Abstract
Rationale
Cytokines are found in both the peripheral and central nervous system. There has been increasing interest in their potential role in some of the behavioral features of depressive disorders. Leukemia inhibitory factor (LIF), a proinflammatory cytokine, produces stimulation of adrenocorticotropic hormone (ACTH) secretion in response to emotional and inflammatory stress and recently has been linked to depressive-type behavior. Both the hypothalamic–pituitary–adrenal axis and the immune system, including cytokine-mediated responses, appear to be susceptible to long-term programming during fetal and neonatal development.
Objective
The present study was designed to characterize the effects of perinatal exposure to corticostereone on behavior, hypothalamic LIF and corticotropin-releasing hormone (CRH) mRNA expression, and basal plasma corticosterone levels in adult female mice.
Methods
Corticosterone was added to the drinking water beginning the last week of gestation and continued until weaning. Behavior in the open field and forced swim tests, baseline plasma corticosterone levels, and hypothalamic LIF and CRH gene expression were evaluated in the adult offspring.
Results
Mice exposed to perinatal corticosterone showed increased immobility in the forced swim test and increased locomotor activity in the open field test. Although there were no differences between treatment groups in terms of basal plasma levels of corticosterone or hypothalamic CRH mRNA, LIF mRNA expression was increased in the hypothalamus.
Conclusions
These results show that perinatal exposure to glucocorticoids can produce long-term behavioral changes and upregulation of central LIF mRNA expression.
Similar content being viewed by others
References
Alonso SJ, Arevalo R, Afonso D, Rodriguez M (1991) Effects of maternal stress during pregnancy on forced swimming test behavior of the offspring. Physiol Behav 50:511–517
Alonso SJ, Navarro E, Rodriguez M (1994) Permanent dopaminergic alterations in the n. accumbens after prenatal stress. Pharmacol Biochem Behav 49:353–358
Angelucci L, Patacchioli FR, Scaccianoce S, Di Sciullo A, Cardillo A, Maccari S (1985) A model for later-life effects of perinatal drug exposure: maternal hormone mediation. Neurobehav Toxicol Teratol 7:511–517
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12
Auernhammer CJ, Melmed S (2000) Leukemia-inhibitory factor—neuroimmune modulator of endocrine function. Endocr Rev 21:313–345
Auernhammer C, Chesnokova V, Melmed S (1998) Leukemia inhibitory factor modulates IL 1β-induced activation of the hypothalamo–pituitary–adrenal axis. Endocrinology 139:2201–2208
Bakker JM, van Bel F, Heijnen CJ (2001) Neonatal glucocorticoids and the developing brain: short-term treatment with long-term consequences? Trends Neurosci 24:649–653
Banner LR, Moayeri NN, Patterson PH (1997) Leukemia inhibitory factor is expressed in astrocytes following brain injury. Exp Neurol 147:1–9
Barros HMT, Ferigolo M (1998) Ethnopharmacology of imipramine in the forced-swimming test: gender differences. Neurosci Biobehav Rev 23:279–286
Borsini F, Meli A (1988) Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology 94:147–160
Brixey SN, Gallagher BJ III, McFalls JA Jr, Parmelee LF (1993) Gestational and neonatal factors in the etiology of schizophrenia. J Clin Psychol 49:447–456
Catalani A, Marinelli M, Scaccianoce S, Nicolai R, Muscolo LAA, Porcu A, Koranyi L, Piazza PV, Angelucci L (1993) Progeny of mothers drinking corticosterone during lactation have low stress-induced corticosterone secretion and better cognitive performance. Brain Res 624:209–215
Catalani A, Casolini P, Scaccianoce S, Patacchioli FR, Sinozzi P, Angelucci L (2000) Maternal corticosterone during lactation permanently affects brain corticosteroid receptors, stress response and behaviour in rat progeny. Neuroscience 100:319–325
Casolini P, Cigliana G, Alema GS, Ruggieri V, Angelucci L, Catalani A (1997) Effect of increased maternal corticosterone during lactation on hippocampal corticosteroid receptors, stress responses and learning in offspring in the early stages of life. Neuroscience 79:1005–1012
Chesnokova V, Melmed S (2000) Leukemia inhibitory factor mediates the hypothalamic pituitary adrenal axis response to inflammation. Endocrinology 141:4032–4040
Chesnokova V, Melmed S (2002) Minireview: neuro-immuno-endocrine modulation of the hypothalamic–pituitary–adrenal (HPA) axis by gp130 signaling molecules. Endocrinology 143:1571–1574
Chesnokova V, Auernhammer CJ, Melmed S (1998) Murine leukemia inhibitory factor gene disruption attenuates the hypothalamo–pituitary–adrenal axis stress response. Endocrinology 139:2209–2216
Clarke AS, Schneider ML (1993) Prenatal stress has long-term effects on behavioral responses to stress in juvenile rhesus monkeys. Dev Psychobiol 26:293–304
Connor TJ, Leonard BE (1998) Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life Sci 62:583–606
Cryan JF, Mombereau C (2004) In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiat 9:326–357
Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245
Dantzer R, Wollman E, Vitkovic L, Yirmiya R (1999) Cytokines and depression: fortuitous or causative association? Mol Psychiat 4:328–332
Dawson GR, Tricklebank MD (1995) Use of the elevated plus maze in the search of novel anxiolytic agents. Trends Pharmacol Sci 16:33–36
Deak T, Bordner KA, McElderry NK, Brnum CJ, Blansino P Jr, Deak MM, Tammariello SP (2005) Stress-induced increases in hypothalamic IL-1: a systematic analysis of multiple stressor paradigms. Brain Res Bull 64:541–556
Domenici MR, Casolini P, Catalani A, Ruggieri V, Angelucci L, Sagratella S (1996) Reduced hippocampal in vitro CA1 long-term potentiation in rat offsprings with increased circulating corticosterone during neonatal life. Neurosci Lett 218:72–74
Drago F, Di Leo F, Giardina L (1999) Prenatal stress induces body weight deficit and behavioural alterations in rats: the effect of diazepam. Eur Neuropsychopharmacol 9:239–245
Fameli M, Kitraki E, Stylianopoulou F (1994) Effects of hyperactivity of the maternal hypothalamic–pituitary–adrenal (HPA) axis during pregnancy on the development of the HPA axis and brain monoamines of the offspring. Int J Dev Neurosci 12:651–659
Fride E, Dan Y, Feldon J, Halevy G, Weinstock M (1986) Effects of prenatal stress on vulnerability to stress in prepubertal and adult rats. Physiol Behav 37:681–687
Gadient RA, Lein P, Higgins D, Patterson PH (1998) Effect of leukemia inhibitory factor (LIF) on the morphology and survival of cultured hippocampal neurons and glial cells. Brain Res 798:140–146
Gertsik L, Poland RE (2004) Psychoneuroendocrinology. In: Schatzberg A, Nemeroff CB (eds) Textbook of psychopharmacology, 3rd edn. American Psychiatric, Arlington, pp 115–129
Grosset C, Taupin JL, Lemercier C, Moreau JF, Reiffers J, Ripoche J (1998) Leukaemia inhibitory factor expression is inhibited by glucocorticoids throughpost-translational mechanisms. Cytokine 11:29–36
Heim C, Nemeroff CB (1999) The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Biol Psychiatry 46:1509–1522
Henry C, Guegant G, Cador M, Arnauld E, Arsaut J, Le Moal M, Demotes-Mainard J (1995) Prenatal stress in rats facilitates amphetamine-induced sensitization and induces long-lasting changes in dopamine receptors in the nucleus accumbens. Brain Res 685:179–186
Kent S, Bluthe RM, Kelley KW, Dantzer R (1992) Sickness behavior as a new target for drug development. Trends Pharmacol Sci 13:24–28
Kesheet GI, Weinstock M (1995) Maternal naltrexone prevents morphological and behavioral alterations induced in rats by prenatal stress. Pharmacol Biochem Behav 50:413–419
Klein SL, Rager DR (1995) Prenatal stress alters immune function in the offspring of rats. Dev Psychobiol 8:321–336
Konsman JP, Parnet P, Dantzer R (2002) Cytokine-induced sickness behavior: mechanisms and implications. Trends Neurosci 25:154–159
Ladd CO, Owens MJ, Nemeroff CB (1996) Persistent changes in CRF neuronal systems induced by maternal deprivation. Endocrinology 137:1212–1218
Lemke R, Gadient RA, Schliebs R, Bigl V, Patterson PH (1996) Neuronal expression of leukemia inhibitory factor (LIF) in the rat brain. Neurosci Lett 13:205–208
Levitt NS, Lindsay RS, Holmes MC, Seckl JR (1996) Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. Neuroendocrinology 64:412–418
Leonard BE (2001) The immune system, depression and the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 25:767–780
Li Y-L, Robinson TE, Bhatnagar S (2003) Effects of maternal separation on behavioural sensitization produced by repeated cocaine administration in adulthood. Brain Res 960:42–47
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
Lou HC, Hansen D, Nordentoft M, Pryds O, Jensen F, Nim J, Hemmingsen R (1994) Prenatal stressors of human life affect fetal brain development. Dev Med Child Neurol 36:826–832
Lucki I (2001) A prescription to resist proscriptions for murine models of depression. Psychopharmacology 153:395–398
Matthews SG (2002) Early programming of the hypothalamo–pituitary–adrenal axis. Trends Endocrinol Metab 13:373–380
McGivern RF, Poland RE, Taylor AN, Branch BJ, Raum WJ (1986) Prenatal stress feminizes adult male saccharin preference and maze learning: antagonism by propranolol. In: Dorner G, McCann SM (eds) Systemic hormones, neurotransmitters and brain development, vol 12. Karger, Basel, pp 172–178
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, Aitken DH, Viau V, Sharma S, Sarrieau A (1989) Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat. Neuroendocrinology 50:597–604
Miller AH (1998) Neuroendocrine and immune system interactions in stress and depression. Psychoneuroendocrinology 21:443–463
Muneoka K, Mikuni M, Ogawa T, Kitera K, Kamei K, Takigawa M, Takahashi K (1997) Prenatal dexamethasone exposure alters brain monoamine metabolism and adrenocortical response in rat offspring. Am J Physiol 273(5 Pt 2):R1669–R1675
Mossner R, Lesch KP (1998) Role of serotonin in the immune system and in neuroimmune interactions. Brain Behav Immun 12:249–271
Nemeroff CB (1998) The neurobiology of depression. Sci Am 278:42–49
Nestler EJ, Gould E, Manji H, Bucan M, Duman RS, Gershenfeld HK, Hen R, Koester S, Lederhendler I, Meany MJ, Robbins T, Winsky W, Zalcman S (2002) Preclinical models: status of basic research in depression. Biol Psychiatry 52:503–528
Neveu PJ, Deleplanque B, Puglisi-Allergra S, D’Amato FR, Cabib S (1994) Influence of early life events on immune reactivity in adult mice. Dev Psychobiol 27:205–213
Newport DJ, Stowe ZN, Nemeroff CB (2002) Parental depression: animal models of an adverse life event. Am J Psychiatry 159:1265–1283
O’Connor KA, Johnson JD, Hansen MK, Wiesler Frank JL, Maksimova E, Watkins LR, Maier SF (2003) Peripheral and central proinflammaory cytokine response to a severe acute stressor. Brain Res 991:123–132
O’Neill KA, Valentino D (1982) Escapability and generalization: effect on ‘behavioral despair’. Eur J Pharmacol 78:379–380
Owen D, Andrews MH, Matthews SG (2005) Maternal adversity, glucocorticoids and programming of neuroendocrine function and behaviour. Neurosci Biobehav Rev 29:209–226
Pechnick RN, Chesnokova VM, Kariagina A, Price S, Bresee CJ, Poland RE (2004) Reduced immobility in the forced swim test in mice with a targeted deletion of the leukemia inhibitory factor (LIF) gene. Neuropsychopharmacology 29:770–776
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
Poland RE, Weichsel ME, Rubin RT (1981) Neonatal dexamethasone administration. I. Temporary delay of development of the circadian serum corticosterone rhythm in rats. Endocrinology 108:1049–1054
Poland RE, Lutchmansingh P, McGeoy S, Au D, Que M, Acosta S, Edelstein M, McCracken JT (1995) Prenatal stress prevents the desensitization of the corticosterone response to TFMPP by desmethylimipramine, but not by phenelzine, in adult male offspring. Life Sci 57:2163–2170
Porsolt RD, Bertin A, Jalfre M (1977a) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336
Porsolt RD, Le Pichon M, Jalfre M (1977b) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732
Porsolt RD, Bertin A, Blavet N, Deniel M, Jalfre M (1979) Immobility induced by forced swimming in rats: effects of agents which modify central catecholamine and serotonin activity. Eur J Pharmacol 57:201–210
Rosenblum LA, Coplan JD, Friedman S, Bassoff T, Gorman JM, Andrews MW (1994) Adverse early experiences affect noradrenergic and serotonergic functioning in adult primates. Biol Psychiatry 35:221–227
Rupniak NMJ (2003) Animal models of depression: challenges from a drug development perspective. Behav Pharmacol 14:385–390
Schiepers OJG, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuropsychopharm Biol Psychiatry 29:210–217
Secoli SR, Teixeira NA (1998) Chronic prenatal stress affects development and behavioral depression in rats. Stress 2:273–280
Shintani F, Nakaki T, Kanba S, Sato K, Yagi G, Shiozawa M, Aiso S, Kato R, Asai M (1995) Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat. J Neurosci 15:1961–1970
Shizuya K, Komori T, Fujiwara R, Miyahara S, Ohmori M, Nomura J (1998) The expressions of mRNAs for interleukin-6 (IL-6) and the IL-6 receptor (IL-6R) in the rat hypothalamus and midbrain during restraint stress. Life Sci 62:2315–2320
Suzuki E, Shintani F, Kanba S, Asai M, Nakaki T (1996) Induction of interleukin-1b and interleukin-1 receptor antagonist mRNA by chronic treatment with various psychotropics in widespread area of rat brain. Neurosci Lett 13:201–204
Takahashi LK, Turner JG, Kalin NH (1992) Prenatal stress alters brain catecholaminergic activity and potentiates stress-induced behavior in adult rats. Brain Res 574:131–137
Talttavull JF, Chefer VI, Shippenberg TS, Kiyatkin EA (2003) Severe brain hypothermia as a factor underlying behavioral immobility during cold-water forced swim. Brain Res 975:244–247
Wadhwa PD, Sandman CA, Porto M, Dunkel-Schetter C, Garite TJ (1993) The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation. Am J Obstet Gynecol 169:858–865
Wang CT, Huang RL, Tai MY, Tsai YF, Peng MT (1995) Dopamine release in the nucleus accumbens during sexual behavior in prenatally stressed adult male rats. Neurosci Lett 200:29–32
Watanabe Y, Hashimoto S, Kakita A, Takahashi H, Ko J, Mizono M, Someya T, Patterson PH, Nawa H (2004) Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats. Neurosci Res 48:345–353
Ward AJ (1991) Prenatal stress and childhood psychopathology. Child Psychiatry Hum Dev 22:97–110
Ware CB, Kariagina A, Zonis S, Alon D, Chesnokova V (2005) Leukemia inhibitory factor signaling is implicated in embrionic development of the HPA axis. FEBS Lett 579:4465–4469
Weinstock M (2001) Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 65:427–451
Weinstock M, Fride E, Hertzberg R (1988) Prenatal stress effects on functional development of the offspring. Prog Brain Res 73:319–331
Welberg LA, Seckl JR, Holmes MC (2001) Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour. Neuroscience 104:71–79
Willner P (1990) Animal models of depression: an overview. Pharmacol Ther 45:425–455
Yirmiya R, Weidenfeld J, Pollak Y, Morgan M, Avitsur R, Barak O, Reichenberg A, Cohen E, Shavit Y, Ovadia H (1999) Cytokines, “depression due to a general medical condition,” and antidepressant drugs. In: Dantzer et al (eds) Cytokines, stress and depression. Plenum, New York, pp 283–316
Acknowledgements
Partially supported by NIH grants R29-DK54862, MH57970, a NARSAD Young Investigator Award to V.M.C, and the Levine Family Fund Research Endowment.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pechnick, R.N., Kariagina, A., Hartvig, E. et al. Developmental exposure to corticosterone: behavioral changes and differential effects on leukemia inhibitory factor (LIF) and corticotropin-releasing hormone (CRH) gene expression in the mouse. Psychopharmacology 185, 76–83 (2006). https://doi.org/10.1007/s00213-005-0258-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-005-0258-2