Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour.

Sex differences are found in brain structure and function across species, and across brain disorders in humans 1-3 . The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan 4 . Specifically, ovarian hormones oestrogens and progesterone are known to dynamically change structure and function of the adult female brain, having a major impact on psychiatric risk 5-7 . However, due to limited molecular studies in female rodents 8 , very little is still known about molecular drivers of female-specific brain and behavioural plasticity. Here we show that overexpressing Egr1, a candidate oestrous cycle-dependent transcription factor 9 , induces sex-specific changes in ventral hippocampal neuronal chromatin, gene expression, and synaptic plasticity, along with hippocampus-dependent behaviours. Importantly, Egr1 overexpression mimics the high-oestrogenic phase of the oestrous cycle, and affects behaviours in ovarian hormone-depleted females but not in males. We demonstrate that Egr1 opens neuronal chromatin directly across the sexes, although with limited genomic overlap. Our study not only reveals the first sex-specific chromatin regulator in the brain, but also provides functional evidence that this sex-specific gene regulation drives neuronal gene expression, synaptic plasticity, and anxiety- and depression-related behaviour. Our study exemplifies an innovative sex-based approach to studying neuronal gene regulation 1 in order to understand sex-specific synaptic and behavioural plasticity and inform novel brain disease treatments.