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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Early-onset memory deficits are poorly understood.
• Wistar Kyoto More Immobile (WMI) rats exhibit stress reactivity and depression-like behaviors, serving as a model for cognitive decline.
• WMI females show significant memory impairment with age compared to controls.

Purpose of the Study:

• To test if environmental enrichment (EE) can attenuate early-onset cognitive decline in WMI rats.
• To investigate the molecular mechanisms underlying memory deficits and EE's effects.
• To identify potential therapeutic targets for age-related cognitive impairment.

Main Methods:

• Utilized Wistar Kyoto More Immobile (WMI) and Less Immobile (WLI) rat strains.
• Assessed memory using contextual fear conditioning and Morris Water Maze.
• Administered environmental enrichment (EE) from 6 to 12 months of age.
• Analyzed hippocampal gene expression via RNA sequencing and confirmed specific gene changes (Slc35a4, Kcnj2).

Main Results:

• Middle-aged WMI females displayed significant fear and spatial memory deficits.
• EE completely reversed memory deficits in middle-aged WMI females and normalized estradiol levels.
• RNA sequencing identified strain, age, and enrichment-dependent gene expression changes in the hippocampus.
• Slc35a4 and Kcnj2 expression correlated with memory performance and EE effects.
• Pathway analysis implicated oxidative phosphorylation and mitochondrial dysfunction.

Conclusions:

• Environmental enrichment effectively reverses early-onset memory decline in the WMI rat model.
• Molecular stress responses and mitochondrial function are critical in early-onset memory deficits.
• Slc35a4 and Kcnj2 represent potential therapeutic targets for cognitive impairment.