Mapping genetic vulnerability to oxidative stress in development and its consequences in age-associated cognitive decline using a novel reduced complexity rat model

University Of Tennessee Health Sci Ctr, Memphis TN

Investigators

Abstract

ABSTRACT In this proposal we test the novel hypothesis that intrinsic cellular vulnerability to oxidative stress (OS) contributes to premature cognitive decline and is an important determinant of cognitive health over the lifespan. OS is known to increase with age and is also associated with Alzheimer’s Disease (AD) and dementia. However, the molecular mechanisms underlying these associations are not well understood. Moreover, we know little about which cell types, molecular processes, and genotypes are the most vulnerable to the detrimental effects of OS on cognitive function across the lifespan. This lack of knowledge may be one reason why current treatments for AD-related dementia and age-associated cognitive decline (e.g., acetylcholinesterase inhibitors and NMDA receptor antagonists) have disappointing efficacy and are unsuitable for early intervention. To overcome these barriers, we leverage a novel genetic rat model developed by our group, the Wistar Kyoto More Immobile (WMI) inbred rat strain and its nearly isogenic control, the Wistar Kyoto Less Immobile strain (WLI). The WMI strain demonstrates increased stress reactivity and enhanced depression-like behavior compared to the WLI strain. Only ~4,300 sequence variants distinguish both genomes creating an ideal genetic model system to identify the contribution of naturally occurring genetic variation to phenotypic differences between strains while still modeling some of the genetic diversity found in human populations. We have recently demonstrated that the WMI strain exhibits higher intrinsic vulnerability to OS relative to the WLI strain. This vulnerability can be detected early in development at embryonic day 18 (E18) in hippocampus-derived astrocytes and neurons. We also showed that, relative to the less vulnerable WLI strain, the WMI strain exhibits premature cognitive decline at midlife that can be reversed by exposure to an Enriched Environment (EE) and exacerbated early in life by Repeated Stress (RS) exposure. We hypothesize that intrinsic genetic vulnerability to OS in WMI, which can be detected early in life at E18, contributes to cognitive function during aging and across different environmental exposures. We test our hypothesis in two aims. In Aim 1 we leverage our efficient reduced complexity model to identify cell populations and molecular pathways most vulnerable to OS and identify the causal gene variant meditating intrinsic vulnerability to OS early in life and cognitive decline later in life. In Aim 2 we quantify Gene x Environment (GxE) interactions in our model to define a set of cellular, epigenetic, and molecular features important for cognitive function as well as a detailed map of how these features contribute to memory performance as a function of age, environmental exposure, sex, and genotype.