Molecular Targets of Aging-Triggered Memory Decline in a Stress-Reactive Rat Strain

Project: Research project

Project Details

Description

In addition to aging, major risk factors for cognitive decline include female gender, stress, and stress-related disorders such as depression. Both major depressive disorder (MDD) and dementia are more common in women than in men. In this proposal, we aim to investigate the sex and strain-specific epigenetic changes that parallel cognitive decline in an animal model of increased stress-reactivity and depression-like traits. Through selective and long-term full-sib breeding, we obtained two inbred strains from the parental Wistar Kyoto (WKY) rat strain: the WKY More Immobile (WMI), and its isogenic control, the WKY Less Immobile (WLI). Compared to WLIs, both male and female WMIs show consistently greater despair-like behavior in the forced swim test. Hippocampus-dependent contextual fear memory did not differ between young WLI and WMI males and females. However, by 12 months of age (middle-age), female WMIs showed a significant decline in fear memory compared to young WMI females, while no decrease in fear memory was observed in female WLIs and male WLIs and WMIs. We propose to test the hypothesis that age-induced strain-specific changes in the hippocampal methylome and transcriptome of female WMIs are associated with the decline in their fear memory. Aim 1 will evaluate the sex-specific strain differences between young (6 months) and middle-aged (12 months) WMI and WLI in the contextual fear conditioning, novel object recognition and Morris water maze paradigms. Additionally, WMI and WLI males and females will be maintained from 6 to 12 months of age in an enriched environment (EE), that is known to enhance memory, and at 12 months of age tested in the same learning/memory tests. Aim 2 will identify differentially expressed genes (DEG) within differentially methylated regions using integrative analysis of Reduced Representation Bisulfite Sequencing and RNA-seq between additional groups of young and middle-aged WMI and WLI males and females after being exposed t
StatusFinished
Effective start/end date9/15/208/31/22

Funding

  • National Institute on Aging (1R21AG062968-01A1)

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