Age-Related Memory Impairment Is Associated with Disrupted Multivariate Epigenetic Coordination in the Hippocampus

被引:60
作者
Castellano, James F. [1 ,2 ]
Fletcher, Bonnie R. [1 ]
Kelley-Bell, Bennett [1 ]
Kim, David H. [1 ]
Gallagher, Michela [3 ]
Rapp, Peter R. [1 ]
机构
[1] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA
[2] Mt Sinai Sch Med, Grad Program Neurosci, New York, NY USA
[3] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD USA
基金
美国国家卫生研究院;
关键词
SPATIAL-LEARNING IMPAIRMENT; GYRUS GRANULE NEURONS; LONG-TERM-MEMORY; SYNAPTIC PLASTICITY; TRANSCRIPTIONAL ACTIVATION; HISTONE ACETYLATION; RAT HIPPOCAMPUS; PHOSPHORYLATION; INHIBITORS; INDUCTION;
D O I
10.1371/journal.pone.0033249
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:11
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