The estrous cycle surpasses sex differences in regulating the transcriptome in the rat medial prefrontal cortex and reveals an underlying role of early growth response 1

Florian Duclot, Mohamed Kabbaj

Males and females differ in cognitive functions and emotional processing, which in part have been associated with baseline sex differences in gene expression in the medial prefrontal cortex. Nevertheless, a growing body of evidence suggests that sex differences in medial prefrontal cortex-dependent cognitive functions are attenuated by hormonal fluctuations within the menstrual cycle. Despite known genomic effects of ovarian hormones, the interaction of the estrous cycle with sex differences in gene expression in the medial prefrontal cortex remains unclear and warrants further investigations. We undertake a large-scale characterization of sex differences and their interaction with the estrous cycle in the adult medial prefrontal cortex transcriptome and report that females with high and low ovarian hormone levels exhibited a partly opposed sexually biased transcriptome. The extent of regulation within females vastly exceeds sex differences, and supports a multi-level reorganization of synaptic function across the estrous cycle. Genome-wide analysis of the transcription factor early growth response 1 binding highlights its role in controlling the synapse-related genes varying within females. We uncover a critical influence of the estrous cycle on the adult rat medial prefrontal cortex transcriptome resulting in partly opposite sex differences in proestrus when compared to diestrus females, and we discovered a direct role for Early Growth Response 1 in this opposite regulation. In addition to illustrating the importance of accounting for the estrous cycle in females, our data set the ground for a better understanding of the female specificities in cognition and emotional processing.