Early Onset Memory Deficit of WMI Rats Compared to Their Nearly Isogenic WLIs Is Reversed by Enriched Environment in Females.

The underlying mechanisms of early onset memory deficit remain poorly understood. We tested the hypothesis that environmental enrichment (EE) can attenuate early-onset cognitive decline in a novel genetic model, the Wistar Kyoto More Immobile (WMI) inbred rat strain, which manifests the risk factors of enhanced stress reactivity and depression-like behavior compared to its nearly isogenic control, the Wistar Kyoto Less Immobile strain (WLI). Middle-aged (12 months) WMI females exhibited dramatically diminished fear and spatial memory in the contextual fear conditioning and Morris Water Maze paradigms, respectively, compared to young females of both strains and to middle-aged WLI females. Middle-aged WMI males showed a lesser, but significant, age-induced deficit. EE from 6 to 12 months of age completely reversed the memory deficits in middle-aged WMI females and reversed age-induced decreases in plasma levels of estradiol. RNA sequencing from female hippocampi revealed significant strain, age, and enrichment-induced differentially expressed genes. Among these, solute carrier family 35, member A4 (Slc35a4) and potassium inwardly rectifying channel, subfamily J, member 2 (Kcnj2) were confirmed to show hippocampal expression changes parallel to that of memory in the WMI. These genes have critical roles in the integrated stress response, cellular metabolism, and the effects of stress on neurovascular coupling, respectively. Pathway analyses revealed the involvement of oxidative phosphorylation and mitochondrial dysfunction in the hippocampal processes of aging and EE-induced reversal. These findings underscore the critical involvement of molecular stress responses in early-onset memory decline and suggest potential therapeutic targets for age-related cognitive impairment.