala implants of corticosterone: an FMRI study. PLoS ONE 5:e8573
Jones MP, Dilley JB, Drossman D, Crowell MD (2006) Brain–gut connections in functional GI disorders: anatomic and physiologic relationships. Neurogastroenterol Motil 18:91–103
Kassinen A, Krogius-Kurikka L, Makivuokko H, Rinttila T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A (2007) The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 133:24–33
Kellow JE, Azpiroz F, Delvaux M, Gebhart GF, Mertz HR, Quigley EM, Smout AJ (2006) Applied principles of neurogastroenterology: physiology/motility sensation. Gastroenterology 130:1412–1420
Kiank C, Mundt A, Schuett C (2009) Mild postnatal separation stress reduces repeated stress-induced immunosuppression in adult BALB/c mice. Neuro Endocrinol Lett 30:761–768
Kilkens TO, Honig A, Rozendaal N, Van Nieuwenhoven MA, Brummer RJ (2003) Systematic review: serotonergic modulators in the treatment of irritable bowel syndrome—influence on psychiatric and gastrointestinal symptoms. Aliment Pharmacol Ther 17:43–51
Kim DY, Camilleri M (2000) Serotonin: a mediator of the brain–gut connection. Am J Gastroenterol 95:2698–2709
Kinnally EL, Capitanio JP, Leibel R, Deng L, Leduc C, Haghighi F, Mann JJ (2010) Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes Brain Behav 9(6):575–582 (Epub 12 Apr 2010)
Klooker TK, Braak B, Painter RC, de Rooij SR, van Elburg RM, van den Wijngaard RM, Roseboom TJ, Boeckxstaens GE (2009) Exposure to severe wartime conditions in early life is associated with an increased risk of irritable bowel syndrome: a population-based cohort study. Am J Gastroenterol 104:2250–2256
Kuhn CM, Pauk J, Schanberg SM (1990) Endocrine responses to mother–infant separation in developing rats. Dev Psychobiol 23:395–410
Kuramochi M, Nakamura S (2009) Effects of postnatal isolation rearing and antidepressant treatment on the density of serotonergic and noradrenergic axons and depressive behavior in rats. Neuroscience 163:448–455
la Fleur SE, Wick EC, Idumalla PS, Grady EF, Bhargava A (2005) Role of peripheral corticotropin-releasing factor and urocortin II in intestinal inflammation and motility in terminal ileum. Proc Natl Acad Sci USA 102:7647–7652
Ladd CO, Huot RL, Thrivikraman KV, Nemeroff CB, Plotsky PM (2004) Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation. Biol Psychiatry 55:367–375
Ladd CO, Thrivikraman KV, Huot RL, Plotsky PM (2005) Differential neuroendocrine responses to chronic variable stress in adult Long Evans rats exposed to handling-maternal separation as neonates. Psychoneuroendocrinology 30:520–533
Langhendries JP (2006) Early bacterial colonisation of the intestine: why it matters? Arch Pediatr 13:1526–1534
Larauche M, Gourcerol G, Wang L, Pambukchian K, Brunnhuber S, Adelson DW, Rivier J, Million M, Tache Y (2009) Cortagine, a CRF1 agonist, induces stresslike alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways. Am J Physiol Gastrointest Liver Physiol 297:G215–G227
Lenz HJ, Druge G (1990) Neurohumoral pathways mediating stress-induced inhibition of gastric acid secretion in rats. Gastroenterology 98:1490–1492
Lenz HJ, Forquignon I (1990) Stimulation of duodenal bicarbonate secretion in conscious rats by cerebral somatostatin-28. Role of neurohumoral pathways. Gastroenterology 99:340–344
Levine S (1994) The ontogeny of the hypothalamic–pituitary–adrenal axis. The influence of maternal factors. Ann NY Acad Sci 746:275–288, discussion 289–293
Levine S (2000) Influence of psychological variables on the activity of the hypothalamic–pituitary–adrenal axis. Eur J Pharmacol 405:149–160
Levine S (2002) Regulation of the hypothalamic–pituitary–adrenal axis in the neonatal rat: the role of maternal behavior. Neurotox Res 4:557–564
Levine S (2005) Developmental determinants of sensitivity and resistance to stress. Psychoneuroendocrinology 30:939–946
Levine S, Huchton DM, Wiener SG, Rosenfeld P (1991) Time course of the effect of maternal deprivation on the hypothalamic–pituitary–adrenal axis in the infant rat. Dev Psychobiol 24:547–558
Lippmann M, Bress A, Nemeroff CB, Plotsky PM, Monteggia LM (2007) Long-term behavioural and molecular alterations associated with maternal separation in rats. Eur J Neurosci 25:3091–3098
Litvin Y, Tovote P, Pentkowski NS, Zeyda T, King LB, Vasconcellos AJ, Dunlap C, Spiess J, Blanchard DC, Blanchard RJ (2010) Maternal separation modulates short-term behavioral and physiological indices of the stress response. Horm Behav 58:241–249
Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ (1997) Maternal care, hippocampal glucocorticoid receptors, and hypothalamic–pituitary–adrenal responses to stress. Science 277:1659–1662
Liu MT, Kuan YH, Wang J, Hen R, Gershon MD (2009) 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J Neurosci 29:9683–9699
Lovinger DM, Partridge JG, Tang KC (2003) Plastic control of striatal glutamatergic transmission by ensemble actions of several neurotransmitters and targets for drugs of abuse. Ann NY Acad Sci 1003:226–240
Lutgendorff F, Akkermans LM, Soderholm JD (2008) The role of microbiota and probiotics in stress-induced gastro-intestinal damage. Curr Mol Med 8:282–298
Mach T (2004) The brain-gut axis in irritable bowel syndrome--clinical aspects. Med Sci Monit 10:RA125–31
Machado-Vieira R, Manji HK, Zarate CA (2009) The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist 15:525–539
Macri S, Chiarotti F, Wurbel H (2008) Maternal separation and maternal care act independently on the development of HPA responses in male rats. Behav Brain Res 191:227–234
Macri S, Laviola G, Leussis MP, Andersen SL (2010) Abnormal behavioral and neurotrophic development in the younger sibling receiving less maternal care in a communal nursing paradigm in rats. Psychoneuroendocrinology 35:392–402
Manabe N, Tanaka T, Hata J, Kusunoki H, Haruma K (2009) Pathophysiology underlying irritable bowel syndrome—from the viewpoint of dysfunction of autonomic nervous system activity. J Smooth Muscle Res 45:15–23
Marais L, van Rensburg SJ, van Zyl JM, Stein DJ, Daniels WM (2008) Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus. Neurosci Res 61:106–112
Martinez V, Tache Y (2006) CRF1 receptors as a therapeutic target for irritable bowel syndrome. Curr Pharm Des 12:4071–4088
Martinez V, Wang L, Rivier JE, Vale W, Tache Y (2002) Differential actions of peripheral corticotropin-releasing factor (CRF), urocortin II, and urocortin III on gastric emptying and colonic transit in mice: role of CRF receptor subtypes 1 and 2. J Pharmacol Exp Ther 301:611–617
Martinez V, Wang L, Rivier J, Grigoriadis D, Tache Y (2004) Central CRF, urocortins and stress increase colonic transit via CRF1 receptors while activation of CRF2 receptors delays gastric transit in mice. J Physiol 556:221–234
Mathew SJ, Murrough JW, Aan Het Rot M, Collins KA, Reich DL, Charney DS (2010) Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol 13:71–82
Matthews K, Dalley JW, Matthews C, Tsai TH, Robbins TW (2001) Periodic maternal separation of neonatal rats produces region- and gender-specific effects on biogenic amine content in postmortem adult brain. Synapse 40:1–10
Mayer EA (2000a) The neurobiology of stress and gastrointestinal disease. Gut 47:861–869
Mayer EA (2000b) Spinal and supraspinal modulation of visceral sensation. Gut 47(Suppl 4):iv69–iv72, discussion iv–76
Mayer EA, Collins SM (2002) Evolving pathophysiologic models of functional gastrointestinal disorders. Gastroenterology 122:2032–2048
Mayer EA, Naliboff BD, Chang L, Coutinho SV (2001) Stress and the gastrointestinal tract. V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 280:G519–G524
Mayer EA, Naliboff BD, Craig AD (2006) Neuroimaging of the brain–gut axis: from basic understanding to treatment of functional GI disorders. Gastroenterology 131:1925–1942
Mayer EA, Bradesi S, Chang L, Spiegel BM, Bueller JA, Naliboff BD (2008) Functional GI disorders: from animal models to drug development. Gut 57:384–404
McKernan DP, Nolan A, Brint EK, O’Mahony SM, Hyland NP, Cryan JF, Dinan TG (2009) Toll-like receptor mRNA expression is selectively increased in the colonic mucosa of two animal models relevant to irritable bowel syndrome. PLoS ONE 4:e8226
Meagher MW, Sieve AN, Johnson RR, Satterlee D, Belyavskyi M, Mi W, Prentice TW, Welsh TH Jr, Welsh CJ (2010) Neonatal maternal separation alters immune, endocrine, and behavioral responses to acute Theiler’s virus infection in adult mice. Behav Genet 40:233–249
Meaney MJ (2001) Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci 24:1161–1192
Meaney MJ, Diorio J, Francis D, Weaver S, Yau J, Chapman K, Seckl JR (2000) Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin. J Neurosci 20:3926–3935
Menard JL, Champagne DL, Meaney MJ (2004) Variations of maternal care differentially influence ‘fear’ reactivity and regional patterns of cFos immunoreactivity in response to the shock-probe burying test. Neuroscience 129:297–308
Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA (1995) Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 109:40–52
Meyer JS, Joy GN (1985) Normal development of brain enolase isozymes in adrenalectomized rats. Brain Res 348:155–158
Million M, Grigoriadis DE, Sullivan S, Crowe PD, McRoberts JA, Zhou H, Saunders PR, Maillot C, Mayer EA, Tache Y (2003) A novel water-soluble selective CRF1 receptor antagonist, NBI 35965, blunts stress-induced visceral hyperalgesia and colonic motor function in rats. Brain Res 985:32–42
Million M, Wang L, Wang Y, Adelson DW, Yuan PQ, Maillot C, Coutinho SV, McRoberts JA, Bayati A, Mattsson H, Wu V, Wei JY, Rivier J, Vale W, Mayer EA, Tache Y (2006) CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation in rats. Gut 55:172–181
Millstein RA, Holmes A (2007) Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. Neurosci Biobehav Rev 31:3–17
Millstein RA, Ralph RJ, Yang RJ, Holmes A (2006) Effects of repeated maternal separation on prepulse inhibition of startle across inbred mouse strains. Genes Brain Behav 5:346–354
Mirescu C, Peters JD, Gould E (2004) Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 7:841–846
Morgane PJ, Mokler DJ, Galler JR (2002) Effects of prenatal protein malnutrition on the hippocampal formation. Neurosci Biobehav Rev 26:471–483
Mulak A, Bonaz B (2004) Irritable bowel syndrome: a model of the brain–gut interactions. Med Sci Monit 10:RA55–RA62
Navailles S, Zimnisky R, Schmauss C (2010) Expression of glucocorticoid receptor and early growth response gene 1 during postnatal development of two inbred strains of mice exposed to early life stress. Dev Neurosci 32:139–148
Neugebauer V (2007) The amygdala: different pains, different mechanisms. Pain 127:1–2
Newport DJ, Wilcox MM, Stowe ZN (2002) Maternal depression: a child’s first adverse life event. Semin Clin Neuropsychiatry 7:113–119
O’Mahony S, Chua AS, Quigley EM, Clarke G, Shanahan F, Keeling PW, Dinan TG (2008) Evidence of an enhanced central 5HT response in irritable bowel syndrome and in the rat maternal separation model. Neurogastroenterol Motil 20:680–688
O’Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG (2009) Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 65:263–267
O’Malley D, Dinan TG, Cryan JF (2010a) Alterations in colonic corticotropin-releasing factor receptors in the maternally separated rat model of irritable bowel syndrome: differential effects of acute psychological and physical stressors. Peptides 31:662–670
O’Malley D, Julio-Pieper M, Gibney SM, Dinan TG, Cryan JF (2010b) Distinct alterations in colonic morphology and physiology in two rat models of enhanced stress-induced anxiety and depression-like behaviour. Stress 13:114–122
Oreland S, Pickering C, Gokturk C, Oreland L, Arborelius L, Nylander I (2009) Two repeated maternal separation procedures differentially affect brain 5-hydroxytryptamine transporter and receptors in young and adult male and female rats. Brain Res 1305(Suppl):S37–S49
Panagiotaropoulos T, Pondiki S, Papaioannou A, Alikaridis F, Stamatakis A, Gerozissis K, Stylianopoulou F (2004) Neonatal handling and gender modulate brain monoamines and plasma corticosterone levels following repeated stressors in adulthood. Neuroendocrinology 80:181–191
Park HJ, Jarrett M, Cain K, Heitkemper M (2008) Psychological distress and GI symptoms are related to severity of bloating in women with irritable bowel syndrome. Res Nurs Health 31:98–107
Phelps EA, LeDoux JE (2005) Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48:175–187
Phillipson M, Johansson ME, Henriksnas J, Petersson J, Gendler SJ, Sandler S, Persson AE, Hansson GC, Holm L (2008) The gastric mucus layers: constituents and regulation of accumulation. Am J Physiol Gastrointest Liver Physiol 295:G806–G812
Piche T (2009) Alterations of intestinal epithelial barrier and flora in the irritable bowel syndrome. Gastroenterol Clin Biol 33 Suppl 1: S40–S47
Pickering C, Gustafsson L, Cebere A, Nylander I, Liljequist S (2006) Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex. Brain Res 1099:101–108
Pihoker C, Owens MJ, Kuhn CM, Schanberg SM, Nemeroff CB (1993) Maternal separation in neonatal rats elicits activation of the hypothalamic–pituitary–adrenocortical axis: a putative role for corticotropin-releasing factor. Psychoneuroendocrinology 18:485–493
Plotsky PM, Meaney MJ (1993) Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res 18:195–200
Plotsky PM, Thrivikraman KV, Nemeroff CB, Caldji C, Sharma S, Meaney MJ (2005) Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring. Neuropsychopharmacology 30:2192–2204
Pryce CR, Feldon J (2003) Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev 27:57–71
Pryce CR, Bettschen D, Nanz-Bahr NI, Feldon J (2003) Comparison of the effects of early handling and early deprivation on conditioned stimulus, context, and spatial learning and memory in adult rats. Behav Neurosci 117:883–893
Rees SL, Akbari E, Steiner M, Fleming AS (2008) Effects of early deprivation and maternal separation on pup-directed behavior and HPA axis measures in the juvenile female rat. Dev Psychobiol 50:315–321
Ren TH, Wu J, Yew D, Ziea E, Lao L, Leung WK, Berman B, Hu PJ, Sung JJ (2007) Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 292:G849–G856
Renard GM, Rivarola MA, Suarez MM (2010) Gender-dependent effects of early maternal separation and variable chronic stress on vasopressinergic activity and glucocorticoid receptor expression in adult rats. Dev Neurosci 32:71–80
Rhee SH, Pothoulakis C, Mayer EA (2009) Principles and clinical implications of the brain–gut–enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6:306–314
Ritchie J (1973) Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 14:125–132
Rivarola MA, Suarez MM (2009) Early maternal separation and chronic variable stress in adulthood changes the neural activity and the expression of glucocorticoid receptor in limbic structures. Int J Dev Neurosci 27:567–574
Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA (2002) Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 7:609–616
Roman E, Gustafsson L, Berg M, Nylander I (2006) Behavioral profiles and stress-induced corticosteroid secretion in male Wistar rats subjected to short and prolonged periods of maternal separation. Horm Behav 50:736–747
Rosenfeld P, Suchecki D, Levine S (1992) Multifactorial regulation of the hypothalamic–pituitary–adrenal axis during development. Neurosci Biobehav Rev 16:553–568
Rosztoczy A, Fioramonti J, Jarmay K, Barreau F, Wittmann T, Bueno L (2003) Influence of sex and experimental protocol on the effect of maternal deprivation on rectal sensitivity to distension in the adult rat. Neurogastroenterol Motil 15:679–686
Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, Dubuquoy C, Merour E, Geboes K, Chamaillard M, Ouwehand A, Leyer G, Carcano D, Colombel JF, Ardid D, Desreumaux P (2007) Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 13:35–37
Roze C (1980) Neurohumoral control of gastrointestinal motility. Reprod Nutr Dev 20:1125–1141
Ryan B, Musazzi L, Mallei A, Tardito D, Gruber SH, El Khoury A, Anwyl R, Racagni G, Mathe AA, Rowan MJ, Popoli M (2009) Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene–environment rat model of depression. Int J Neuropsychopharmacol 12:553–559
Sadik R, Bjornsson E, Simren M (2010) The relationship between symptoms, body mass index, gastrointestinal transit and stool frequency in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol 22:102–108
Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V, Krystal JH (2007) Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry 61:822–825
Sanchez MM, Ladd CO, Plotsky PM (2001) Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models. Dev Psychopathol 13:419–449
Saper CB (2002) The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu Rev Neurosci 25:433–469
Sapolsky RM, Meaney MJ (1986) Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res 396:64–76
Sapolsky RM, Armanini MP, Packan DR, Sutton SW, Plotsky PM (1990) Glucocorticoid feedback inhibition of adrenocorticotropic hormone secretagogue release. Relationship to corticosteroid receptor occupancy in various limbic sites. Neuroendocrinology 51:328–336
Sawano S, Arimura A, Schally AV, Redding TW, Schapiro S (1969) Neonatal corticoid administration: effects upon adult pituitary growth hormone and hypothalamic growth hormone-releasing hormone activity. Acta Endocrinol 61:57–67
Schemann M, Hafsi N, Michel K, Kober OI, Wollmann J, Li Q, Zeller F, Langer R, Lee K, Cellek S (2010) The beta3-adrenoceptor agonist GW427353 (Solabegron) decreases excitability of human enteric neurons via release of somatostatin. Gastroenterology 138:266–274
Schwetz I, McRoberts JA, Coutinho SV, Bradesi S, Gale G, Fanselow M, Million M, Ohning G, Tache Y, Plotsky PM, Mayer EA (2005) Corticotropin-releasing factor receptor 1 mediates acute and delayed stress-induced visceral hyperalgesia in maternally separated Long–Evans rats. Am J Physiol Gastrointest Liver Physiol 289:G704–G712
Sengupta JN (2009) Visceral pain: the neurophysiological mechanism. Handb Exp Pharmacol 194:31–74
Sikander A, Rana SV, Sinha SK, Prasad KK, Arora SK, Sharma SK, Singh K (2009) Serotonin transporter promoter variant: analysis in Indian IBS patients and control population. J Clin Gastroenterol 43:957–961
Singewald N (2007) Altered brain activity processing in high-anxiety rodents revealed by challenge paradigms and functional mapping. Neurosci Biobehav Rev 31:18–40
Soderholm JD, Yates DA, Gareau MG, Yang PC, MacQueen G, Perdue MH (2002) Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol 283:G1257–G1263
Stanley S, Wynne K, McGowan B, Bloom S (2005) Hormonal regulation of food intake. Physiol Rev 85:1131–1158
Suchecki D, Mozaffarian D, Gross G, Rosenfeld P, Levine S (1993) Effects of maternal deprivation on the ACTH stress response in the infant rat. Neuroendocrinology 57:204–212
Suchecki D, Nelson DY, Van Oers H, Levine S (1995) Activation and inhibition of the hypothalamic–pituitary–adrenal axis of the neonatal rat: effects of maternal deprivation. Psychoneuroendocrinology 20:169–182
Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y (2004) Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J Physiol 558:263–275
Sung YH, Shin MS, Cho S, Baik HH, Jin BK, Chang HK, Lee EK, Kim CJ (2010) Depression-like state in maternal rats induced by repeated separation of pups is accompanied by a decrease of cell proliferation and an increase of apoptosis in the hippocampus. Neurosci Lett 470:86–90
Tache Y, Perdue MH (2004) Role of peripheral CRF signalling pathways in stress-related alterations of gut motility and mucosal function. Neurogastroenterol Motil 16(Suppl 1):137–142
Tache Y, Martinez V, Million M, Maillot C (2002) Role of corticotropin releasing factor receptor subtype 1 in stress-related functional colonic alterations: implications in irritable bowel syndrome. Eur J Surg Suppl 587:16–22
Tache Y, Martinez V, Wang L, Million M (2004) CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome. Br J Pharmacol 141:1321–1330
Tache Y, Million M, Nelson AG, Lamy C, Wang L (2005) Role of corticotropin-releasing factor pathways in stress-related alterations of colonic motor function and viscerosensibility in female rodents. Gend Med 2:146–154
Tache Y, Kiank C, Stengel A (2009) A role for corticotropin-releasing factor in functional gastrointestinal disorders. Curr Gastroenterol Rep 11:270–277
Talley NJ (1999) Irritable bowel syndrome: definition, diagnosis and epidemiology. Baillières Best Pract Res Clin Gastroenterol 13:371–384
Tecott LH (2003) The genes and brains of mice and men. Am J Psychiatry 160:646–656
Tillisch K, Mayer EA (2005) Pain perception in irritable bowel syndrome. CNS Spectr 10:877–882
Tjong YW, Ip SP, Lao L, Wu J, Fong HH, Sung JJ, Berman B, Che CT (2010) Neonatal maternal separation elevates thalamic corticotrophin releasing factor type 1 receptor expression response to colonic distension in rat. Neuro Endocrinol Lett 31:215–220
Tougas G (2000) The autonomic nervous system in functional bowel disorders. Gut 47(Suppl 4):iv78–iv80, discussion iv87
Traub RJ, Silva E, Gebhart GF, Solodkin A (1996) Noxious colorectal distention induced-c-Fos protein in limbic brain structures in the rat. Neurosci Lett 215:165–168
Trimble N, Johnson AC, Foster A, Greenwood-van Meerveld B (2007) Corticotropin-releasing factor receptor 1-deficient mice show decreased anxiety and colonic sensitivity. Neurogastroenterol Motil 19:754–760
Troakes C, Ingram CD (2009) Anxiety behaviour of the male rat on the elevated plus maze: associated regional increase in c-fos mRNA expression and modulation by early maternal separation. Stress 12:362–369
Turnbaugh PJ, Gordon JI (2009) The core gut microbiome, energy balance and obesity. J Physiol 587:4153–4158
van den Wijngaard RM, Klooker TK, Welting O, Stanisor OI, Wouters MM, van der Coelen D, Bulmer DC, Peeters PJ, Aerssens J, de Hoogt R, Lee K, de Jonge WJ, Boeckxstaens GE (2009) Essential role for TRPV1 in stress-induced (mast cell-dependent) colonic hypersensitivity in maternally separated rats. Neurogastroenterol Motil 21:1107–1194
van Heerden JH, Conesa A, Stein DJ, Montaner D, Russell V, Illing N (2009) Parallel changes in gene expression in peripheral blood mononuclear cells and the brain after maternal separation in the mouse. BMC Res Notes 2:195
van Heerden JH, Russell V, Korff A, Stein DJ, Illing N (2010) Evaluating the behavioural consequences of early maternal separation in adult C57BL/6 mice; the importance of time. Behav Brain Res 207:332–342
van Oers HJ, de Kloet ER, Whelan T, Levine S (1998) Maternal deprivation effect on the infant’s neural stress markers is reversed by tactile stimulation and feeding but not by suppressing corticosterone. J Neurosci 18:10171–10179
Varghese AK, Verdu EF, Bercik P, Khan WI, Blennerhassett PA, Szechtman H, Collins SM (2006) Antidepressants attenuate increased susceptibility to colitis in a murine model of depression. Gastroenterology 130:1743–1753
Vazquez DM (1998) Stress and the developing limbic–hypothalamic–pituitary–adrenal axis. Psychoneuroendocrinology 23:663–700
Vazquez DM, Lopez JF, Van Hoers H, Watson SJ, Levine S (2000) Maternal deprivation regulates serotonin 1A and 2A receptors in the infant rat. Brain Res 855:76–82
Vazquez DM, Bailey C, Dent GW, Okimoto DK, Steffek A, Lopez JF, Levine S (2006) Brain corticotropin-releasing hormone (CRH) circuits in the developing rat: effect of maternal deprivation. Brain Res 1121:83–94
Veenema AH, Reber SO, Selch S, Obermeier F, Neumann ID (2008) Early life stress enhances the vulnerability to chronic psychosocial stress and experimental colitis in adult mice. Endocrinology 149:2727–2736
Verdu EF, Bercik P, Verma-Gandhu M, Huang XX, Blennerhassett P, Jackson W, Mao Y, Wang L, Rochat F, Collins SM (2006) Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 55:182–190
Verdu EF, Bercik P, Huang XX, Lu J, Al-Mutawaly N, Sakai H, Tompkins TA, Croitoru K, Tsuchida E, Perdue M, Collins SM (2008) The role of luminal factors in the recovery of gastric function and behavioral changes after chronic Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol 295:G664–G670
Walker CD, Scribner KA, Cascio CS, Dallman MF (1991) The pituitary–adrenocortical system of neonatal rats is responsive to stress throughout development in a time-dependent and stressor-specific fashion. Endocrinology 128:1385–1395
Wallon C, Soderholm JD (2009) Corticotropin-releasing hormone and mast cells in the regulation of mucosal barrier function in the human colon. Ann NY Acad Sci 1165:206–210
Weaver IC, La Plante P, Weaver S, Parent A, Sharma S, Diorio J, Chapman KE, Seckl JR, Szyf M, Meaney MJ (2001) Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Mol Cell Endocrinol 185:205–218
Weber BC, Manfredo HN, Rinaman L (2009) A potential gastrointestinal link between enhanced postnatal maternal care and reduced anxiety-like behavior in adolescent rats. Behav Neurosci 123:1178–1184
Wei L, David A, Duman RS, Anisman H, Kaffman A (2010) Early life stress increases anxiety-like behavior in Balbc mice despite a compensatory increase in levels of postnatal maternal care. Horm Behav 57:396–404
Whitehead WE, Holtkotter B, Enck P, Hoelzl R, Holmes KD, Anthony J, Shabsin HS, Schuster MM (1990) Tolerance for rectosigmoid distention in irritable bowel syndrome. Gastroenterology 98:1187–1192
Wilber AA, Southwood CJ, Wellman CL (2009) Brief neonatal maternal separation alters extinction of conditioned fear and corticolimbic glucocorticoid and NMDA receptor expression in adult rats. Dev Neurobiol 69:73–87
Yang GB, Lackner AA (2004) Proximity between 5-HT secreting enteroendocrine cells and lymphocytes in the gut mucosa of rhesus macaques (Macaca mulatta) is suggestive of a role for enterochromaffin cell 5-HT in mucosal immunity. J Neuroimmunol 146:46–49
Yang PC, Jury J, Soderholm JD, Sherman PM, McKay DM, Perdue MH (2006) Chronic psychological stress in rats induces intestinal sensitization to luminal antigens. Am J Pathol 168:104–114, quiz 363
Zaiachkivs’ka OS, Hzhehots’kyi MR, Kovalyshyn VI (2005) Oral and gastric diffuse neuroendocrine system: discussion questions of structure and function. Fiziol Zh 51:79–90
Zhang XJ, Li Z, Chung EK, Zhang HQ, Xu HX, Sung JJ, Bian ZX (2009) Activation of extracellular signal-regulated protein kinase is associated with colorectal distension-induced spinal and supraspinal neuronal response and neonatal maternal separation-induced visceral hyperalgesia in rats. J Mol Neurosci 37:274–287
Zhang M, Leung FP, Huang Y, Bian ZX (2010) Increased colonic motility in a rat model of irritable bowel syndrome is associated with up-regulation of L-type calcium channels in colonic smooth muscle cells. Neurogastroenterol Motil 22:e162–e170
Acknowledgements
The Alimentary Pharmabiotic Centre is a research centre funded by Science Foundation Ireland (SFI) through the Irish Government’s National Development Plan. The authors and their work were supported by SFI (grant nos. 02/CE/B124 and 07/CE/B1368). The centre is also funded by GlaxoSmithKline. JFC is also funded by European Community’s Seventh Framework Programme (grant no. FP7/2007–2013, Grant Agreement 201714). The authors would like to thank Dr. Marcela Julio-Bravo for assisting with the artwork in this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
O’Mahony, S.M., Hyland, N.P., Dinan, T.G. et al. Maternal separation as a model of brain–gut axis dysfunction. Psychopharmacology 214, 71–88 (2011). https://doi.org/10.1007/s00213-010-2010-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-010-2010-9