Using organoids to model sex differences in the human brain

Sex differences are widespread during neurodevelopment and play a role in neuropsychiatric conditions such as autism, which is more prevalent in males than females. In humans, males have been recorded to have larger brain volume compared to females with development of the hippocampus and amygdala showing prominent sex differences. Mechanistically, sex steroids and sex chromosomes drive these differences in brain development which seem to peak during prenatal and pubertal stages. Animal models have played a crucial role in understanding sex differences, but the study of human sex differences requires an experimental model that can recapitulate complex genetic traits. To fill this gap, human induced pluripotent stem cell derived brain organoids are now being used to study how complex genetic traits influence prenatal brain development. For example, brain organoids from autistic individuals and individuals with X-chromosome linked Rett syndrome and Fragile X syndrome revealed prenatal differences in cell proliferation – a measure of brain volume differences, and excitatory-inhibitory imbalances. Brain organoids also revealed increased neurogenesis of excitatory neurons due to androgens. However, despite growing interest in using brain organoids, several key challenges remain that affect its validity as a model system. In this review we discuss how sex steroids and the sex chromosomes each contribute to sex differences in brain development. We then examine the role of X-chromosome inactivation as a factor driving sex differences. Finally we discuss the combined challenges of modelling X-chromosome inactivation and limitations of brain organoids that need to be taken into consideration when studying sex differences.