title: Intrahippocampal glucocorticoids generated by 11β-HSD1 affect memory in aged mice.
abstract: 11Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) locally amplifies active glucocorticoids within specific tissues including in brain. In the hippocampus, 11β-HSD1 messenger RNA increases with aging. Here, we report significantly greater increases in intrahippocampal corticosterone (CORT) levels in aged wild-type (WT) mice during the acquisition and retrieval trials in a Y-maze than age-matched 11β-HSD1(-/-) mice, corresponding to impaired and intact spatial memory, respectively. Acute stress applied to young WT mice led to increases in intrahippocampal CORT levels similar to the effects of aging and impaired retrieval of spatial memory. 11β-HSD1(-/-) mice resisted the stress-induced memory impairment. Pharmacologic inhibition of 11β-HSD1 abolished increases in intrahippocampal CORT levels during the Y-maze trials and prevented spatial memory impairments in aged WT mice. These data provide the first in vivo evidence that dynamic increases in hippocampal 11β-HSD1 regenerated CORT levels during learning and retrieval play a key role in age- and stress-associated impairments of spatial memory.
authors.affiliation: Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Endocrinology Unit, British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. Electronic address: joyce.yau@ed.ac.uk.
authors.forename: Joyce L W
authors.initials: JL
authors.lastname: Yau
authors.affiliation: Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Endocrinology Unit, British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Wheelan
authors.affiliation: Endocrinology Unit, British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: June
authors.initials: J
authors.lastname: Noble
authors.affiliation: Endocrinology Unit, British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: Endocrinology Unit, British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.affiliation: Endocrinology Unit, British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Endocrinology Unit, British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000523:psychology*; D000818:Animals; D005938:Glucocorticoids / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D065852:Spatial Memory / Q000502:physiology*; D013315:Stress, Psychological / Q000523:psychology; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000601250:(4-(2-chlorophenyl-4-fluoro-1-piperidinyl)(5-(1H-pyrazol-4-yl)-3-thienyl)methanone; D005938:Glucocorticoids; D011720:Pyrazoles; D012333:RNA, Messenger; D013876:Thiophenes; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
keywords: 11β-HSD1; Aging; Corticosterone; Hippocampus; Spatial memory; Stress
references.citation: J Neurosci. 2008 Mar 26;28(13):3474-8
references.pmid: 18367613
references.citation: J Neurosci. 2010 Oct 13;30(41):13867-72
references.pmid: 20943927
references.citation: Behav Neurosci. 1996 Oct;110(5):1074-83
references.pmid: 8919010
references.citation: J Endocrinol. 2011 May;209(2):153-67
references.pmid: 21357682
references.citation: Behav Neurosci. 1996 Dec;110(6):1321-34
references.pmid: 8986335
references.citation: Behav Neural Biol. 1993 Sep;60(2):103-9
references.pmid: 8117235
references.citation: J Neuroendocrinol. 2007 Nov;19(11):891-900
references.pmid: 17927667
references.citation: Front Aging Neurosci. 2012 Aug 29;4:24
references.pmid: 22952463
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12790-5
references.pmid: 11606764
references.citation: Learn Mem. 2010 Sep 30;17(10):522-30
references.pmid: 20884754
references.citation: J Neurosci. 2010 May 19;30(20):6916-20
references.pmid: 20484633
references.citation: Eur J Neurosci. 1997 Jan;9(1):76-83
references.pmid: 9042571
references.citation: Mol Cell Endocrinol. 2006 Mar 27;248(1-2):9-14
references.pmid: 16413106
references.citation: J Neuroendocrinol. 2009 Nov;21(11):879-87
references.pmid: 19602102
references.citation: J Neuroendocrinol. 1994 Jun;6(3):285-90
references.pmid: 7920594
references.citation: Am J Physiol Endocrinol Metab. 2005 Nov;289(5):E823-8
references.pmid: 15956051
references.citation: Eur J Neurosci. 2006 Jun;23(11):3051-5
references.pmid: 16819994
references.citation: Proc Natl Acad Sci U S A. 2013 May 7;110(19):7910-5
references.pmid: 23613579
references.citation: Anal Chem. 2013 Dec 3;85(23):11576-84
references.pmid: 24134553
references.citation: Nature. 1998 Aug 20;394(6695):787-90
references.pmid: 9723618
references.citation: J Neurosci. 1995 Jan;15(1 Pt 1):61-9
references.pmid: 7823152
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6734-9
references.pmid: 15071189
references.citation: Curr Alzheimer Res. 2007 Apr;4(2):205-12
references.pmid: 17430248
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19204-7
references.pmid: 16361444
references.citation: Neurobiol Learn Mem. 1999 Jul;72(1):39-46
references.pmid: 10371714
references.citation: J Steroid Biochem Mol Biol. 1997 Jun;62(2-3):195-9
references.pmid: 9393954
references.citation: Stress. 1996 Jul;1(1):1-19
references.pmid: 9807058
references.citation: Endocrinology. 2012 Sep;153(9):4346-53
references.pmid: 22822164
references.citation: Endocrinology. 1990 Sep;127(3):1450-5
references.pmid: 2387261
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14924-9
references.pmid: 9405715
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4716-21
references.pmid: 11274359
references.citation: Brain Res. 1994 Mar 7;639(1):167-70
references.pmid: 8180832
references.citation: Stress. 2011 Jul;14(4):398-406
references.pmid: 21663538
references.citation: J Neurosci. 2007 Sep 26;27(39):10487-96
references.pmid: 17898220
references.citation: Lab Anim. 2000 Oct;34(4):372-8
references.pmid: 11072857
references.citation: Dose Response. 2006 Jun 20;4(1):55-74
references.pmid: 18648634
references.citation: Eur J Neurosci. 2006 Jul;24(2):595-605
references.pmid: 16903861
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):853-8
references.pmid: 14711996
references.citation: Nat Neurosci. 1998 May;1(1):69-73
references.pmid: 10195112
references.citation: J Neurosci. 2011 Mar 16;31(11):4188-93
references.pmid: 21411659
references.citation: Hippocampus. 2010 Jan;20(1):196-207
references.pmid: 19360856
references.citation: Annu Rev Neurosci. 2007;30:123-52
references.pmid: 17417939
references.citation: Neurobiol Learn Mem. 2002 Nov;78(3):578-95
references.pmid: 12559837
references.citation: Neurobiol Learn Mem. 2010 Mar;93(3):343-51
references.pmid: 19948234
references.citation: Mol Endocrinol. 2008 Sep;22(9):2049-60
references.pmid: 18617597
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9697-701
references.pmid: 7568200