Biological sex plays a major role in how certain brain disorders develop and progress. For example, men are more likely to develop conditions like Parkinson’s disease and autism, while women are more frequently affected by depression and Alzheimer’s disease. Men and women can also experience different symptoms and respond differently to certain treatments.

Given the differences in the prevalence and presentation of these conditions between men and women, it is thought that sex differences in the brain underlie these variations. These differences arise from the influence of the sex chromosomes, X and Y, and steroid hormones such as estradiol and testosterone, which are thought to affect brain development early in life. However, it is not fully understood how much of these differences are due to genetics and how much are due to hormones. Therefore, understanding how sex chromosomes and steroid hormones affect the developing brain could provide insights into the origins of sex differences in brain function and brain disorders.

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Scientists are particularly interested in the development of synapses, the connections between neurons, as synapse dysfunction has been linked to several brain disorders. Variations in genes that control synaptic function are thought to increase the likelihood of developing conditions such as autism, schizophrenia, and Alzheimer’s disease. However, it is unclear whether there are sex differences in how synapses develop in the human brain, and they function. This is partly because studying human brain development has been difficult until recently. However, it is now possible to grow brain organoids, small, three-dimensional models of the human brain in the lab, that can be used to study brain development and synapse formation.

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This project aims to investigate how synapses are influenced by sex and hormones like estrogen in brain organoids. To explore this, the team will use a unique set of stem cells derived from an individual with both XX and XY chromosomes, allowing “male” and “female” brain organoids to be compared without genetic variability. This means that researchers can directly measure how having an X or Y chromosome or sex hormone affects brain development. Specifically, they will study how synapses form in these organoids by measuring electrical activity using electrodes and analyzing gene expression under different conditions. Sex hormones will also be added to see how it influences growth and function.

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By combining these approaches, the project aims to provide a clearer understanding of how male and female brains differ at the cellular level, and how sex chromosomes and steroid hormones affect brain development. This knowledge could be crucial for developing personalized treatments for neurological and psychiatric diseases, addressing the unique needs of men and women. It will also give us a better understanding of why conditions like depression, Alzheimer’s, and schizophrenia differ between the sexes.

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