Hippocampal tissue mechanics are sensitive to fluctuations in estrogen across the rat estrous cycle

Abstract

Sex hormones exert profound effects on brain structure and function throughout the female reproductive lifespan. While previous studies have documented hormone-dependent changes in neuronal morphology and synaptic connectivity, the impact of estrogen on brain tissue mechanical properties has been unexplored. Alterations to hippocampal microstructure are particularly sensitive to fluctuations in sex steroids, and studies in peripheral tissues reveal that estrogen is a powerful modulator of tissue elasticity and organization. Here, we employed magnetic resonance elastography (MRE) to quantify whole brain and hippocampal viscoelastic properties across the estrous cycle in female rats in vivo and following targeted α estrogen receptor antagonism. We demonstrate that hippocampal stiffness and damping ratio (viscosity) exhibit dynamic, phase-dependent fluctuations that correlate with hormonal status. Notably, hippocampal damping ratio, a measure of relative viscosity, increased by nearly 40% during the transition from proestrus to estrus phases, mirroring the steep drop in estrogen production that is characteristic of this phase progression. Pharmacological inhibition of estrogen receptors with Fulvestrant prevented this cyclical change and instead maintained elevated hippocampal damping ratio that was comparable to that measured during estrus in normally-cycling rats. Histological analyses revealed that these mechanical changes were accompanied by alterations in astrocyte and neuronal number, receptor expression, and dendritic spine morphology in the CA1 subregion. Notably, estrogen signaling was crucial for maintaining both astrocyte and neuronal populations and receptor density was elevated with the greatest effect on astrocytes (+48%) following Fulvestrant administration. These findings establish a mechanistic link between estrogen fluctuations, cellular architecture, and tissue mechanical properties in the female brain, offering novel insights into how reproductive endocrinology may influence hippocampal microstructure through mechanobiological pathways. Understanding these hormone-dependent mechanical changes may provide new therapeutic targets for addressing altered cognitive capacity associated with reproductive transitions and aging in women.