Placenta and the cerebellum

Many of these observations come from the following paper: Vacher et al. 2021

• Placenta is a transient endocrine organ that is hugely underappreciated
• Placenta is also an endocrine organ that makes a variety of steroids and peptide hormones that are essential for uterine health.
• We haven’t considered how those compounds contribute directly to fetal development, particularly the fetal brain.
• Progesterone - dominates early in pregnancy creating a healthy uterine environment, and late in pregnancy, estrogen levels rise, upregulating oxytocin receptors in preparation for the induction of contractions when the time is right.
• Premature fetuses are being deprived of allopregnaolone at a time when the brain is rapidly developing.
• Penn et al. study: created a mouse model in which allopregnanolone production by the placenta was selectively prevented to determine if there were consequences from the loss. Transcriptomic analysis of multiple brain regions at postnatal day 30 revealed the cerebellum to be the region most affected. Gene expression associated with white matter was broadly altered in the cerebellum.
• Birth is a particularly important point in cerebellar development, because of the sudden physical demands of living outside the womb.
• Premature loss of allopregnanolone affected males and females differently
• In males: when assessed for their sociability, allopregnanolone-deprived males showed less preference for interacting with another mouse over an object, they were also deficient at emitting a distress call when isolated from their mothers.
• Males: greater myelination and increased connectivity (neuronal activity is a goldilocks phenomenon: needs to be just right)
• A single injection of allopregnanolone in pregnant mice was sufficient to reduce both the cerebellar myelination and behavioral abnormalities in male offspring lacking placental allopregnanolone and restore them to values observed in their unaffected littermates and females.
• Results also confirmed via cerebella of infants who were born prematurely or after a normal-length pregnancy and found compelling evidence of accelerated myelination in boys born prematurely but not in girls
• Why do males and females respond so differently to the loss of allopregnanolone?