title: Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals.
abstract: Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety- and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders.
authors.affiliation: Molecular and Behavioral Neuroscience Institute , University of Michigan, Ann Arbor, MI 48109, USA. caturner@umich.edu
authors.forename: Cortney A
authors.initials: CA
authors.lastname: Turner
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Clinton
authors.forename: Robert C
authors.initials: RC
authors.lastname: Thompson
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watson
authors.forename: Huda
authors.initials: H
authors.lastname: Akil
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D008297:Male; D019964:Mood Disorders / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020812:Receptor, trkC / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics
chemical_list: C491072:Bcl2l2 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D020812:Receptor, trkC