title: Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: a potential model of geriatric depression.
abstract: Numerous studies support the hypothesis that deficiency of insulin-like growth factor I (IGF-1) in adults contributes to depression, but direct evidence is limited. Many psychological and pro-cognitive effects have been attributed to IGF-1, but appropriate animal models of adult-onset IGF-1 deficiency are lacking. In this study, we use a viral-mediated Cre-loxP system to knockout the Igf1 gene in either the liver, neurons of the CA1 region of the hippocampus, or both. Knockout of liver Igf1 reduced serum IGF-1 levels by 40% and hippocampal IGF-1 levels by 26%. Knockout of Igf1 in CA1 reduced hippocampal IGF-1 levels by 13%. The most severe reduction in hippocampal IGF-1 occurred in the group with knockouts in both liver and CA1 (36% reduction), and was associated with a 3.5-fold increase in immobility in the forced swim test. Reduction of either circulating or hippocampal IGF-1 levels did not alter anxiety measured in an open field and elevated plus maze, nor locomotion in the open field. Furthermore, local compensation for deficiencies in circulating IGF-1 did not occur in the hippocampus, nor were serum levels of IGF-1 upregulated in response to the moderate decline of hippocampal IGF-1 caused by the knockouts in CA1. We conclude that adult-onset IGF-1 deficiency alone is sufficient to induce a depressive phenotype in mice. Furthermore, our results suggest that individuals with low brain levels of IGF-1 are at increased risk for depression and these behavioral effects are not ameliorated by increased local IGF-1 production or transport. Our study supports the hypothesis that the natural IGF-1 decline in aging humans may contribute to geriatric depression.
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1303, Oklahoma City, OK 73104, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mitschelen
authors.forename: H
authors.initials: H
authors.lastname: Yan
authors.forename: J A
authors.initials: JA
authors.lastname: Farley
authors.forename: J P
authors.initials: JP
authors.lastname: Warrington
authors.forename: S
authors.initials: S
authors.lastname: Han
authors.forename: C B
authors.initials: CB
authors.lastname: Hereñú
authors.forename: A
authors.initials: A
authors.lastname: Csiszar
authors.forename: Z
authors.initials: Z
authors.lastname: Ungvari
authors.forename: L C
authors.initials: LC
authors.lastname: Bailey-Downs
authors.forename: C E
authors.initials: CE
authors.lastname: Bass
authors.forename: W E
authors.initials: WE
authors.lastname: Sonntag
mesh_terms: D000375:Aging; D000818:Animals; D001522:Behavior, Animal; D003863:Depression / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D019417:Hindlimb Suspension / Q000379:methods; D006624:Hippocampus / Q000473:pathology*; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000378:metabolism; D016014:Linear Models; D008099:Liver / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013550:Swimming / Q000523:psychology
chemical_list: D051796:Inhibitor of Differentiation Proteins; D011506:Proteins; C485184:enhanced green fluorescent protein; C035737:major urinary proteins; C067679:Idb3 protein, mouse; D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I