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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 restores memory formation in aged adults. (A) Aged adults experience a 5-week EE protocol prior to behavioral experiments. Age-matched non-enriched controls received similar handling procedures; (B) A Novelty discrimination index indicate that memory impairment in aged adults was rescued with EE. Object exploration during training and testing phases (NOR and OL) for non-enriched aged controls (C) and aged-enriched adults (D) are presented as the total duration, in seconds, of exploration. Objects 1 and 2 represent the sample objects during acquisition. During the retrieval phase, object 1 represents the familiar object or familiar object location. Group sizes NOR: Aged, n = 5; Aged + EE, n = 6; OL: Aged, n = 4; Aged + EE, n = 5. Student’s t-test; *p < 0.05 between indicated groups. *p < 0.05, **p < 0.01 between indicated groups. Error bars represent SEM.
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biology-04-00298-f006: Environmental enrichment restores memory formation in aged adults. (A) Aged adults experience a 5-week EE protocol prior to behavioral experiments. Age-matched non-enriched controls received similar handling procedures; (B) A Novelty discrimination index indicate that memory impairment in aged adults was rescued with EE. Object exploration during training and testing phases (NOR and OL) for non-enriched aged controls (C) and aged-enriched adults (D) are presented as the total duration, in seconds, of exploration. Objects 1 and 2 represent the sample objects during acquisition. During the retrieval phase, object 1 represents the familiar object or familiar object location. Group sizes NOR: Aged, n = 5; Aged + EE, n = 6; OL: Aged, n = 4; Aged + EE, n = 5. Student’s t-test; *p < 0.05 between indicated groups. *p < 0.05, **p < 0.01 between indicated groups. Error bars represent SEM.

Mentions: Aged adults were exposed to the modified EE protocol consisting of a variety of toys and social interaction for 1 h each day for a period of 5 weeks prior to exposure to the NOR and OL memory tasks (Figure 6A). Analysis of the discrimination index revealed that aged controls that did not receive EE demonstrated no preference for the novel object or novel location, which is characteristic of memory impairments (Figure 6B). Aged adults exposed to the EE showed a significant improvement over non-enriched controls in both NOR and OL memory tasks (Figure 6C,D).


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 restores memory formation in aged adults. (A) Aged adults experience a 5-week EE protocol prior to behavioral experiments. Age-matched non-enriched controls received similar handling procedures; (B) A Novelty discrimination index indicate that memory impairment in aged adults was rescued with EE. Object exploration during training and testing phases (NOR and OL) for non-enriched aged controls (C) and aged-enriched adults (D) are presented as the total duration, in seconds, of exploration. Objects 1 and 2 represent the sample objects during acquisition. During the retrieval phase, object 1 represents the familiar object or familiar object location. Group sizes NOR: Aged, n = 5; Aged + EE, n = 6; OL: Aged, n = 4; Aged + EE, n = 5. Student’s t-test; *p < 0.05 between indicated groups. *p < 0.05, **p < 0.01 between indicated groups. Error bars represent SEM.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4498301&req=5

biology-04-00298-f006: Environmental enrichment restores memory formation in aged adults. (A) Aged adults experience a 5-week EE protocol prior to behavioral experiments. Age-matched non-enriched controls received similar handling procedures; (B) A Novelty discrimination index indicate that memory impairment in aged adults was rescued with EE. Object exploration during training and testing phases (NOR and OL) for non-enriched aged controls (C) and aged-enriched adults (D) are presented as the total duration, in seconds, of exploration. Objects 1 and 2 represent the sample objects during acquisition. During the retrieval phase, object 1 represents the familiar object or familiar object location. Group sizes NOR: Aged, n = 5; Aged + EE, n = 6; OL: Aged, n = 4; Aged + EE, n = 5. Student’s t-test; *p < 0.05 between indicated groups. *p < 0.05, **p < 0.01 between indicated groups. Error bars represent SEM.
Mentions: Aged adults were exposed to the modified EE protocol consisting of a variety of toys and social interaction for 1 h each day for a period of 5 weeks prior to exposure to the NOR and OL memory tasks (Figure 6A). Analysis of the discrimination index revealed that aged controls that did not receive EE demonstrated no preference for the novel object or novel location, which is characteristic of memory impairments (Figure 6B). Aged adults exposed to the EE showed a significant improvement over non-enriched controls in both NOR and OL memory tasks (Figure 6C,D).

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