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Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.

ABSTRACT: Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape.

SUBMITTER: Castellano JF

PROVIDER: S-EPMC3305324 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.

Castellano James F JF Fletcher Bonnie R BR Kelley-Bell Bennett B Kim David H DH Gallagher Michela M Rapp Peter R PR

PloS one 20120315 3

Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant m ...[more]

PMID: 22438904

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Project description:The mechanisms underlying age-associated memory impairment are not well understood. We have shown that the onset of memory disturbances in the aging brain is associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation. To analyze if deregulated H4K12 acetylation impacts on learning-induced gene-expression required for memory consolidation we performed a high-density oligonucleotide microarray to compare the entire hippocampal gene-expression profile of 3 and 16-month-old mice during memory consolidation. In order to identify genes differentially regulated between 3- and 16-month old mice upon fear conditioning we subjected 3- and 16-month old mice to fear conditioning (4 mice each group, total 8 mice) . Mice of the same age that were handled but not subjected to any of the employed behavior paradigms served as control (4 mice 3-month old and 4 mice 16-month old, total 8 mice). During fear conditioning mice are subjected to a novel context followed by a mild electric foot-shock (context-shock exposure). In order to identify genes that are differentially regulated upon fear conditioning and are specific to associative learning we also tested the hippocampal gene-expression profile of 3-month old mice subjected to the same context-exposure that is not followed by a foot-shock (Context-exposure) (4 mice) or receive an immediate foot shock once they are placed in the context and only afterwards are allowed to explore the context (shock-context exposure) (4 mice). In order to identify genes that are regulated upon fear conditioning and are specific to associative learning we compared the hippocampal gene-expression profile of mice subjected to fear conditioning (context-shock), context or shock-context exposure regarding to their age-matched control mice (3 month old) mentioned above (control). Hippocampi from each mice were tested resulting to 24 samples which were separately hybridized (OneColor Array Design).

Project description:Aging is a progressive functional decline characterized by a gradual deterioration in physiological function and behavior. The most important age-related change in cognitive function is decline in cognitive performance (i.e., the processing or transformation of information to make decisions that includes speed of processing, working memory, and learning). The purpose of this study is to outline the changes in age-related cognitive performance (i.e., short-term recognition memory and long-term learning and memory) in long-lived Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects makes it a unique animal model for exploring the mechanisms underlying the behavioral and cognitive deficits related to natural aging. In this study, we examined young adult female degus (12- and 24-months-old) and aged female degus (38-, 56-, and 75-months-old) that were exposed to a battery of cognitive-behavioral tests. Multivariate analyses of data from the Social Interaction test or Novel Object/Local Recognition (to measure short-term recognition memory), and the Barnes maze test (to measure long-term learning and memory) revealed a consistent pattern. Young animals formed a separate group of aged degus for both short- and long-term memories. The association between the first component of the principal component analysis (PCA) from short-term memory with the first component of the PCA from long-term memory showed a significant negative correlation. This suggests age-dependent differences in both memories, with the aged degus having higher values of long-term memory ability but poor short-term recognition memory, whereas in the young degus an opposite pattern was found. Approximately 5% of the young and 80% of the aged degus showed an impaired short-term recognition memory; whereas for long-term memory about 32% of the young degus and 57% of the aged degus showed decreased performance on the Barnes maze test. Throughout this study, we outlined age-dependent cognitive performance decline during natural aging in degus. Moreover, we also demonstrated that the use of a multivariate approach let us explore and visualize complex behavioral variables, and identified specific behavioral patterns that allowed us to make powerful conclusions that will facilitate further the study on the biology of aging. In addition, this study could help predict the onset of the aging process based on behavioral performance.

Dataset Information

Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.

Publications

Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.

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