TY - JOUR
T1 - Stress-induced anxiety- and depressive-like phenotype associated with transient reduction in neurogenesis in adult Nestin-CreERT2/diphtheria toxin fragment A transgenic mice
AU - Yun, Sanghee
AU - Donovan, Michael H.
AU - Ross, Michele N.
AU - Richardson, Devon R.
AU - Reister, Robin
AU - Farnbauch, Laure A.
AU - Fischer, Stephanie J.
AU - Riethmacher, Dieter
AU - Gershenfeld, Howard K.
AU - Lagace, Diane C.
AU - Eisch, Amelia J.
N1 - Funding Information:
This work was supported by grants to AJE from the National Institutes of Health (DA023701, DA023555, MH107945), the National Aeronautics and Space Administration (NNX12AB55G, NNX07AP84G), and an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression/Brain and Behavior Foundation. DCL was funded by a Canadian Institute for Health Research (CIHR) postdoctoral fellowship and CIHR operating grant, as well as a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression/Brain and Behavior Foundation, and an Early Research Award from the Ontario Ministry of Research and Innovation. MHD was funded by F31-MH075457. MNR was funded by NIH F31-DA021045. MNR and SJF were supported by NIH T32-DA007290, Basic Science Training Program in Drug Abuse Research, PI: Amelia J. Eisch. SY is funded by NIH T32-MH076690, Basic Science Training Program in the Neurobiology of Mental Illness, PI: Carol A. Tamminga. The authors acknowledge David Petrik with interim figure help. Current contact information, MHD: Center for Neurobiology and Psychiatry, University of California, San Francisco, 401 Parnassus Ave., San Francisco, California 94143–0984, U.S.A., michael.donovan@ucsf.edu . LAF: lfarnbau@kent.edu , Department of Psychological Sciences, 144 Kent Hall, 600 Hilltop Drive, Kent State University, Kent, OH 44242. HKG: hkgersh@gmail.com , Unit 7100 Box 1505, DPO, AE 09842–1505. DCL: Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada, diane.lagace@uottawa.ca . DR (dual): Department of Biomedical Sciences, Nazarbayev University, School of Medicine, 53 Kabanbay Batyr Ave., Astana, 01000, Kazakhstan, dieter.riethmacher@nu.edu.kz ; and Human Development and Health, Southampton University, School of Medicine, Duthie Building (Mail Point 808), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom. d.riethmacher@southampton.ac.uk .
Publisher Copyright:
© 2016 Yun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient-rather than permanent-inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA + mice tested between 12-30 days post-TAM displayed indices of a stress-induced anxiety phenotype-longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype-longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety and a depressive phenotype, and recovery of DCX+ cell number corresponds to normalization of these behaviors.
AB - Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient-rather than permanent-inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA + mice tested between 12-30 days post-TAM displayed indices of a stress-induced anxiety phenotype-longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype-longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety and a depressive phenotype, and recovery of DCX+ cell number corresponds to normalization of these behaviors.
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U2 - 10.1371/journal.pone.0147256
DO - 10.1371/journal.pone.0147256
M3 - Article
C2 - 26795203
AN - SCOPUS:84958554890
VL - 11
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 1
M1 - e0147256
ER -