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Stress-induced anxiety- and depressive-like phenotype associated with transient reduction in neurogenesis in adult Nestin-CreERT2/diphtheria toxin fragment A transgenic mice

Stress-induced anxiety- and depressive-like phenotype associated with transient reduction in neurogenesis in adult Nestin-CreERT2/diphtheria toxin fragment A transgenic mice
Stress-induced anxiety- and depressive-like phenotype associated with transient reduction in neurogenesis in adult Nestin-CreERT2/diphtheria toxin fragment A transgenic mice
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.
1932-6203
e0147256
Yun, Sanghee
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Donovan, Michael H.
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Ross, Michele N.
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Richardson, Devon R.
4819eca3-953d-48ed-8d53-8da48d5dcae3
Reister, Robin
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Farnbauch, Laure A.
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Fischer, Stephanie J.
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Riethmacher, Dieter
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Gershenfeld, Howard K.
ae58905a-94cf-48ee-ae63-c246313775c3
Lagace, Diane C.
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Eisch, Amelia J.
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Yun, Sanghee
c5edb806-fe34-4c86-816a-d7a159ae5fc6
Donovan, Michael H.
60146b21-ca20-42a3-8db1-9f7d657e4143
Ross, Michele N.
6d73bcfe-dc7d-4c44-a7a6-3f1cd63d34b8
Richardson, Devon R.
4819eca3-953d-48ed-8d53-8da48d5dcae3
Reister, Robin
79da990a-b582-4ca3-8725-e75c460e51df
Farnbauch, Laure A.
1d71c761-5171-4b07-ab7f-0dd2b4a14407
Fischer, Stephanie J.
49780ee5-7b92-47a1-8d1d-509e0c01b7da
Riethmacher, Dieter
1a0a0c2e-e94d-4d0a-a890-90107a2545bc
Gershenfeld, Howard K.
ae58905a-94cf-48ee-ae63-c246313775c3
Lagace, Diane C.
529ec676-fd11-41c6-a5bf-80d2e8080264
Eisch, Amelia J.
3a95f847-be72-4a58-b43c-4ecba340e540

Yun, Sanghee, Donovan, Michael H., Ross, Michele N., Richardson, Devon R., Reister, Robin, Farnbauch, Laure A., Fischer, Stephanie J., Riethmacher, Dieter, Gershenfeld, Howard K., Lagace, Diane C. and Eisch, Amelia J. (2016) Stress-induced anxiety- and depressive-like phenotype associated with transient reduction in neurogenesis in adult Nestin-CreERT2/diphtheria toxin fragment A transgenic mice. PLoS ONE, 11 (1), e0147256. (doi:10.1371/journal.pone.014725). (PMID:26795203)

Record type: Article

Abstract

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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Accepted/In Press date: 2 January 2016
Published date: 21 January 2016
Additional Information: 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.
Organisations: Human Development & Health

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Local EPrints ID: 386555
URI: http://eprints.soton.ac.uk/id/eprint/386555
ISSN: 1932-6203
PURE UUID: 45c1755c-0ae4-4e5a-b921-df8aa9664b54
ORCID for Dieter Riethmacher: ORCID iD orcid.org/0000-0002-4206-5529

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Date deposited: 02 Feb 2016 11:45
Last modified: 17 Dec 2019 01:43

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Contributors

Author: Sanghee Yun
Author: Michael H. Donovan
Author: Michele N. Ross
Author: Devon R. Richardson
Author: Robin Reister
Author: Laure A. Farnbauch
Author: Stephanie J. Fischer
Author: Dieter Riethmacher ORCID iD
Author: Howard K. Gershenfeld
Author: Diane C. Lagace
Author: Amelia J. Eisch

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