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Fibroblast Growth Factor-2 (FGF2) Augmentation Early in Life Alters Hippocampal Development and Rescues the Anxiety Phenotype in Vulnerable Animals

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Fibroblast Growth Factor-2 (FGF2) Augmentation Early in Life Alters Hippocampal Development and Rescues the Anxiety Phenotype in Vulnerable Animals Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals Cortney A. Turnera,1, Sarah M. Clintona, Robert C. Thompsona,b, Stanley J. Watson, Jr.a,b, and Huda Akila,b aMolecular and Behavioral Neuroscience Institute and bDepartment of Psychiatry, University of Michigan, Ann Arbor, MI 48109 Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved April 7, 2011 (received for review March 7, 2011) Individuals with mood disorders exhibit alterations in the fibroblast We focused on the hippocampus because of its critical role in growth factor system, including reduced hippocampal fibroblast processing emotionally salient information and controlling be- growth factor-2 (FGF2). It is difficult, however, to pinpoint whether havior (9–11). Although the present study focuses on the impact these alterations are a cause or consequence of the disorder. The of FGF2 treatment on the hippocampus, this does not exclude the present study asks whether FGF2 administered the day after birth possibility of its effects on other brain regions. Indeed, other has long-lasting effects on hippocampal development and emo- studies have shown how this manipulation results in increased tionality. We show that early-life FGF2 shifts the pace of neuro- cerebellar growth (12). FGF2 also has known organizational genesis, with an early acceleration around weaning followed by a effects in the hippocampus, including increased cell number, deceleration in adulthood. This, in turn, results in a denser dentate volume, and survival in the dentate gyrus 3 wk after administra- gyrus with more neurons. To assess the impact of early-life FGF2 tion on the second day of life (13, 14). Neurogenesis peaks during on emotionality, we use rats selectively bred for differences in lo- the first week of life, and FGF2 treatment during this time win- comotor response to novelty. Selectively bred low-responder (bLR) dow has been previously shown to cross the blood–brain barrier rats show low levels of novelty-induced locomotion and exhibit (13–15). However, the long-term effects of early-life FGF2 have high levels of anxiety- and depression-like behavior compared with not been described. Moreover, the consequences of this treat- their selectively bred high-responder counterparts. Early-life FGF2 ment on adult behavior have not yet been elucidated. decreased anxiety-like behavior in highly anxious bLRs without Here, we ask if a brief exposure to increased levels of FGF2 altering other behaviors and without affecting high-responder rats. early in life can alter the trajectory of hippocampal development Laser capture microscopy of the dentate gyrus followed by micro- and affect anxiety-like behavior. Would this effect be powerful array analysis revealed genes that were differentially expressed enough to rescue rats that are genetically predisposed to high in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of levels of anxiety-like behavior and reverse their phenotype? If so, what are the molecular changes that accompany this behavioral the differentially expressed genes that have been positively asso- fi ciated with anxiety were down-regulated, whereas genes that modi cation? To this end, we assessed hippocampal neurogenesis of wean- promote cell survival were up-regulated. Overall, these results NEUROSCIENCE show a key role for FGF2 in the developmental trajectory of the ling and adult rats exposed to one injection of FGF2 during early hippocampus as well as the modulation of anxiety-like behavior in life. We then assessed the effect of early-life FGF2 on anxiety- adulthood, and they point to potential downstream targets for the like behavior in rats selectively bred to differ in this behavior and treatment of anxiety disorders. characterized the alterations in hippocampal gene expression in the adult rats most impacted by this treatment. elevated plus maze | gene expression microarray Results FGF2 Treatment Boosts Cell Proliferation and Survival in the Dentate fi uman postmortem studies suggest a role for the broblast Gyrus 3 Wk Later. We first assessed the effect of FGF2 or vehicle Hgrowth factor (FGF) system in the pathophysiology of mood on cell proliferation and survival in the dentate gyrus 3 wk after disorders. The expression of several members of the FGF family treatment [postnatal day 23 (PND23)] on the day after birth was altered in the forebrain of patients with major depressive (PND2). Fig. 1A illustrates BrdU and K -67 immunoreactivities fi i disorder (MDD). Speci cally, FGF2 mRNA expression was in the dentate gyrus at PND23. There was a significant increase down-regulated in cortical areas and the hippocampus in MDD in the number of Ki-67–labeled cells in the subgranular zone of compared with controls (1, 2). The hippocampus seems to be the dentate gyrus in FGF2 rats compared with vehicle rats 3 wk particularly affected in MDD (3). A potential role for FGF2 in after treatment, which is indicative of increased cell proliferation depression and anxiety disorders was first suggested by pharma- (Fig. 1B). There was also a significant increase in the number of cological studies in rodents, which showed that administration BrdU-labeled cells in the dentate gyrus 3 wk after injection in of antidepressant and anxiolytic drugs can increase FGF2 expres- FGF2 rats compared with vehicle rats, which is indicative of sion in the hippocampus (3–6). We then asked whether FGF2 is a modulator of emotionality in rodents and discovered that repeated administration of FGF2 was both antidepressant and Author contributions: C.A.T., S.M.C., R.C.T., S.J.W., and H.A. designed research; C.A.T. and anxiolytic (7, 8). S.M.C. performed research; R.C.T. and S.J.W. contributed new reagents/analytic tools; Using rats selectively bred for differences in novelty-seeking, C.A.T. and S.M.C. analyzed data; and C.A.T., S.M.C., and H.A. wrote the paper. we found that hippocampal expression of FGF2 mRNA was Conflict of interest statement: The authors are members of the Pritzker Neuropsychiatric higher in high responders to novelty (bHRs) than in the low re- Disorders Research Consortium, which is supported by the Pritzker Neuropsychiatric Dis- orders Research Fund LLC. A shared intellectual property agreement exists between this sponders to novelty (bLRs). The bHRs have higher FGF2 levels philanthropic fund and University of Michigan, University of California, Stanford Univer- and exhibit less anxiety-like behavior, whereas the bLRs exhibit sity, Hudson-Alpha Institute, and Cornell University to encourage the development of more anxiety-like behavior. FGF2 seems to be a protective factor appropriate findings for research and clinical applications. against anxiety-like behavior in the adult (7). These results sug- This article is a PNAS Direct Submission. gest that FGF2 could mediate the genetic influences on anxiety- 1To whom correspondence should be addressed. E-mail: [email protected]. like behavior and led us to ask whether it plays a causative role This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. during early development. 1073/pnas.1103732108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1103732108 PNAS | May 10, 2011 | vol. 108 | no. 19 | 8021–8025 Downloaded by guest on September 25, 2021 A Vehicle FGF2 B 20000 * 7 10000 6 - Number of Number Ki-67+ Cells Ki 0 Vehicle FGF2 C 20000 * U 10000 Brd Number of Number BrdU+ Cells 0 Vehicle FGF2 Fig. 1. FGF2 increased cell proliferation and cell survival in the dentate gyrus 3 wk later (PND23). (A) Ki-67 immunoreactivity (Upper) in the subgranular zone of the dentate gyrus and BrdU immunoreactivity (Lower) in the granule cell layer of the dentate gyrus in vehicle (Left) and FGF2 (Right) rats. Sections were stained with the monoclonal antibody anti–Ki-67 or the monoclonal antibody anti-BrdU. (Scale bar: 50 μm.) (B)FGF2(n = 3) increased cell proliferation in the subgranular zone of the dentate gyrus compared with vehicle (n =3)rats(t(4) = −4.25, P < 0.05). (C)FGF2(n = 3) increased cell survival in the granule cell layer of the dentate gyrus compared with vehicle (n =3)rats(t(4) = −12.50, P < 0.001). All values are mean ± SEM. increased cell survival (Fig. 1C). These results suggest that FGF2 reduced anxiety-like behavior in bLR. Although FGF2 reduced can boost cell proliferation and cell survival in the dentate gyrus anxiety-like behavior in bLRs, it is important to note that it did not during the first 3 wk of life. completely reverse their phenotypic behavior. FGF2 also impacted the latency of bLRs to enter the open arms of the EPM, with FGF2 FGF2 Treatment Alters Neurogenesis in the Adult Dentate Gyrus. rats exhibiting shorter latency to initially enter the open arms; Next, we determined whether FGF2 altered the adult hippo- again, this suggests reduced anxiety-like behavior (Fig. 3B). campus. We assessed differences in cell proliferation in the In the light–dark box, bHRs spent more time in the light box subgranular zone of the dentate gyrus and the composition of the than bLRs (Fig. 3C) and exhibited a shorter latency to enter the granule cell layer in adult rats (PND60). NeuN was used to D fi light than bLRs (Fig. 3 ), indicating reduced anxiety-like behav- distinguish neurons. As adults, there was a signi cant increase in ior. Although there was no effect of FGF2, there was a significant the total number of neurons in FGF2-exposed rats compared phenotype by treatment interaction. bLRs/FGF2 spent more time with vehicle rats in the dentate gyrus (Fig. 2A). Although volume A B in the light box compared with bLRs/vehicle (VEH). (Fig. S1 ) and total cell numbers (Fig. S1 ) were not different In terms of locomotor activity, all bHR rats exhibited signifi- between the two groups in adulthood, FGF2 rats had a denser cantly more locomotor activity than bLRs (Fig.
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