Cargando…

Forebrain‐Specific Transgene Rescue of 11β‐HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain‐Derived Neurotrophic Factor mRNA Levels in Aged 11β‐HSD1 Deficient Mice

Mice lacking the intracellular glucocorticoid‐regenerating enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) are protected from age‐related spatial memory deficits. 11β‐HSD1 is expressed predominantly in the brain, liver and adipose tissue. Reduced glucocorticoid levels in the brain in the a...

Descripción completa

Detalles Bibliográficos
Autores principales: Caughey, S., Harris, A. P., Seckl, J. R., Holmes, M. C., Yau, J. L. W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244685/
https://www.ncbi.nlm.nih.gov/pubmed/27859809
http://dx.doi.org/10.1111/jne.12447
_version_ 1782496738761768960
author Caughey, S.
Harris, A. P.
Seckl, J. R.
Holmes, M. C.
Yau, J. L. W.
author_facet Caughey, S.
Harris, A. P.
Seckl, J. R.
Holmes, M. C.
Yau, J. L. W.
author_sort Caughey, S.
collection PubMed
description Mice lacking the intracellular glucocorticoid‐regenerating enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) are protected from age‐related spatial memory deficits. 11β‐HSD1 is expressed predominantly in the brain, liver and adipose tissue. Reduced glucocorticoid levels in the brain in the absence of 11β‐HSD1 may underlie the improved memory in aged 11β‐HSD1 deficient mice. However, the improved glucose tolerance, insulin sensitisation and cardioprotective lipid profile associated with reduced peripheral glucocorticoid regeneration may potentially contribute to the cognitive phenotype of aged 11β‐HSD1 deficient mice. In the present study, transgenic mice with forebrain‐specific overexpression of 11β‐HSD1 (Tg) were intercrossed with global 11β‐HSD1 knockout mice (HSD1KO) to examine the influence of forebrain and peripheral 11β‐HSD1 activity on spatial memory in aged mice. Transgene‐mediated delivery of 11β‐HSD1 to the hippocampus and cortex of aged HSD1KO mice reversed the improved spatial memory retention in the Y‐maze but not spatial learning in the watermaze. Brain‐derived neurotrophic factor (BDNF) mRNA levels in the hippocampus of aged HSD1KO mice were increased compared to aged wild‐type mice. Rescue of forebrain 11β‐HSD1 reduced BDNF mRNA in aged HSD1KO mice to levels comparable to aged wild‐type mice. These findings indicate that 11β‐HSD1 regenerated glucocorticoids in the forebrain and decreased levels of BDNF mRNA in the hippocampus play a role in spatial memory deficits in aged wild‐type mice, although 11β‐HSD1 activity in peripheral tissues may also contribute to spatial learning impairments in aged mice.
format Online
Article
Text
id pubmed-5244685
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-52446852017-01-25 Forebrain‐Specific Transgene Rescue of 11β‐HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain‐Derived Neurotrophic Factor mRNA Levels in Aged 11β‐HSD1 Deficient Mice Caughey, S. Harris, A. P. Seckl, J. R. Holmes, M. C. Yau, J. L. W. J Neuroendocrinol Original Articles Mice lacking the intracellular glucocorticoid‐regenerating enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) are protected from age‐related spatial memory deficits. 11β‐HSD1 is expressed predominantly in the brain, liver and adipose tissue. Reduced glucocorticoid levels in the brain in the absence of 11β‐HSD1 may underlie the improved memory in aged 11β‐HSD1 deficient mice. However, the improved glucose tolerance, insulin sensitisation and cardioprotective lipid profile associated with reduced peripheral glucocorticoid regeneration may potentially contribute to the cognitive phenotype of aged 11β‐HSD1 deficient mice. In the present study, transgenic mice with forebrain‐specific overexpression of 11β‐HSD1 (Tg) were intercrossed with global 11β‐HSD1 knockout mice (HSD1KO) to examine the influence of forebrain and peripheral 11β‐HSD1 activity on spatial memory in aged mice. Transgene‐mediated delivery of 11β‐HSD1 to the hippocampus and cortex of aged HSD1KO mice reversed the improved spatial memory retention in the Y‐maze but not spatial learning in the watermaze. Brain‐derived neurotrophic factor (BDNF) mRNA levels in the hippocampus of aged HSD1KO mice were increased compared to aged wild‐type mice. Rescue of forebrain 11β‐HSD1 reduced BDNF mRNA in aged HSD1KO mice to levels comparable to aged wild‐type mice. These findings indicate that 11β‐HSD1 regenerated glucocorticoids in the forebrain and decreased levels of BDNF mRNA in the hippocampus play a role in spatial memory deficits in aged wild‐type mice, although 11β‐HSD1 activity in peripheral tissues may also contribute to spatial learning impairments in aged mice. John Wiley and Sons Inc. 2017-01-09 2017-01 /pmc/articles/PMC5244685/ /pubmed/27859809 http://dx.doi.org/10.1111/jne.12447 Text en © 2016 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Caughey, S.
Harris, A. P.
Seckl, J. R.
Holmes, M. C.
Yau, J. L. W.
Forebrain‐Specific Transgene Rescue of 11β‐HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain‐Derived Neurotrophic Factor mRNA Levels in Aged 11β‐HSD1 Deficient Mice
title Forebrain‐Specific Transgene Rescue of 11β‐HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain‐Derived Neurotrophic Factor mRNA Levels in Aged 11β‐HSD1 Deficient Mice
title_full Forebrain‐Specific Transgene Rescue of 11β‐HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain‐Derived Neurotrophic Factor mRNA Levels in Aged 11β‐HSD1 Deficient Mice
title_fullStr Forebrain‐Specific Transgene Rescue of 11β‐HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain‐Derived Neurotrophic Factor mRNA Levels in Aged 11β‐HSD1 Deficient Mice
title_full_unstemmed Forebrain‐Specific Transgene Rescue of 11β‐HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain‐Derived Neurotrophic Factor mRNA Levels in Aged 11β‐HSD1 Deficient Mice
title_short Forebrain‐Specific Transgene Rescue of 11β‐HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain‐Derived Neurotrophic Factor mRNA Levels in Aged 11β‐HSD1 Deficient Mice
title_sort forebrain‐specific transgene rescue of 11β‐hsd1 associates with impaired spatial memory and reduced hippocampal brain‐derived neurotrophic factor mrna levels in aged 11β‐hsd1 deficient mice
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244685/
https://www.ncbi.nlm.nih.gov/pubmed/27859809
http://dx.doi.org/10.1111/jne.12447
work_keys_str_mv AT caugheys forebrainspecifictransgenerescueof11bhsd1associateswithimpairedspatialmemoryandreducedhippocampalbrainderivedneurotrophicfactormrnalevelsinaged11bhsd1deficientmice
AT harrisap forebrainspecifictransgenerescueof11bhsd1associateswithimpairedspatialmemoryandreducedhippocampalbrainderivedneurotrophicfactormrnalevelsinaged11bhsd1deficientmice
AT seckljr forebrainspecifictransgenerescueof11bhsd1associateswithimpairedspatialmemoryandreducedhippocampalbrainderivedneurotrophicfactormrnalevelsinaged11bhsd1deficientmice
AT holmesmc forebrainspecifictransgenerescueof11bhsd1associateswithimpairedspatialmemoryandreducedhippocampalbrainderivedneurotrophicfactormrnalevelsinaged11bhsd1deficientmice
AT yaujlw forebrainspecifictransgenerescueof11bhsd1associateswithimpairedspatialmemoryandreducedhippocampalbrainderivedneurotrophicfactormrnalevelsinaged11bhsd1deficientmice