THE ROLE OF HORMONE CRH IN HUMAN BRAIN DEVELOPMENT

Corticotropin-Releasing Hormone (CRH) was first identified as a neurohormone secreted by the hypothalamus in response to stressful stimuli. However, large amounts of CRH are also secreted by the placenta of anthropoid primates during pregnancy. Although the role of hypothalamic CRH has been extensively studied, there is a remarkable lack of evidence regarding the role of placental CRH, while the biological significance of its unique expression pattern in anthropoid primates remains elusive. In order to investigate the effects of placental CRH on human brain development and to overcome the limitations raised in experimenting with human tissue, we have generated human 3D-neural spheroids and human cerebral cortical organoids from human embryonic stem cells (hESCs). Exposure of neural spheroids or/and cortical organoids to CRH results in significant differences in their size and cellular composition. In addition, immunohistological analyses using cortical layer-specific antibodies, revealed differences in the cytoarchitecture of the organoids exposed to CRH as compared to control. Pharmacological disruption of CRH signaling using the specific CRH receptor 1 antagonist, NBI, reverses the effects of CRH. Moreover, RNA sequencing analysis of the CRH and NBI exposed organoids revealed altered expression of genes related to neurodevelopmental processes such as HOXB9 and FOXG1, depicting CRH as an essential modulator of human brain development. Our findings suggest that this in vitro approach provides a unique tool for our understanding of the mechanisms underlying the role of stress hormones in human brain development.