Androgens increase excitatory neurogenic potential in human brain organoids

The biological basis of male-female brain differences has been difficult to elucidate in humans. The most striking morphological difference is size, with males having on average a larger brain than females; yet a mechanistic understanding of how this difference arises remains to be elucidated. Here, we use brain organoids to demonstrate that while sex chromosomal complement has no observable effect on neurogenesis, sex steroids, namely androgens, lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on HDAC activity and mTOR pathway. Finally, we show that androgens specifically increase neurogenic output of excitatory neuronal progenitors, while inhibitory neuronal progenitors are not increased. These findings uncover a hitherto unknown role for androgens in regulating excitatory neuron number and represent a first step towards understanding the origin of human sex-related brain differences. Overall design: Bulk and single-cell RNA sequencing was performed on organoids treated with sex steroid hormones and subjected to differential gene expression analysis.