Cell-Type-Specific Impact of Glucocorticoid Receptor Activation on the Developing Brain: A Cerebral Organoid Study.

OBJECTIVE: A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing many health outcomes. In utero, glucocorticoids have been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type-specific effects. An in vitro model of fetal human brain development, induced human pluripotent stem cell (hiPSC)-derived cerebral organoids, was used to test whether cerebral organoids are suitable for studying the impact of prenatal glucocorticoid exposure on the developing brain. METHODS: The GR was activated with the synthetic glucocorticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development. RESULTS: The GR was expressed in all cell types, with increasing expression levels through development. Not only did its activation elicit translocation to the nucleus and the expected effects on known GR-regulated pathways, but also neurons and progenitor cells showed targeted regulation of differentiation- and maturation-related transcripts. Uniquely in neurons, differentially expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This human neuronal glucocorticoid response profile was validated across organoids from three independent hiPSC lines reprogrammed from different source tissues from both male and female donors. CONCLUSIONS: These findings suggest that excessive glucocorticoid exposure could interfere with neuronal maturation in utero, leading to increased disease susceptibility through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure. Cerebral organoids are a valuable translational resource for exploring the effects of glucocorticoids on early human brain development.

Understanding of object rotation between two and three years of age.

Toddlers' understanding of object rotation was investigated using a multimethod approach. Participants were 44 toddlers between 22 and 38 months of age. In an eye-tracking task, they observed a shape that rotated and disappeared briefly behind an occluder. In an object-fitting task, they rotated wooden blocks and fit them through apertures. Results of the eye-tracking task showed that with increasing age, the toddlers encoded the visible rotation using a more complex eye-movement pattern, increasingly combining tracking movements with gaze shifts to the pivot point. During occlusion, anticipatory looks to the location where the shape would reappear increased with age, whereas looking back to the location where the shape had just disappeared decreased. This suggests that, with increasing age, the toddlers formed a clearer mental representation about the object and its rotational movement. In the object-fitting task, the toddlers succeeded more with increasing age and also rotated the wooden blocks more often correctly before they tried to insert them. Importantly, these preadjustments correlated with anticipatory eye movements, suggesting that both measures tap the same underlying understanding of object rotation. The findings yield new insights into the relation between tasks using looking times and behavioral measures as dependent variables and thus may help to clarify performance differences that have previously been observed in studies with infants and young children. (PsycINFO Database Record (c) 2020 APA, all rights reserved).