Adult-onset deficiency in growth hormone and insulin-like growth factor-I decreases survival of dentate granule neurons: insights into the regulation of adult hippocampal neurogenesis.
Insulin-like growth factor-I (IGF-I), long thought to provide critical trophic support during development, also has emerged as a candidate for regulating ongoing neuronal production in adulthood. Whether and how IGF-I influences each phase of neurogenesis, however, remains unclear. In the current study, we used a selective model of growth hormone (GH) and plasma IGF-I deficiency to evaluate the role of GH and IGF-I in regulating cell proliferation, survival, and neuronal differentiation in the adult dentate gyrus. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete throughout development via twice daily injections of GH, and then GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Bromodeoxyuridine (BrdU) labeling revealed no effect of GH/IGF-I deficiency on cell proliferation, but adult-onset depletion of GH and plasma IGF-I significantly reduced the survival of newly generated cells in the dentate gyrus. Colabeling for BrdU and markers of immature and mature neurons revealed a selective effect of GH/IGF-I deficiency on the survival of more mature new neurons. The number of BrdU-labeled cells expressing the immature neuronal marker TUC-4 did not differ between GH/IGF-I-deficient and -replete animals, but the number expressing only the marker of maturity NeuN was lower in depleted animals. Taken together, results from the present study suggest that, under conditions of short-term GH/IGF-I deficiency during adulthood, dentate granule cells continue to be produced, to commit to a neuronal fate, and to begin the process of neuronal maturation, whereas survival of the new neurons is impaired.
Lichtenwalner
Robin J
RJ
Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1010, USA.
Forbes
M Elizabeth
ME
Sonntag
William E
WE
Riddle
David R
DR
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018891:Dentate Gyrus / Q000473:pathology*; D004392:Dwarfism / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005260:Female; D013006:Growth Hormone / Q000008:administration & dosage / Q000097:blood / Q000172:deficiency*; D007150:Immunohistochemistry / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D038081:Organogenesis; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains
C449760:Dpysl3 protein, rat; D009419:Nerve Tissue Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine