Limits...
Environmental enrichment reverses histone methylation changes in the aged hippocampus and restores age-related memory deficits.

Morse SJ, Butler AA, Davis RL, Soller IJ, Lubin FD - Biology (Basel) (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Environmental enrichment elevates H3K4me3 methylation levels at the Bdnf gene in the aged hippocampus. (A) Object Learning increases Bdnf mRNA level in the hippocampus of EE aged adults (n = 4) relative to non-enriched aged adults (n = 5); (B) ChIP analysis revealed EE dependent increases in H3K4me3 levels at the Bdnf promoter 4 during memory formation; Group sizes for (B): Aged-Trained, n = 4; EE + Aged-trained, n = 3. Student’s t-test; *p < 0.05 compared to non-enriched aged-trained adults. Data are shown ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4498301&req=5

biology-04-00298-f007: Environmental enrichment elevates H3K4me3 methylation levels at the Bdnf gene in the aged hippocampus. (A) Object Learning increases Bdnf mRNA level in the hippocampus of EE aged adults (n = 4) relative to non-enriched aged adults (n = 5); (B) ChIP analysis revealed EE dependent increases in H3K4me3 levels at the Bdnf promoter 4 during memory formation; Group sizes for (B): Aged-Trained, n = 4; EE + Aged-trained, n = 3. Student’s t-test; *p < 0.05 compared to non-enriched aged-trained adults. Data are shown ± SEM.

Mentions: We next assessed the effect of EE on expression of the memory permissive genes Bdnf and Zif268 in laser capture microdissection (LCM)-captured pyramidal neurons from area CA1. Prior to object learning aged animals were divided into two separate groups, one group experienced the 5-week EE protocol and the other group served as non-enriched aged controls. At 1 h after object training, we found that EE significantly increased Bdnf, but not Zif268, mRNA levels in LCM-captured pyramidal neurons from area CA1 during memory formation (Figure 7A; t(7) = 2.923, p < 0.05).


Environmental enrichment reverses histone methylation changes in the aged hippocampus and restores age-related memory deficits.

Morse SJ, Butler AA, Davis RL, Soller IJ, Lubin FD - Biology (Basel) (2015)

Environmental enrichment elevates H3K4me3 methylation levels at the Bdnf gene in the aged hippocampus. (A) Object Learning increases Bdnf mRNA level in the hippocampus of EE aged adults (n = 4) relative to non-enriched aged adults (n = 5); (B) ChIP analysis revealed EE dependent increases in H3K4me3 levels at the Bdnf promoter 4 during memory formation; Group sizes for (B): Aged-Trained, n = 4; EE + Aged-trained, n = 3. Student’s t-test; *p < 0.05 compared to non-enriched aged-trained adults. Data are shown ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4498301&req=5

biology-04-00298-f007: Environmental enrichment elevates H3K4me3 methylation levels at the Bdnf gene in the aged hippocampus. (A) Object Learning increases Bdnf mRNA level in the hippocampus of EE aged adults (n = 4) relative to non-enriched aged adults (n = 5); (B) ChIP analysis revealed EE dependent increases in H3K4me3 levels at the Bdnf promoter 4 during memory formation; Group sizes for (B): Aged-Trained, n = 4; EE + Aged-trained, n = 3. Student’s t-test; *p < 0.05 compared to non-enriched aged-trained adults. Data are shown ± SEM.
Mentions: We next assessed the effect of EE on expression of the memory permissive genes Bdnf and Zif268 in laser capture microdissection (LCM)-captured pyramidal neurons from area CA1. Prior to object learning aged animals were divided into two separate groups, one group experienced the 5-week EE protocol and the other group served as non-enriched aged controls. At 1 h after object training, we found that EE significantly increased Bdnf, but not Zif268, mRNA levels in LCM-captured pyramidal neurons from area CA1 during memory formation (Figure 7A; t(7) = 2.923, p < 0.05).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus