Accelerated Ovarian Failure Causes Neuronal Detriments in the Menopausal Transition that are not Recovered by High Intensity Interval Training

Abstract

The impact of menopause on Alzheimer’s disease risk has been widely investigated using the ovariectomy (OVX) mouse model, however, this model does not fully capture the gradual hormone depletion that occurs in humans. The novel vinylcyclohexene diepoxide (VCD) model allows for the study of how different stages in the menopausal transition can impact physiology and the brain. Exercise can be introduced during the transitionary perimenopausal phase to limit the negative effects of the menopausal transition on the brain. This thesis aimed to characterize the cognitive and neuronal effects of the VCD model at different stages of ovarian depletion. We later aimed to determine if a high intensity interval training (HIIT) protocol introduced at the menopausal stage would be able to attenuate the detriments caused by the VCD transition. Mice weighing 20-25 grams were injected with VCD for 15 days (160 mg/kg/d) after the transition began. This transition has four landmarks: 60 days post injection = early perimenopause, 120 days post injection = perimenopause, 137 days post injection = early menopause, and 176 days post injection = menopause. Novel object recognition tests (NORT) were conducted on the mice at each timepoint prior to tissue collection. In the second aim of this thesis, another subset of VCD injected mice were either sedentary or put through a HIIT protocol three times a week starting at the 120-day timepoint. HIIT is frequently used as it is a time efficient modality of exercise and its implementation at the 120-day timepoint allows us to determine if its use can improve the neuronal detriments caused by VCD. NORTs were analyzed through DeepLabCut and the collected tissue was western blotted for neuronal and synaptic markers such as NeuN, SNAP25, PSD95 and BDNF. Mice that received VCD had lower discrimination index (%) on the NORT alongside lower SNAP25 and NeuN. Mice that received VCD in combination with exercise had no improvements in cognition, however, they had lower activity of AD hallmarks.