Abstract
The current longitudinal study examined factors (sex, physical function, response to novelty, ability to adapt to a shift in light/dark cycle, brain connectivity), which might predict the emergence of impaired memory during aging. Male and female Fisher 344 rats were tested at 6, 12, and 18 months of age. Impaired spatial memory developed in middle-age (12 months), particularly in males, and the propensity for impairment increased with advanced age. A reduced response to novelty was observed over the course of aging, which is inconsistent with cross-sectional studies. This divergence likely resulted from differences in the history of environmental enrichment/impoverishment for cross-sectional and longitudinal studies. Animals that exhibited lower level exploration of the inner region on the open field test exhibited better memory at 12 months. Furthermore, males that exhibited a longer latency to enter a novel environment at 6 months, exhibited better memory at 12 months. For females, memory at 12 months was correlated with the ability to behaviorally adapt to a shift in light/dark cycle. Functional magnetic resonance imaging of the brain, conducted at 12 months, indicated that the decline in memory was associated with altered functional connectivity within different memory systems, most notably between the hippocampus and multiple regions such as the retrosplenial cortex, thalamus, striatum, and amygdala. Overall, some factors, specifically response to novelty at an early age and the capacity to adapt to shifts in light cycle, predicted spatial memory in middle-age, and spatial memory is associated with corresponding changes in brain connectivity. We discuss similarities and differences related to previous longitudinal and cross-sectional studies, as well as the role of sex differences in providing a theoretical framework to guide future longitudinal research on the trajectory of cognitive decline. In addition to demonstrating the power of longitudinal studies, these data highlight the importance of middle-age for identifying potential predictive indicators of sexual dimorphism in the trajectory in brain and cognitive aging.
Highlights
Variability in cognitive function with age is due, in part, to a lifetime of differences in experiences
Since animals were healthy at 12 months, these animals were included in Functional Magnetic Resonance Imaging (fMRI) studies and multiple regressions of cognitive function at 12 months
The current study provides longitudinal analysis of age- and sexrelated changes in physical, psychological, and cognitive function
Summary
Variability in cognitive function with age is due, in part, to a lifetime of differences in experiences. Many tasks that involve repeated acquisition of rapidly acquired and flexible spatial information (e.g., spatial episodic or working memory) exhibit minimal carryover effects and longitudinal studies indicate that, similar to humans (Nyberg and Pudas, 2019), impaired memory emerges around middle-age in rats and mice (Ando and Ohashi, 1991; Forster and Lal, 1992; Vallee et al, 1999; Hartman et al, 2001; Markowska and Savonenko, 2002; Dellu-Hagedorn et al, 2004; Sabolek et al, 2004). The analysis of brain wide resting state functional connectivity in the rodent brain is facilitated by the use of network science algorithms, which provide insight on the topology of connectivity patterns under normal and disease states (Diaz-Parra et al, 2017)
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