Integration of electrophysiological and transcriptomic signatures of cognitive resilience in the hippocampus using patch-seq

As we age, most individuals will experience normal declines in cognitive abilities, including memory. These changes are a natural part of aging and are not associated with pathological causes of memory impairment or cognitive decline. However, rates of cognitive aging differ among individuals, with some people exhibiting high levels of cognitive function even late in life — a phenomenon known as “cognitive resilience,” where cognitive function is better than predicted based on a person’s chronological age. While the causes of age-related cognitive decline are largely unknown, heritability estimates indicate there is a strong influence of yet-to-be-identified genetic factors in age-related cognitive resilience. Identification of these factors represents an opportunity to develop new therapeutic approaches to enhance and preserve cognitive function in aging individuals. As the population ages, the need for such interventions becomes increasingly urgent, but efforts to understand the mechanisms governing cognitive resilience in humans has been limited by a lack of access to brain tissue from successful aging humans as well as longitudinal measures of cognitive function across the lifespan. Model organisms such as mice represent a powerful tool to interrogate the underlying genetic and molecular mechanisms governing cognitive resilience, but most models fail to capture the natural genetic variation existing in human populations, limiting translational applicability.