Identifying Mechanisms of Normal Cognitive Aging Using a Novel Mouse Genetic Reference Panel.

Amy R Dunn,Logan Dumitrescu,Kristen M S O’Connell,Jeremy H Herskowitz,Ji-Gang Zhang,Vivek M Philip,Niran Hadad,Timothy J Hohman,Sarah M Neuner,Catherine C Kaczorowski

doi:10.3389/fcell.2020.562662

Abstract

Developing strategies to maintain cognitive health is critical to quality of life during aging. The basis of healthy cognitive aging is poorly understood; thus, it is difficult to predict who will have normal cognition later in life. Individuals may have higher baseline functioning (cognitive reserve) and others may maintain or even improve with age (cognitive resilience). Understanding the mechanisms underlying cognitive reserve and resilience may hold the key to new therapeutic strategies for maintaining cognitive health. However, reserve and resilience have been inconsistently defined in human studies. Additionally, our understanding of the molecular and cellular bases of these phenomena is poor, compounded by a lack of longitudinal molecular and cognitive data that fully capture the dynamic trajectories of cognitive aging. Here, we used a genetically diverse mouse population (B6-BXDs) to characterize individual differences in cognitive abilities in adulthood and investigate evidence of cognitive reserve and/or resilience in middle-aged mice. We tested cognitive function at two ages (6 months and 14 months) using y-maze and contextual fear conditioning. We observed heritable variation in performance on these traits (h2RIx̄ = 0.51–0.74), suggesting moderate to strong genetic control depending on the cognitive domain. Due to the polygenetic nature of cognitive function, we did not find QTLs significantly associated with y-maze, contextual fear acquisition (CFA) or memory, or decline in cognitive function at the genome-wide level. To more precisely interrogate the molecular regulation of variation in these traits, we employed RNA-seq and identified gene networks related to transcription/translation, cellular metabolism, and neuronal function that were associated with working memory, contextual fear memory, and cognitive decline. Using this method, we nominate the Trio gene as a modulator of working memory ability. Finally, we propose a conceptual framework for identifying strains exhibiting cognitive reserve and/or resilience to assess whether these traits can be observed in middle-aged B6-BXDs. Though we found that earlier cognitive reserve evident early in life protects against cognitive impairment later in life, cognitive performance and age-related decline fell along a continuum, with no clear genotypes emerging as exemplars of exceptional reserve or resilience – leading to recommendations for future use of aging mouse populations to understand the nature of cognitive reserve and resilience.

Highlights

Cognitive decline with age, even in the absence of overt dementia, is common and highly heritable (Dutta et al, 2014; Reynolds and Finkel, 2015)
Cognitive function in old age is an important predictor of quality of life (Pan et al, 2011, 2015), and developing strategies to improve cognitive longevity will be critical as life expectancy continues to increase through modern medicine
Quantitative trait locus (QTL) mapping revealed no single locus controlling a significant proportion of the variance on performance on y-maze at either 6 months or 14 months of age (Figure 2C), or combined with age as a covariate

Summary

Introduction

Even in the absence of overt dementia, is common and highly heritable (Dutta et al, 2014; Reynolds and Finkel, 2015). Given the lack of longitudinal molecular data, and to a lesser extent, longitudinal cognitive data from human populations, it remains unclear if the mechanisms underlying baseline cognitive function mediate normal cognitive aging These factors are highly complex and poorly understood, despite extensive study (Harris and Deary, 2011; Bis et al, 2012; De Jager et al, 2012; Davies et al, 2014; Mukherjee et al, 2014; Zhang and Pierce, 2014; Debette et al, 2015; Lu et al, 2017; Raj et al, 2017; Tasaki et al, 2018; Yen et al, 2018; Kamboh et al, 2019; Wingo et al, 2019). Discovering highimpact targets for bolstering baseline cognitive function and enhancing cognitive longevity will facilitate the development of pharmacotherapeutics to enhance cognitive health in middleage and beyond

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Conclusion