Characterization of Neural Estrogen Signaling and Neurotrophic Changes in the Accelerated Ovarian Failure Mouse Model of Menopause

Abstract

Accelerated ovarian failure (AOF) can be induced in young mice with low doses of 4-vinylcyclohexene diepoxide (VCD), modeling the hormone changes observed across menopause. We assessed markers of synaptic plasticity in the hippocampus, anxiety-like behavior, and spatial learning longitudinally at 4 time points across the AOF model: premenopause, early perimenopause, late perimenopause, and postmenopause (POST). As others have shown, VCD administration decreased ovarian follicle counts and increased acyclicity as the model progressed to POST but with no impact on organ or body weights. The morphology of Iba1 immunoreactive microglia did not differ between vehicle- and VCD-administered mice. Hippocampal postsynaptic density 95 levels were minimally altered across the AOF model but decreased at POST in CA3b 24 hours after exogenous estradiol benzoate (EB). In contrast, hippocampal phosphorylated AKT levels transiently decreased in premenopause but increased at POST after 24 hours of EB in select subregions. Electron microscopy revealed fewer estrogen receptor α containing dendritic spines and terminals in CA1 stratum radiatum at POST. mRNA levels of most brain-derived neurotrophic factor exons (except V and VI) were lower in POST compared with ovariectomized mice. Exon V was sensitive to 24 hours of EB administration in POST-VCD. Anxiety-like behavior was unaffected at any menopause phase. Spatial learning was unaffected in all groups, but POST-VCD mice performed below chance. Our results suggest that the AOF model is suitable for longitudinal studies of neurobiological changes across the menopause transition in mice. Our findings also point to complex interactions between estrogen receptors and pathways involved in synaptic plasticity.

Redistribution of NMDA Receptors in Estrogen-Receptor-β-Containing Paraventricular Hypothalamic Neurons following Slow-Pressor Angiotensin II Hypertension in Female Mice with Accelerated Ovarian Failure

“…Previous studies demonstrate that the mouse model of AOF uniquely recapitulates hormonal changes seen in human menopause [16, 17, 39, 40]. Injections of low doses of 4-vinylcyclohexene diepoxide (VCD) selectively eliminate primary follicles in the ovary and, following ovarian failure, result in undetectable levels of estradiol [39, 40].…”

“…Unfortunately, neither of these approaches has been able to elucidate potential mechanisms related to ovarian hormone irregularity and decline that contribute to perimenopausal hypertension. We addressed this gap in knowledge by using a mouse model of accelerated ovarian failure (AOF) that uniquely recapitulates hormonal changes seen in human menopause including the menopause transition while controlling for the effects of aging [16, 17]. …”

Understanding the broad influence of sex hormones and sex differences in the brain

“…However, slow-pressor AngII-infusion induces hypertension in OVX mice that model surgical menopause (Hay et al 2014, Xue et al 2013) and in aged rodents (Fortepiani et al 2003, Marques-Lopes et al 2015b, Tiwari et al 2009) that model the acyclicity (Nelson et al 1995) seen in post-menopause. Using a mouse model of Accelerated Ovarian Failure (AOF) that uniquely recapitulates hormonal changes seen in human menopause (Van Kempen et al 2014, Van Kempen et al 2011), we showed that the susceptibility to slow-pressor AngII hypertension begins at emerges at a timepoint that mimics perimenopause (i.e., when estrogens are present but erratically fluctuating) [9].…”

Sex and regional differences in microglia morphology and complement receptor 3 are independent of constitutive neuroinflammatory protein concentrations in healthy mice

“…However, a benefit of the accelerated ovarian failure model is that the "perimenopause" and ovarian failure status is inducible in young mice, therefore excluding the confounding variable of age (Brooks et al, 2016). As has been previously demonstrated, the three week VCD treatment protocol (160 mg/kg/i.p./day), employed in this study, did not elicit a neuroimmune response when compared to a positive control, either immediately following treatment or at a later time point (Van Kempen et al, 2014).…”

“…Additional female C57Bl6/J mice were purchased at 5wk old in order to induce OF as a model of the human post-menopause period. We employed the OF protocol as previously published (Haas et al, 2007;Van Kempen et al, 2014). Briefly, 5wk old female mice were injected for 21 days with 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg/i.p./day).…”