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

Area of Science:

• Neuroscience
• Genetics
• Aging Research

Background:

• Maintaining cognitive health is crucial for quality of life during aging.
• Cognitive reserve and resilience are key factors in healthy cognitive aging but are poorly understood.
• Inconsistent definitions and lack of longitudinal data hinder understanding of cognitive reserve and resilience mechanisms.

Purpose of the Study:

• To characterize individual differences in cognitive abilities in a genetically diverse mouse population.
• To investigate evidence of cognitive reserve and/or resilience in middle-aged mice.
• To identify molecular mechanisms underlying cognitive variation and age-related cognitive decline.

Main Methods:

• Utilized a genetically diverse mouse population (B6-BXDs).
• Assessed cognitive function at two ages (6 and 14 months) using y-maze and contextual fear conditioning.
• Employed RNA-sequencing to identify gene networks associated with cognitive traits and decline.

Main Results:

• Observed significant heritable variation in cognitive performance (h² = 0.51–0.74).
• Identified gene networks related to transcription, metabolism, and neuronal function associated with cognitive performance and decline.
• Nominated the Trio gene as a modulator of working memory ability.

Conclusions:

• Cognitive performance and age-related decline exist on a continuum, without clear exceptional genotypes for reserve or resilience in this model.
• Early cognitive reserve can protect against later cognitive impairment.
• Further studies using aging mouse populations are recommended to elucidate the nature of cognitive reserve and resilience.