Longitudinal Effects of Immediate and Delayed Estradiol on Cognitive Performance in a Spatial Maze and Hippocampal Volume in Menopausal Macaques Under an Obesogenic Diet

Abstract

The consumption of a diet high in fat and refined sugars has several health risks, including the development of cognitive decline and neurodegeneration. For women, menopause carries additional health risks that may interact with a high-fat diet in negative ways. Some symptoms of menopause, including cognitive impairments, can be modulated by hormone replacement therapy (HRT), but the hormonal formulation and the timing of the treatment relative to the onset of menopause are critical factors determining its efficacy. Little is known about how obesogenic, high-fat, high-sugar diets interact with HRT in menopause to affect cognition and neurodegeneration. Given the high prevalence of the consumption of an obesogenic Western-style diet, understanding how the effects of HRT are modulated by an obesogenic diet is critical for developing optimized therapeutic strategies for peri-and post-menopausal women. In this study, we investigated by magnetic resonance imaging (MRI) the effects of either immediate or delayed estradiol hormone therapy on cognition and neuroanatomy following ovo-hysterectomy (OvH) of aged, female rhesus macaques on an obesogenic diet. The macaques were followed for 2.5 years after ovo-hysterectomy, with four time points at which anatomical MRIs were acquired. Analysis of hippocampal volumes revealed an interaction between time point and treatment; hippocampal volumes in the delayed estrogen group, but not the immediate estrogen group, increased over time compared to those in untreated controls. Performance on a hippocampal-dependent spatial maze task showed improved performance in estrogen treated animals compared to OvH macaques given placebo. These results indicate that HRT may contribute to beneficial cognitive outcomes after menopause under an obesogenic diet.

Feeding the Brain: Effect of Nutrients on Cognition, Synaptic Function, and AMPA Receptors

“…In male rats, gonadectomy reverted HFD-HFru effects on some learning and memory tasks, but did not improve or even worsen the effects in females [ 71 ]. In non-human primates on an obesogenic diet, estrogen replacement therapy after an ovo-hysterectomy increased cognitive performance [ 73 ]. More in-depth studies analyzing sex- and hormone-dependent effects of an HFD or HSD on synaptic and cognitive injury could lead to better diet interventions for patients with MetS, especially for women after the menopause.…”

Estrogen, Cognitive Performance, and Functional Imaging Studies: What Are We Missing About Neuroprotection?

“…Chronic stress, chronic exposure to obesogenic, and hypercaloric diets can potentiate cognitive and behavioral alterations in OVX rats. In OVX macaques previously fed with a 6-week western diet, the animals treated with E 2 for 30 months performed better spatial tasks than animals that received treatment via vehicle (Zimmerman et al, 2020 ).…”

Early- but not late-adolescent Western diet consumption programs for long-lasting memory impairments in male but not female rats

“…Indeed, estrogen has previously been identified as a protective factor against aging (Norbury et al, 2003; Wise et al, 2001; Yang et al, 2020). Moreover, evidence suggests estrogen is also protective against WD-induced memory impairments in both rats and macaques (Estrada-Cruz et al, 2023; Scudiero & Verderame, 2017; Zimmerman et al, 2020). In addition to sex hormones, it is also possible that the gut microbiome is related to the sex-dependent results observed in the present study.…”