The ovarian cycle and estradiol modulate cortical network state and auditory entrainment in mice and women

Abstract

The human brain is remarkably dynamic, continuously adapting to internal and external signals across rapid and protracted timescales. While both male and female brains are influenced by sex hormones to drive adaptive behavioural and physiological changes, the ovarian cycle in female mammals represents a conserved naturalistic model to understand how hormones such as estradiol (E2) alter cellular and network states to shape brain function. To understand whether and how the ovarian cycle influences sensory cortical processing, we investigated cortical network activity at rest and upon auditory stimulation across the ovarian cycle in mice and human subjects. We recorded EEG activity in men and women and intracortical local field potentials in male and female mice. Female participants were tested during two phases of their ovarian cycle characterized by low E2 levels (early follicular phase in women; late estrus in mice) and high E2 levels (late follicular phase in women; proestrus in mice). Across species, high endogenous or exogenous estradiol was associated with a steeper aperiodic power spectral slope, indicating decreased excitatory/inhibitory drive and attenuated auditory entrainment following a 40Hz stimulation. At the single-cell level, high E2 selectively increased the baseline and sustained 40-Hz firing of putative fast-spiking interneurons while reducing their temporal coherence during both spontaneous and stimulus-evoked activity, suggesting that E2 enhances inhibitory tone, while disrupting the temporal coordination of inhibitory networks. Altogether, these findings demonstrate that estradiol dynamically modulates cortical network states and auditory responsiveness. This underscores the necessity of investigating hormone-brain coupling as an evolutionarily conserved model essential for yielding translational insights into sex-specific neurobiology.