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

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $248,888

## Abstract

PROJECT SUMMARY
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 to the
contextual fear conditioning test. Comparisons will be prioritized to those DEGs that differ exclusively between
WMI females of 6- and 12-months of age. The WMI and WLI genome have been sequenced and will serve
as the reference genomes for these analyses. Expression of DEGs within differentially methylated regions
will be measured by quantitative RT-PCR in the hippocampus of young and middle-aged male and female
WMIs and WLIs with and without enriched environment housing from 6 to 12 months of age (Aim 1) to identify
changes induced by age and EE. Candidate DEGs will also be measured in the hippocampi of all animals
from Aim 2, when expression data of DEGs will be associated with contextual fear memory in the same
animals. Prediction models for memory will be built using the obtained and confirmed DEGs and methylation
data.

## Key facts

- **NIH application ID:** 9895135
- **Project number:** 1R21AG062968-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Eva E Redei
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,888
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895135

## Citation

> US National Institutes of Health, RePORTER application 9895135, Molecular Targets of Aging-Triggered Memory Decline in a Stress-Reactive Rat Strain (1R21AG062968-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9895135. Licensed CC0.

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