title: Environmental enrichment reverses histone methylation changes in the aged hippocampus and restores age-related memory deficits.
abstract: A decline in long-term memory (LTM) formation is a common feature of the normal aging process, which corresponds with abnormal expression of memory-related genes in the aged hippocampus. Epigenetic modulation of chromatin structure is required for proper transcriptional control of genes, such as the brain-derived neurotrophic factor (Bdnf) and Zif268 in the hippocampus during the consolidation of new memories. Recently, the view has emerged that aberrant transcriptional regulation of memory-related genes may be reflective of an altered epigenetic landscape within the aged hippocampus, resulting in memory deficits with aging. Here, we found that baseline resting levels for tri-methylation of histone H3 at lysine 4 (H3K4me3) and acetylation of histone H3 at lysine 9 and 14 (H3K9,K14ac) were altered in the aged hippocampus as compared to levels in the hippocampus of young adult rats. Interestingly, object learning failed to increase activity-dependent H3K4me3 and di-methylation of histone H3 at lysine 9 (H3K9me2) levels in the hippocampus of aged adults as compared to young adults. Treatment with the LSD-1 histone demethylase inhibitor, t-PCP, increased baseline resting H3K4me3 and H3K9,K14ac levels in the young adult hippocampus, while young adult rats exhibited similar memory deficits as observed in aged rats. After environmental enrichment (EE), we found that object learning induced increases in H3K4me3 levels around the Bdnf, but not the Zif268, gene region in the aged hippocampus and rescued memory deficits in aged adults. Collectively, these results suggest that histone lysine methylation levels are abnormally regulated in the aged hippocampus and identify histone lysine methylation as a transcriptional mechanism by which EE may serve to restore memory formation with aging.
authors.affiliation: Department of Neurobiology, The Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA. umbraphiles@gmail.com.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Morse
authors.affiliation: Department of Neurobiology, The Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA. aabutler@uab.edu.
authors.forename: Anderson A
authors.initials: AA
authors.lastname: Butler
authors.affiliation: Department of Neurobiology, The Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA. robinlynndavis@gmail.com.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davis
authors.affiliation: Department of Neurobiology, The Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA. ijsoller@uab.edu.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Soller
authors.affiliation: Department of Neurobiology, The Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA. flubin@uab.edu.
authors.forename: Farah D
authors.initials: FD
authors.lastname: Lubin
references.citation: Neuroscience. 2004;124(1):71-9
references.pmid: 14960340
references.citation: Mech Ageing Dev. 2011 May;132(5):240-8
references.pmid: 21530571
references.citation: Neurobiol Aging. 2003 Jul-Aug;24(4):615-26
references.pmid: 12714119
references.citation: J Neurosci. 2010 Mar 10;30(10):3589-99
references.pmid: 20219993
references.citation: Aging Cell. 2010 Dec;9(6):971-8
references.pmid: 20961390
references.citation: Nat Neurosci. 2000 Jun;3(6):533-5
references.pmid: 10816306
references.citation: J Neurosci. 2009 Feb 11;29(6):1805-16
references.pmid: 19211887
references.citation: Neuroscience. 2013 Sep 17;248:602-19
references.pmid: 23811393
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13427-31
references.pmid: 10557337
references.citation: J Neurosci. 2012 Apr 18;32(16):5440-53
references.pmid: 22514307
references.citation: J Biol Chem. 2004 Sep 24;279(39):40545-59
references.pmid: 15273246
references.citation: Neurobiol Learn Mem. 2008 Oct;90(3):511-8
references.pmid: 18675926
references.citation: ACS Chem Neurosci. 2012 Feb 15;3(2):120-128
references.pmid: 22754608
references.citation: Neurobiol Learn Mem. 2015 Feb;118:96-104
references.pmid: 25434818
references.citation: Neurobiol Aging. 2011 Dec;32(12):2198-210
references.pmid: 20189687
references.citation: Nat Neurosci. 2015 Feb;18(2):199-209
references.pmid: 25599223
references.citation: Rev Neurosci. 2013;24(4):375-87
references.pmid: 23729618
references.citation: Neuroscientist. 2011 Dec;17(6):616-32
references.pmid: 22130638
references.citation: Eur J Neurosci. 2004 Nov;20(10):2580-90
references.pmid: 15548201
references.citation: Front Behav Neurosci. 2007 Dec 30;1:6
references.pmid: 18958188
references.citation: Nat Protoc. 2006;1(3):1306-11
references.pmid: 17406415
references.citation: Neurobiol Aging. 2009 Apr;30(4):646-55
references.pmid: 17889407
references.citation: PLoS One. 2012;7(3):e33249
references.pmid: 22438904
references.citation: Neurobiol Aging. 2006 Oct;27(10):1405-15
references.pmid: 16183171
references.citation: Eur J Neurosci. 2011 May;33(10):1799-811
references.pmid: 21535455
references.citation: Neurobiol Learn Mem. 2011 Jul;96(1):68-78
references.pmid: 21419233
references.citation: Nature. 2007 May 10;447(7141):178-82
references.pmid: 17468743
references.citation: Neuroscience. 2003;122(3):647-57
references.pmid: 14622908
references.citation: Science. 2010 May 7;328(5979):753-6
references.pmid: 20448184
references.citation: Annu Rev Psychol. 1997;48:339-70
references.pmid: 9046563
references.citation: Behav Brain Res. 1989 Jun 1;33(2):197-207
references.pmid: 2765166
references.citation: Mol Cell Biol. 2010 Apr;30(8):1997-2005
references.pmid: 20123967
references.citation: J Neurosci. 2007 Mar 21;27(12):3098-110
references.pmid: 17376971
references.citation: J Neurosci. 2003 May 1;23(9):3807-19
references.pmid: 12736351
references.citation: Neuropharmacology. 2014 May;80:70-82
references.pmid: 24495398
references.citation: Front Aging Neurosci. 2010 Oct 14;2:140
references.pmid: 21048902
references.citation: Neurobiol Aging. 2012 May;33(5):1005.e1-10
references.pmid: 22035592
references.citation: J Neurosci. 2008 Oct 15;28(42):10576-86
references.pmid: 18923034
references.citation: Sheng Li Xue Bao. 2014 Oct 25;66(5):559-68
references.pmid: 25332001
references.citation: Neurobiol Learn Mem. 2014 Nov;115:116-27
references.pmid: 25130533
references.citation: Prog Brain Res. 2007;163:453-71
references.pmid: 17765733
references.citation: Hippocampus. 2011 Feb;21(2):127-32
references.pmid: 20232397