Environmental Enrichment Reverses Histone Methylation Changes in the Aged Hippocampus and Restores Age-Related Memory Deficits

Morse, Sarah; Butler, Anderson A.; Davis, Robin L.; Soller, Ian J.; Lubin, Farah D.

doi:10.3390/biology4020298

Cited by 57 publications

(60 citation statements)

References 42 publications

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“…Although enrichment failed to protect learning against age-related deficit, it alleviated the deficit in short-term memory exhibited by SC aged rats. Thus, late enriched environment exposure mitigates age-related deficit, in agreement with previous studies (e.g., Kobayashi et al 2002;Harburger et al 2007;Freret et al 2012;Kumar et al 2012;Morse et al 2015;Fuchs et al 2016;but Bouet et al 2011). The present results also showed that, although EE young adults outperformed SC young adults on a measure of platform-search accuracy (annulus crossing), enrichment had no beneficial effects on the recent memory probe trial in aged subjects.…”

Section: Spatial Memory Is Impaired In Aged Rats Housed In Standard Csupporting

confidence: 92%

Late enrichment maintains accurate recent and remote spatial memory only in aged rats that were unimpaired when middle aged

et al. 2016

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Exposure of rodents to a stimulating environment has beneficial effects on some cognitive functions that are impaired during physiological aging, and especially spatial reference memory. The present study investigated whether environmental enrichment rescues these functions in already declining subjects and/or protects them from subsequent decline. Subgroups of 17-mo-old female rats with unimpaired versus impaired performance in a spatial reference memory task (Morris water maze) were housed until the age of 24 mo in standard or enriched environment. They were then trained in a second reference memory task, conducted in a different room than the first, and recent (1 d) and remote (10 d) memory were assessed. In unimpaired subgroups, spatial memory declined from 17 to 24 mo in rats housed in standard conditions; an enriched environment during this period allowed maintenance of accurate recent and remote spatial memory. At 24 mo, rats impaired at the age of 17 mo housed in enriched environment learned the task and displayed substantial recent memory, but their performance remained lower than that of unimpaired rats, showing that enrichment failed to rescue spatial memory in already cognitively declining rats. Controls indicated carryover effects of the first water maze training, especially in aged rats housed in standard condition, and confirmed the beneficial effect of enrichment on remote memory of aged rats even if they performed poorly than young adults housed for the same duration in standard or enriched condition.

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Section: Spatial Memory Is Impaired In Aged Rats Housed In Standard Csupporting

confidence: 92%

Late enrichment maintains accurate recent and remote spatial memory only in aged rats that were unimpaired when middle aged

et al. 2016

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“…Combined with evidence for H3.3 accumulation, our data suggest that histone subunit composition of nucleosomes is altered with age, which may have broad effects on surrounding chromatin. For example, H2A.Z tends to occupy nucleosomes containing distinct H3 modifications compared to canonical H2A (Sevilla and Binda, 2014), such that age-related shifts in H2A.Z may be accompanied by shifts in other histone marks, many of which are also altered in aged mice (Peleg et al, 2010, Walker et al, 2013, Morse et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus

et al. 2018

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Summary Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal H2A.Z occupancy is positively associated with steady-state transcription, whereas learning-induced H2A.Z removal is associated with learning-induced gene expression. AAV-mediated H2A.Z depletion enhanced fear memory and resulted in gene-specific alterations of learning-induced transcription, reinforcing the role of H2A.Z as a memory suppressor. H2A.Z accumulated with age, although it remained sensitive to learning-induced eviction. Learning-related H2A.Z removal occurred at largely distinct genes in young vs old mice, suggesting that H2A.Z is subject to regulatory shifts in the aged brain despite similar memory performance. When combined with prior evidence of H3.3 accumulation in neurons, our data suggest that nucleosome composition in the brain is reorganized with age.

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“…In the context of aging and neurodegenerative conditions, histone acetylation has been extensively studied and is unmistakably associated with facilitating learning and memory (Mai et al, 2009;Gräff et al, 2012). On the other hand, changes in histone methylation states in the brain, relative to cognitive functions, is a relatively unexplored area of research (Gupta et al, 2010;Jarome and Lubin, 2014;Morse et al, 2015). Methylation of the histone tail typically occurs at specific lysine (K) residues, such as H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20, and can either activate or repress transcription (Vakoc et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus

et al. 2016

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An increasing number of studies show that an altered epigenetic landscape may cause impairments in regulation of learning and memory-related genes within the aged hippocampus, eventually resulting in cognitive deficits in the aged brain. One such epigenetic repressive mark is trimethylation of H3K9 (H3K9me3), which is typically implicated in gene silencing. Here, we identify, for the first time, an essential role for H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions. Pharmacological inhibition of SUV39H1 using a novel and selective inhibitor decreased levels of H3K9me3 in the hippocampus of aged mice, and improved performance in the objection location memory and fear conditioning tasks and in a complex spatial environment learning task. The inhibition of SUV39H1 induced an increase in spine density of thin and stubby but not mushroom spines in the hippocampus of aged animals and increased surface GluR1 levels in hippocampal synaptosomes, a key index of spine plasticity. Furthermore, there were changes at BDNF exon I gene promoter, in concert with overall BDNF levels in the hippocampus of drug-treated animals compared with control animals. Together, these data demonstrate that SUV39H1 inhibition and the concomitant H3K9me3 downregulation mediate gene transcription in the hippocampus and reverse age-dependent deficits in hippocampal memory.

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Environmental Enrichment Reverses Histone Methylation Changes in the Aged Hippocampus and Restores Age-Related Memory Deficits

Cited by 57 publications

References 42 publications

Late enrichment maintains accurate recent and remote spatial memory only in aged rats that were unimpaired when middle aged

Late enrichment maintains accurate recent and remote spatial memory only in aged rats that were unimpaired when middle aged

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus

H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus

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