c79be5b70c985e6bb760c5b1d8bc348f 269302.pdf fe28c3f2f9801c622ff97e53b73a7306eb9aa9b9 269302.pdf 7fa3454df06d2e58654a92bcc4a2f103b3beab57ab695c2b6645fcada54bc5b3 269302.pdf Title: Sex- and Neuropsychiatric-Dependent Circadian Alterations in Daily Voluntary Physical Activity Engagement and Patterns in Aged 3xTg-AD Mice Subject: Alzheimer’s disease (AD) patients suffer from circadian rhythm alterations affecting their daily physical activity patterns with less willingness to perform a voluntary exercise. In preclinical studies, there is no clarity on whether animal models of AD can replicate these impairments. Here, we provide a proof of concept of the performance and behavioral effects of four weeks of voluntary wheel running (VWR) in a group of 14-month-old male and female 3xTg-AD mice at advanced stages of AD and the daily variance (behavioral circadian rhythmicity) of VWR associated with sex and their neuropsychiatric-like phenotype. Higher levels of horizontal exploration in the open field (OF) test were found in mice submitted to exercise. A linear mixed effect model showed significant sex-dependent differences in the VWR activity performed on the first night of follow-up, with high-NIBI males running less than high-NIBI females. Thus, an influence of NPS-like symptoms on the circadian patterns of VWR may account for such differences. In addition, males remained more active than females during diurnal periods. We hypothesize that this increment in energy expenditure during resting periods may be related to hyperactive behavior, similar to that observed in humans’ exacerbated agitation or sundowning behavior. These findings support the usage of the 3xTg-AD mouse as a reliable model for studying circadian rhythm alterations in AD and, at the translational level, the importance of tailored and individualized physical activity programs in clinical settings. Keywords: Alzheimer’s disease; animal model; sex differences; rehabilitation; exercise; physical activity; circadian rhythms Author: Daniel Alveal-Mellado, Lidia Castillo-Mariqueo and Lydia Giménez-Llort Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Nov 15 12:05:08 2022 CET ModDate: Tue Nov 15 12:11:39 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4120773 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- AWHDWW+VnURWPalladioL Type 1 Custom yes yes no 10 0 YYGXTB+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 VCCIPH+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 XUOWOD+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 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exercise. In preclinical studies, there is no clarity on whether animal models of AD can replicate these impairments. Here, we provide a proof of concept of the performance and behavioral effects of four weeks of voluntary wheel running (VWR) in a group of 14-month-old male and female 3xTg-AD mice at advanced stages of AD and the daily variance (behavioral circadian rhythmicity) of VWR associated with sex and their neuropsychiatric-like phenotype. Higher levels of horizontal exploration in the open field (OF) test were found in mice submitted to exercise. A linear mixed effect model showed significant sex-dependent differences in the VWR activity performed on the first night of follow-up, with high-NIBI males running less than high-NIBI females. Thus, an influence of NPS-like symptoms on the circadian patterns of VWR may account for such differences. In addition, males remained more active than females during diurnal periods. We hypothesize that this increment in energy expenditure during resting periods may be related to hyperactive behavior, similar to that observed in humans’ exacerbated agitation or sundowning behavior. These findings support the usage of the 3xTg-AD mouse as a reliable model for studying circadian rhythm alterations in AD and, at the translational level, the importance of tailored and individualized physical activity programs in clinical settings. 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