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Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors

      Abstract

      Background

      Despite strong evidence linking fibroblast growth factor 2 (FGF2) with anxiety and depression in both rodents and humans, the molecular mechanisms linking FGF2 with anxiety are not understood.

      Methods

      We compare 1) mice that lack a functional Fgf2 gene (Fgf2 knockout [KO]), 2) wild-type mice, and 3) Fgf2 KO with adult rescue by FGF2 administration on measures of anxiety, depression, and motor behavior, and further investigate the mechanisms of this behavior by cellular, molecular, and neuroendocrine studies.

      Results

      We demonstrate that Fgf2 KO mice have increased anxiety, decreased hippocampal glucocorticoid receptor (GR) expression, and increased hypothalamic-pituitary-adrenal axis activity. FGF2 administration in adulthood was sufficient to rescue the entire phenotype. Blockade of GR in adult mice treated with FGF2 precluded the therapeutic effects of FGF2 on anxiety behavior, suggesting that GR is necessary for FGF2 to regulate anxiety behavior. The level of Egr-1/NGFI-A was decreased in Fgf2 KO mice and was reestablished with FGF2 treatment. By chromatin immunoprecipitation studies, we found decreased binding of EGR-1 to the GR promoter region in Fgf2 KO mice. Finally, we examined anxiety behavior in FGF receptor (FGFR) KO mice; however, FGFR1, FGFR2, and FGFR3 KO mice did not mimic the phenotype of Fgf2 KO mice, suggesting a role for other receptor subtypes (i.e., FGFR5).

      Conclusions

      These data suggest that FGF2 levels are critically related to anxiety behavior and hypothalamic-pituitary-adrenal axis activity, likely through modulation of hippocampal glucocorticoid receptor expression, an effect that is likely receptor mediated, albeit not by FGFR1, FGFR2, and FGFR3.

      Keywords

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      References

        • Woodbury M.E.
        • Ikezu T.
        Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration.
        J Neuroimmune Pharmacol. 2014; 9: 92-101
        • Vaccarino F.M.
        • Grigorenko E.L.
        • Smith K.M.
        • Stevens H.E.
        Regulation of cerebral cortical size and neuron number by fibroblast growth factors: Implications for autism.
        J Autism Dev Disord. 2009; 39: 511-520
        • Vaccarino F.M.
        • Schwartz M.L.
        • Raballo R.
        • Nilsen J.
        • Rhee J.
        • Zhou M.
        • et al.
        Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis.
        Nat Neurosci. 1999; 2: 246-253
        • Raballo R.
        • Rhee J.
        • Lyn-Cook R.
        • Leckman J.F.
        • Schwartz M.L.
        • Vaccarino F.M.
        Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex.
        J Neurosci. 2000; 20: 5012-5023
        • Korada S.
        • Zheng W.
        • Basilico C.
        • Schwartz M.L.
        • Vaccarino F.M.
        Fgf2 is necessary for the growth of glutamate projection neurons in the anterior neocortex.
        J Neurosci. 2002; 22: 863-875
        • Zheng W.
        • Nowakowski R.S.
        • Vaccarino F.M.
        Fibroblast growth factor 2 is required for maintaining the neural stem cell pool in the mouse brain subventricular zone.
        Dev Neurosci. 2004; 26: 181-196
        • Flores C.
        • Stewart J.
        • Salmaso N.
        • Zhang Y.
        • Boksa P.
        Astrocytic basic fibroblast growth factor expression in dopaminergic regions after perinatal anoxia.
        Biol Psychiatry. 2002; 52: 362
        • Ganat Y.
        • Soni S.
        • Chacon M.
        • Schwartz M.L.
        • Vaccarino F.M.
        Chronic hypoxia up-regulates fibroblast growth factor ligands in the perinatal brain and induces fibroblast growth factor -responsive radial glial cells in the sub-ependymal zone.
        Neuroscience. 2002; 112: 977-991
        • Rai K.S.
        • Hattiangady B.
        • Shetty A.K.
        Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions.
        Eur J Neurosci. 2007; 26: 1765-1779
        • Akil H.
        • Evans S.J.
        • Turner C.A.
        • Perez J.
        • Myers R.M.
        • Bunney W.E.
        • et al.
        The fibroblast growth factor family and mood disorders.
        Novartis Found Symp. 2008; 289 (discussion 97–100, 193–105): 94-96
        • Eren-Kocak E.
        • Turner C.A.
        • Watson S.J.
        • Akil H.
        Short-hairpin RNA silencing of endogenous fibroblast growth factor 2 in rat hippocampus increases anxiety behavior.
        Biol Psychiatry. 2011; 69: 534-540
        • Evans S.J.
        • Choudary P.V.
        • Neal C.R.
        • Li J.Z.
        • Vawter M.P.
        • Tomita H.
        • et al.
        Dysregulation of the fibroblast growth factor system in major depression.
        Proc Natl Acad Sci U S A. 2004; 101: 15506-15511
        • Perez J.A.
        • Clinton S.M.
        • Turner C.A.
        • Watson S.J.
        • Akil H.
        A new role for FGF2 as an endogenous inhibitor of anxiety.
        J Neurosci. 2009; 29: 6379-6387
        • Turner C.A.
        • Gula E.L.
        • Taylor L.P.
        • Watson S.J.
        • Akil H.
        Antidepressant-like effects of intracerebroventricular FGF2 in rats.
        Brain Res. 2008; 1224: 63-68
        • Salmaso N.
        • Vaccarino F.M.
        Toward a novel endogenous anxiolytic factor, fibroblast growth factor 2.
        Biol Psychiatry. 2011; 69: 508-509
        • Bachis A.
        • Mallei A.
        • Cruz M.I.
        • Wellstein A.
        • Mocchetti I.
        Chronic antidepressant treatments increase basic fibroblast growth factor and fibroblast growth factor-binding protein in neurons.
        Neuropharmacology. 2008; 55: 1114-1120
        • Zhou M.
        • Sutliff R.L.
        • Paul R.J.
        • Lorenz J.N.
        • Hoying J.B.
        • Haudenschild C.C.
        • et al.
        Fibroblast growth factor 2 controls vascular tone.
        Nat Med. 1998; 4: 201-207
        • Stevens H.E.
        • Smith K.M.
        • Maragnoli M.E.
        • Fagel D.
        • Borok E.
        • Shanabrough M.
        • et al.
        Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits.
        J Neurosci. 2010; 30: 5590-5602
        • Deng C.
        • Wynshaw-Boris A.
        • Zhou F.
        • Kuo A.
        • Leder P.
        Fibroblast growth factor receptor 3 is a negative regulator of bone growth.
        Cell. 1996; 84: 911-921
        • Rash B.G.
        • Lim H.D.
        • Breunig J.J.
        • Vaccarino F.M.
        FGF signaling expands embryonic cortical surface area by regulating notch-dependent neurogenesis.
        J Neurosci. 2011; 31: 15604-15617
        • Comeau W.
        • Gibb R.
        • Hastings E.
        • Cioe J.
        • Kolb B.
        Therapeutic effects of complex rearing or bFGF after perinatal frontal lesions.
        Dev Psychobiol. 2008; 50: 134-146
        • Wagner J.P.
        • Black I.B.
        • DiCicco-Bloom E.
        Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor.
        J Neurosci. 1999; 19: 6006-6016
        • de Kloet E.R.
        • Oitzl M.S.
        • Joels M.
        Functional implications of brain corticosteroid receptor diversity.
        Cell Mol Neurobiol. 1993; 13: 433-455
        • De Kloet E.R.
        • Vreugdenhil E.
        • Oitzl M.S.
        • Joels M.
        Brain corticosteroid receptor balance in health and disease.
        Endocr Rev. 1998; 19: 269-301
        • Sapolsky R.M.
        • Krey L.C.
        • McEwen B.S.
        Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response.
        Proc Natl Acad Sci U S A. 1984; 81: 6174-6177
        • 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.
        • Krey L.C.
        • McEwen B.S.
        The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis.
        Endocr Rev. 1986; 7: 284-301
        • Garcia A.
        • Steiner B.
        • Kronenberg G.
        • Bick-Sander A.
        • Kempermann G.
        Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus.
        Aging Cell. 2004; 3: 363-371
        • 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: 1659-1662
        • Weaver I.C.
        • Cervoni N.
        • Champagne F.A.
        • D’Alessio A.C.
        • Sharma S.
        • Seckl J.R.
        • et al.
        Epigenetic programming by maternal behavior.
        Nat Neurosci. 2004; 7: 847-854
        • Jiang C.
        • Salton S.R.
        The role of neurotrophins in major depressive disorder.
        Transl Neurosci. 2013; 4: 46-58
        • Sapolsky R.M.
        • Meaney M.J.
        • McEwen B.S.
        The development of the glucocorticoid receptor system in the rat limbic brain. III. Negative-feedback regulation.
        Brain Res. 1985; 350: 169-173
        • Ridder S.
        • Chourbaji S.
        • Hellweg R.
        • Urani A.
        • Zacher C.
        • Schmid W.
        • et al.
        Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions.
        J Neurosci. 2005; 25: 6243-6250
        • Brown E.S.
        • Rush A.J.
        • McEwen B.S.
        Hippocampal remodeling and damage by corticosteroids: Implications for mood disorders.
        Neuropsychopharmacology. 1999; 21: 474-484
        • Calvo N.
        • Volosin M.
        Glucocorticoid and mineralocorticoid receptors are involved in the facilitation of anxiety-like response induced by restraint.
        Neuroendocrinology. 2001; 73: 261-271
        • Korte S.M.
        • de Boer S.F.
        • de Kloet E.R.
        • Bohus B.
        Anxiolytic-like effects of selective mineralocorticoid and glucocorticoid antagonists on fear-enhanced behavior in the elevated plus-maze.
        Psychoneuroendocrinology. 1995; 20: 385-394
        • Gonzalez A.-M.
        • Berry M.
        • Maher P.A.
        • Logan A.
        • Baird A.
        A comprehensive analysis of the distribution of FGF-2 and FGF-1 in the rat brain.
        Brain Res. 1995; 701: 201-226
        • Belluardo N.
        • Wu G.-Y.
        • Mudo G.
        • Hansson A.C.
        • Petterson R.
        • Fuxe K.
        Comparative localization of fibroblast growth factor receptor-1, -2, and -3 mRNAs in the rat brain: In situ hybridization analysis.
        J Comp Neurol. 1997; 379: 226-246
        • McCormick J.A.
        • Lyons V.
        • Jacobson M.D.
        • Noble J.
        • Diorio J.
        • Nyirenda M.
        • et al.
        5’-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: Differential regulation of variant transcripts by early-life events.
        Mol Endocrinol. 2000; 14: 506-517
        • Zhang T.Y.
        • Labonte B.
        • Wen X.L.
        • Turecki G.
        • Meaney M.J.
        Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans.
        Neuropsychopharmacology. 2013; 38: 111-123
        • Anisman H.
        • Zaharia M.D.
        • Meaney M.J.
        • Merali Z.
        Do early-life events permanently alter behavioral and hormonal responses to stressors?.
        Int J Dev Neurosci. 1998; 16: 149-164
        • Francis D.D.
        • Meaney M.J.
        Maternal care and the development of stress responses.
        Curr Opin Neurobiol. 1999; 9: 128-134
        • Hellstrom I.C.
        • Dhir S.K.
        • Diorio J.C.
        • Meaney M.J.
        Maternal licking regulates hippocampal glucocorticoid receptor transcription through a thyroid hormone-serotonin-NGFI-A signalling cascade.
        Philos Trans R Soc Lond B Biol Sci. 2012; 367: 2495-2510
        • Bredy T.W.
        • Humpartzoomian R.A.
        • Cain D.P.
        • Meaney M.J.
        Partial reversal of the effect of maternal care on cognitive function through environmental enrichment.
        Neuroscience. 2003; 118: 571-576
        • Muller Smith K.
        • Fagel D.M.
        • Stevens H.E.
        • Rabenstein R.L.
        • Maragnoli M.E.
        • Ohkubo Y.
        • et al.
        Deficiency in inhibitory cortical interneurons associates with hyperactivity in fibroblast growth factor receptor 1 mutant mice.
        Biol Psychiatry. 2008; 63: 953-962
        • Smith K.M.
        • Williamson T.L.
        • Schwartz M.L.
        • Vaccarino F.M.
        Impaired motor coordination and disrupted cerebellar architecture in Fgfr1 and Fgfr2 double knockout mice.
        Brain Res. 2012; 1460: 12-24
        • Stevens H.E.
        • Jiang G.Y.
        • Schwartz M.L.
        • Vaccarino F.M.
        Learning and memory depend on fibroblast growth factor receptor 2 functioning in hippocampus.
        Biol Psychiatry. 2012; 71: 1090-1098
        • Aurbach E.L.
        • Inui E.G.
        • Turner C.A.
        • Hagenauer M.H.
        • Prater K.E.
        • Li J.Z.
        • et al.
        Fibroblast growth factor 9 is a novel modulator of negative affect.
        Proc Natl Acad Sci U S A. 2015; 112: 11953-11958
        • Kessler R.C.
        • Chiu W.T.
        • Demler O.
        • Merikangas K.R.
        • Walters E.E.
        Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 617-627

      Linked Article

      • Fibroblast Growth Factor 2 Sits at the Interface of Stress and Anxiety
        Biological PsychiatryVol. 80Issue 6
        • Preview
          The role of growth factors in the control of mood and emotions has gained considerable interest. In particular, discoveries during the past decade have pointed to the involvement of the fibroblast growth factor (FGF) family in affect regulation and have underscored the ability of one member, FGF2, to decrease depression and anxiety behaviors in animal models (1). In the present report, Salmaso et al. (2) show that Fgf2 knockout (KO) mice exhibit increased anxiety behavior, and this phenotype is rescued by FGF2 administration in adulthood (2).
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