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

Abstract

Sex differences are found in brain structure and function across species, and across brain disorders in humans1-3. The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan4. 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 risk5-7. However, due to limited molecular studies in female rodents8, 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 factor9, 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 regulation1in order to understand sex-specific synaptic and behavioural plasticity and inform novel brain disease treatments.

Circadian clock neurons use activity-regulated gene expression for structural plasticity

“…While not all neurons may use this switch-type regulation, we note that the female hippocampus shows rhythms in dendritic spine number and synaptic density which follow the 4-5 day oestrous cycle (Jaric et al , 2019; Shors et al , 2001; Woolley & McEwen, 1992). The molecular mechanisms may even be similar with the mammalian Sr ortholog Egr1 linked to these changes in plasticity in female hippocampal neurons (Rocks et al , 2023).…”