Early onset memory deficit of WMI rats compared to their nearly isogenic WLIs is reversed by enriched environment in females.

Unlabelled: We tested the hypothesis that environmental enrichment (EE) can attenuate early-onset cognitive decline in a stress-hyperresponsive rat strain. The novel genetic model, the Wistar Kyoto More Immobile (WMI) inbred rat strain demonstrates increased stress reactivity and enhanced depression-like behavior compared to its nearly isogenic control, the Wistar Kyoto Less Immobile strain (WLI). Middle-aged (12 months) WMI females exhibited diminished fear, and spatial memory in the contextual fear conditioning and Morris Water Maze paradigms, respectively, compared to young animals (6 months) of both strains and to middle-aged WLIs. Middle-aged WMI males showed a lesser age-induced deficit. EE from six to 12 months of age reversed these memory deficits in middle-aged WMI females and attenuated them in WMI males. Plasma levels of estradiol followed the same pattern as memory in WMI females following EE. RNA sequencing from female hippocampi revealed significant strain, age, and enrichment-induced differentially expressed genes. Among these, solute carrier family 35, member A4 ( ) and potassium inwardly rectifying channel, subfamily J, member 2 ( ) 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.

Highlights: Heightened innate stress response and depression leads to early onset memory declineEnriched environment reverses memory decline of middle-aged femalesEnriched environment also reverses declining estrogen levels of middle-aged femalesMitochondrial dysfunction may underly mid-life cognitive and molecular changes.