Selective breeding for physical inactivity preference produces an Alzheimer's Disease-like phenotype in Wistar rats

Physical inactivity is the 4th leading cause of death globally and has been shown to significantly increase one’s risk for developing Alzheimer’s Disease (AD). A recent study by McGreevy et al. discovered that exercised father rats prior to breeding transfer heritable benefits to the brains of their offspring, suggesting that the physical activity status of previous generations could play an important role in one’s brain health and their subsequent risk for neurodegenerative diseases. Thus, this study aimed to address the effect of intergenerational physical inactivity on brain health. We utilized our selective breeding Wistar rat models of physical inactivity preference, termed Low Voluntary Runners (LVR), and high physical activity preference, High Voluntary Runners (HVR). We hypothesized that LVR would display cognitive deficits and an AD-like phenotype due to selecting for physical inactivity preference while HVR would demonstrate enhancements in cognition and an added resiliency against AD due to their high physical activity preference. First, we evaluated the animals’ innate cognitive status. Male and female wild-type (WT), LVR, and HVR Wistar rats kept in cages with no wheel access underwent cognitive behavioral testing at 3 months old followed by either mitochondrial respiration analysis via oroboros or molecular analysis of the hippocampus region of the brain via RT-PCR, western blotting, and immunohistochemistry (IHC). Cognitive behavioral testing demonstrated spatial memory deficits in LVR relative to WT; interestingly, these deficits were more prevalent in females than males. Behavioral testing results were associated with reductions in hippocampal mitochondrial respiration in female, but not male, LVR. Immunohistochemistry staining revealed that female LVR had fewer immature neurons in the dentate gyrus region of the hippocampus. This suggests that selecting for physical inactivity preference produced deficits in learning and memory, mitochondrial efficiency, and neurogenesis, all of which are hallmark signs of AD. Additionally, male LVR displayed signs of other AD risk factors like insulin resistance and obesity while female LVR appeared to be resistant to these effects. None of these deficits were present in HVR rats, as they performed as well as, or better than, WT. To the best of our knowledge, these findings provide the first evidence that physical inactivity has a heritable and detrimental effect on cognition, hippocampal plasticity, and insulin sensitivity. This emphasizes the importance of remaining physically active as chronic physical inactivity likely increases one’s susceptibility to neurodegenerative diseases like AD for both the inactive individual and their offspring. Self-funded by Dr. Frank Booth This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.