Sex-dependent variations in voluntary exercise of 14-month-old 3xTgAD mice associated with novelty inhibition

Alzheimer’s Disease (AD) patients suffer from circadian rhythm alterations involving sleep, thermoregulation, and movement activity disorders. The latter affects their daily patterns of physical activity (PA) and willingness to perform voluntary exercise, impeding benefit from routine PA practice. Neuropsychiatric symptoms (NPS) have been postulated to influence human physical activity engagement. However, there is no clarity on whether animal models can replicate these effects. Here, we evaluated the behavioral circadian rhythmicity of voluntary physical exercise (VPE) in a group of 14-month-old 3xTg-AD animals of both sexes at advanced stages of the disease and compared their performance according to the presence of NPS-like symptoms. Mice (n=9 females and n=7 males) were provided with an in-cage running wheel for 30 days with daily control of the diurnal and nocturnal amount of VPE performed. Using a Linear Mixed Model Analysis, we found that all animals kept similar nocturnal patterns of VPE. However, sex-dependent differences associated with previous novelty inhibition (NI) response, an NPS-like symptom frequently observed in this model, were found during diurnal periods. Thus, males with high NI showed significantly higher levels of VPE compared with high NI females. No sex differences were found in low NI animals. Our results suggest that the influence of NPS-like symptoms in VPA engagement may vary depending on the sex of 3xTg-AD mice. Further studies are needed to help elucidate molecular and genetic factors associated with these differences.