Hippocampal DNA Methylation, Epigenetic Age and Spatial Memory Performance in Young And Old Rats

LEHMANN, MARIANNE; HERENU, CLAUDIA B; GOYA, RODOLFO G; CANATELLI MALLAT, MARTINA; MOREL, GUSTAVO R; CHIAVELLINI, PRISCILA; ZOLLER, JOSEPH A; HORVATH, STEVE

JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES

GERONTOLOGICAL SOC AMER

Año: 2022

1079-5006

ABSTRACTIn humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the hippocampus. Here, we assessed age-related changes in DNA methylation (DNAm) landscape in the rat hippocampus and the correlation of spatial memory with hippocampal DNAm age in 2.6 months and 26.6 months old rats. Spatial memory performance was assessed with the Barnes maze test. In order to evaluate learning ability as well as spatial memory retention, we assessed the time spent by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. The rat pan-tissue clock was applied to DNA methylation data from hippocampal tissue. An enrichment pathway analysis revealed that neuron fate commitment, brain development, and central nervous system development were processes whose underlying genes were enriched in hypermethylated CpGs in the old rats. In the old rat hippocampi, the methylation levels of CpGs proximal to transcription factors associated with genes Pax5, Lbx1, Nr2f2, Hnf1b, Zic1, Zic4, Hoxd9; Hoxd10, Gli3, Gsx1 and Lmx1b, and Nipbl showed a significant regression with spatial memory performance. Regression analysis of different memory performance indices with hippocampal DNAm age was significant These results suggest that age-related hypermethylation of transcription factors related to certain gene families, like Zic and Gli, may play a causal role in the decline in spatial memory in old rats. Hippocampal DNAm age seems to be a reliable index of spatial memory performance in young and old rats.Keywords: Aging - Hippocampus- Spatial memory - Methylation landscape - DNAm age