Drug-Dependent Requirement of Hippocampal Neurogenesis in a Model of Depression and of Antidepressant Reversal


      Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.


      Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF1) antagonist SSR125543, or the vasopressin 1b (V1b) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling.


      Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF1 and the V1b antagonists.


      Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.

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        • Caspi A.
        • Sugden K.
        • Moffitt T.E.
        • Taylor A.
        • Craig I.W.
        • Harrington H.
        Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.
        Science. 2003; 301: 386-389
        • Heuser I.
        Anna-Monika-Prize paper.
        Pharmacopsychiatry. 1998; 31: 10-13
        • Herman J.P.
        • Schafer M.K.
        • Young E.A.
        • Thompson R.
        • Douglass J.
        • Akil H.
        Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis.
        J Neurosci. 1989; 9: 3072-3082
        • Mizoguchi K.
        • Ishige A.
        • Aburada M.
        • Tabira T.
        Chronic stress attenuates glucocorticoid negative feedback: Involvement of the prefrontal cortex and hippocampus.
        Neuroscience. 2003; 119: 887-897
        • Bremner J.D.
        • Narayan M.
        • Anderson E.R.
        • Staib L.H.
        • Miller H.L.
        • Charney D.S.
        Hippocampal volume reduction in major depression.
        Am J Psychiatry. 2000; 157: 115-118
        • Frodl T.
        • Meisenzahl E.M.
        • Zetzsche T.
        • Hohne T.
        • Banac S.
        • Schorr C.
        Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up.
        J Clin Psychiatry. 2004; 65: 492-499
        • MacQueen G.M.
        • Campbell S.
        • McEwen B.S.
        • Macdonald K.
        • Amano S.
        • Joffe R.T.
        Course of illness, hippocampal function, and hippocampal volume in major depression.
        Proc Natl Acad Sci U S A. 2003; 100: 1387-1392
        • Sheline Y.I.
        • Wang P.W.
        • Gado M.H.
        • Csernansky J.G.
        • Vannier M.W.
        Hippocampal atrophy in recurrent major depression.
        Proc Natl Acad Sci U S A. 1996; 93: 3908-3913
        • Campbell S.
        • MacQueen G.
        An update on regional brain volume differences associated with mood disorders.
        Curr Opin Psychiatry. 2006; 19: 25-33
        • Duman R.S.
        • Malberg J.
        • Thome J.
        Neural plasticity to stress and antidepressant treatment.
        Biol Psychiatry. 1999; 46: 1181-1191
        • Sapolsky R.M.
        Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders.
        Arch Gen Psychiatry. 2000; 57: 925-935
        • Gould E.
        • McEwen B.S.
        • Tanapat P.
        • Galea L.A.
        • Fuchs E.
        Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation.
        J Neurosci. 1997; 17: 2492-2498
        • Vollmayr B.
        • Simonis C.
        • Weber S.
        • Gass P.
        • Henn F.
        Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness.
        Biol Psychiatry. 2003; 54: 1035-1040
        • Malberg J.E.
        • Duman R.S.
        Cell proliferation in adult hippocampus is decreased by inescapable stress: Reversal by fluoxetine treatment.
        Neuropsychopharmacology. 2003; 28: 1562-1571
        • Pham K.
        • Nacher J.
        • Hof P.R.
        • McEwen B.S.
        Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus.
        Eur J Neurosci. 2003; 17: 879-886
        • Alonso R.
        • Griebel G.
        • Pavone G.
        • Stemmelin J.
        • Le Fur G.
        • Soubrie P.
        Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression.
        Mol Psychiatry. 2004; 9: 278-286
        • Czeh B.
        • Michaelis T.
        • Watanabe T.
        • Frahm J.
        • de Biurrun G.
        • van Kampen M.
        Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine.
        Proc Natl Acad Sci U S A. 2001; 98: 12796-12801
        • Gould E.
        • Tanapat P.
        • McEwen B.S.
        • Flugge G.
        • Fuchs E.
        Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress.
        Proc Natl Acad Sci U S A. 1998; 95: 3168-3171
        • McEwen B.S.
        Plasticity of the hippocampus: Adaptation to chronic stress and allostatic load.
        Ann N Y Acad Sci. 2001; 933: 265-277
        • Sapolsky R.M.
        Stress and plasticity in the limbic system.
        Neurochem Res. 2003; 28: 1735-1742
        • Malberg J.E.
        • Eisch A.J.
        • Nestler E.J.
        • Duman R.S.
        Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.
        J Neurosci. 2000; 20: 9104-9110
        • Santarelli L.
        • Saxe M.
        • Gross C.
        • Surget A.
        • Battaglia F.
        • Dulawa S.
        Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.
        Science. 2003; 301: 805-809
        • van der Hart M.G.
        • Czeh B.
        • de Biurrun G.
        • Michaelis T.
        • Watanabe T.
        • Natt O.
        Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume.
        Mol Psychiatry. 2002; 7: 933-941
        • Jiang W.
        • Zhang Y.
        • Xiao L.
        • Van Cleemput J.
        • Ji S.P.
        • Bai G.
        Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects.
        J Clin Invest. 2005; 115: 3104-3116
        • Rupniak N.M.
        Elucidating the antidepressant actions of substance P (NK1 receptor) antagonists.
        Curr Opin Investig Drugs. 2002; 3: 257-261
        • Yoshimizu T.
        • Chaki S.
        Increased cell proliferation in the adult mouse hippocampus following chronic administration of group II metabotropic glutamate receptor antagonist, MGS0039.
        Biochem Biophys Res Commun. 2004; 315: 493-496
        • McEwen B.S.
        • Magarinos A.M.
        • Reagan L.P.
        Structural plasticity and tianeptine: Cellular and molecular targets.
        Eur Psychiatry. 2002; 17: 318-330
        • Louis C.
        • Cohen C.
        • Depoortere R.
        • Griebel G.
        Antidepressant-like effects of the corticotropin-releasing factor 1 receptor antagonist, SSR125543, and the vasopressin 1b receptor antagonist, SSR149415, in a DRL-72 s schedule in the rat.
        Neuropsychopharmacology. 2006; 31: 2180-2187
        • Griebel G.
        • Simiand J.
        • Serradeil-Le Gal C.
        • Wagnon J.
        • Pascal M.
        • Scatton B.
        • et al.
        Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders.
        Proc Natl Acad Sci U S A. 2002; 99: 6370-6375
        • Griebel G.
        • Simiand J.
        • Steinberg R.
        • Jung M.
        • Gully D.
        • Roger P.
        4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist.
        J Pharmacol Exp Ther. 2002; 301: 333-345
        • Zobel A.W.
        • Nickel T.
        • Kunzel H.E.
        • Ackl N.
        • Sonntag A.
        • Ising M.
        Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: The first 20 patients treated.
        J Psychiatr Res. 2000; 34: 171-181
        • Kunzel H.E.
        • Zobel A.W.
        • Nickel T.
        • Ackl N.
        • Uhr M.
        • Sonntag A.
        Treatment of depression with the CRH-1-receptor antagonist R121919: Endocrine changes and side effects.
        J Psychiatr Res. 2003; 37: 525-533
        • Ising M.
        • Zimmermann U.S.
        • Kunzel H.E.
        • Uhr M.
        • Foster A.C.
        • Learned-Coughlin S.M.
        High-affinity CRF1 receptor antagonist NBI-34041: Preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response.
        Neuropsychopharmacology. 2007; 32: 1941-1949
        • Willner P.
        • Muscat R.
        • Papp M.
        Chronic mild stress-induced anhedonia: A realistic animal model of depression.
        Neurosci Biobehav Rev. 1992; 16: 525-534
        • Belzung C.
        • Surget A.
        Unpredictable chronic mild stress in mice.
        in: Kalueff A.V. LaPorte J.L. Experimental Models in Neurobehavioral Research. Nova Science, New York2008
        • Ducottet C.
        • Belzung C.
        Correlations between behaviours in the elevated plus-maze and sensitivity to unpredictable subchronic mild stress: Evidence from inbred strains of mice.
        Behav Brain Res. 2005; 156: 153-162
        • Yalcin I.
        • Aksu F.
        • Belzung C.
        Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol.
        Eur J Pharmacol. 2005; 514: 165-174
        • Soubrie P.
        • Kulkarni S.
        • Simon P.
        • Boissier J.R.
        [Effects of antianxiety drugs on the food intake in trained and untrained rats and mice (author's transl)].
        Psychopharmacologia. 1975; 45: 203-210
        • Dulawa S.C.
        • Hen R.
        Recent advances in animal models of chronic antidepressant effects: The novelty-induced hypophagia test.
        Neurosci Biobehav Rev. 2005; 29: 771-783
        • Gully D.
        • Geslin M.
        • Serva L.
        • Fontaine E.
        • Roger P.
        • Lair C.
        4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): A potent and selective corticotrophin-releasing factor(1) receptor antagonist.
        J Pharmacol Exp Ther. 2002; 301: 322-332
        • Griebel G.
        • Simiand J.
        • Stemmelin J.
        • Serradeil-Le Gal C.
        • Wagnon J.
        • Steinberg R.
        • et al.
        Anxiolytic- and antidepressant-like effects of non-peptide vasopressin V1b receptor antagonists.
        Act Chim Ther. 2004; 30: 37-54
        • Hodgson R.A.
        • Higgins G.A.
        • Guthrie D.H.
        • Lu S.X.
        • Pond A.J.
        • Mullins D.E.
        Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression.
        Pharmacol Biochem Behav. 2007; 86: 431-440
        • Meshi D.
        • Drew M.R.
        • Saxe M.
        • Ansorge M.S.
        • David D.
        • Santarelli L.
        Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment.
        Nat Neurosci. 2006; 9: 729-731
        • Holick K.A.
        • Lee D.C.
        • Hen R.
        • Dulawa S.C.
        Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor.
        Neuropsychopharmacology. 2008; 33: 406-417
        • Huang G.J.
        • Bannerman D.
        • Flint J.
        Chronic fluoxetine treatment alters behavior, but not adult hippocampal neurogenesis, in BALB/cJ mice.
        Mol Psychiatry. 2008; 13: 119-121
        • Mineur Y.S.
        • Belzung C.
        • Crusio W.E.
        Functional implications of decreases in neurogenesis following chronic mild stress in mice.
        Neuroscience. 2007; 150: 251-259
        • Carlson P.J.
        • Singh J.B.
        • Zarate Jr., C.A.
        • Drevets W.C.
        • Manji H.K.
        Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets.
        NeuroRx. 2006; 3: 22-41
        • Tanapat P.
        • Hastings N.B.
        • Rydel T.A.
        • Galea L.A.
        • Gould E.
        Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism.
        J Comp Neurol. 2001; 437: 496-504
        • Lelas S.
        • Zeller K.L.
        • Ward K.A.
        • McElroy J.F.
        The anxiolytic CRF(1) antagonist DMP696 fails to function as a discriminative stimulus and does not substitute for chlordiazepoxide in rats.
        Psychopharmacology (Berl). 2003; 166: 408-415
        • McElroy J.F.
        • Ward K.A.
        • Zeller K.L.
        • Jones K.W.
        • Gilligan P.J.
        • He L.
        The CRF(1) receptor antagonist DMP696 produces anxiolytic effects and inhibits the stress-induced hypothalamic-pituitary-adrenal axis activation without sedation or ataxia in rats.
        Psychopharmacology (Berl). 2002; 165: 86-92
        • Serradeil-Le Gal C.
        • Wagnon J.
        • Simiand J.
        • Griebel G.
        • Lacour C.
        • Guillon G.
        • et al.
        Characterization of (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl) −2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), a selective and orally active vasopressin V1b receptor antagonist.
        J Pharmacol Exp Ther. 2002; 300: 1122-1130
        • Aihara M.
        • Ida I.
        • Yuuki N.
        • Oshima A.
        • Kumano H.
        • Takahashi K.
        HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions.
        Psychiatry Res. 2007; 155: 245-256
        • Linkowski P.
        • Mendlewicz J.
        • Kerkhofs M.
        • Leclercq R.
        • Golstein J.
        • Brasseur M.
        24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: Effect of antidepressant treatment.
        J Clin Endocrinol Metab. 1987; 65: 141-152
        • Nemeroff C.B.
        • Owens M.J.
        Pharmacologic differences among the SSRIs: Focus on monoamine transporters and the HPA axis.
        CNS Spectr. 2004; 9: 23-31
        • Pariante C.M.
        • Miller A.H.
        Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment.
        Biol Psychiatry. 2001; 49: 391-404