title: Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Child Study Center, New Haven, Connecticut; Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Natalina
authors.initials: N
authors.lastname: Salmaso
authors.affiliation: Child Study Center, New Haven, Connecticut.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Stevens
authors.affiliation: Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: McNeill
authors.affiliation: Department of Psychiatry, New Haven, Connecticut.
authors.forename: Maha
authors.initials: M
authors.lastname: ElSayed
authors.affiliation: Child Study Center, New Haven, Connecticut.
authors.forename: Qiuyin
authors.initials: Q
authors.lastname: Ren
authors.affiliation: Child Study Center, New Haven, Connecticut.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Maragnoli
authors.affiliation: Department of Neuroscience, New Haven, Connecticut.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schwartz
authors.affiliation: Child Study Center, New Haven, Connecticut.
authors.forename: Simone
authors.initials: S
authors.lastname: Tomasi
authors.affiliation: Departments of Biological Sciences, Neurology, and Neurosurgery, Stanford University, Stanford, California.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sapolsky
authors.affiliation: Department of Psychiatry, New Haven, Connecticut.
authors.forename: Ronald
authors.initials: R
authors.lastname: Duman
authors.affiliation: Child Study Center, New Haven, Connecticut; Department of Neuroscience, New Haven, Connecticut; Department of Yale Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut. Electronic address: flora.vaccarino@yale.edu.
authors.forename: Flora M
authors.initials: FM
authors.lastname: Vaccarino
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D011965:Receptors, Glucocorticoid; D016222:Fibroblast Growth Factor 2; D015735:Mifepristone
keywords: Anxiety; FGF receptors; FGF2; Glucocorticoids; Hippocampus; Mouse; Stress