HIPPOCAMPAL DNA METHYLATION, EPIGENETIC AGE AND SPATIAL MEMORY PERFORMANCE IN YOUNG AND OLD RATS

CHIAVELLINI, PRISCILA; MARIANNE LEHMANN; MARTINA CANATELLI MALLAT; JOSEPH A. ZOLLER; CLAUDIA B. HERENU3; GUSTAVO R. MOREL; STEVE HORVATH; GOYA, RODOLFO G.

JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES

GERONTOLOGICAL SOC AMER

Año: 2022

1079-5006

In humans and rats, aging is associated with a progressive deterioration of spatiallearning and memory. These functional alterations are correlated with morphologicaland molecular changes in the brain, particularly in the hippocampus. Here, we assessedage-related changes in DNA methylation (DNAm) landscape in the rat hippocampusand the correlation of spatial memory with hippocampal DNAm age in 2.6 months and26.6 months old rats. Spatial memory performance was assessed with the Barnes mazetest. In order to evaluate learning ability as well as spatial memory retention, weassessed the time spent by animals in goal sector 1 (GS1) and 3 (GS3) when the escapebox was removed. The rat pan-tissue clock was applied to DNA methylation data fromhippocampal tissue. An enrichment pathway analysis revealed that neuron fatecommitment, brain development, and central nervous system development wereprocesses whose underlying genes were enriched in positively methylated CpGs. In theold rat hippocampi, the methylation levels of CpGs proximal to transcription factorsassociated with genes Pax5, Lbx1, Nr2f2, Hnf1b, Zic1, Zic4, Hoxd9; Hoxd10, Gli3,Gsx1 and Lmx1b, and Nipbl showed a significant regression with spatial memoryperformance. Regression analysis of different memory performance indices withhippocampal DNAm age was significant These results suggest that age-relatedhypermethylation of transcription factors related to certain gene families, like Zic andGli, may play a causal role in the decline in spatial memory in old rats. HippocampalDNAm age seems to be a reliable index of spatial memory performance in young andold rats.