Uncovering the Placenta’s Role in Brain Development

March 1, 2023

During pregnancy the placenta, the interface between mother and fetus, performs a multitude of critical functions: it ferries oxygen and nutrients from the mother to her fetus, filters toxins from the fetal blood supply, allows the maternal and fetal immune systems to coexist, regulates exposure to stress hormones such as cortisol, and much more. “It performs the many functions the fetus needs before its organs are completely formed,” says Anna Penn, MD, PhD, Columbia’s chief of neonatology. The placental function that most interests Dr. Penn is the production of hormones that are key to healthy brain development.

Microscope image of placenta cell

Cerebellar slice highlighting myelin.  Courtesy of CM Vacher.

To understand how placental hormones help orchestrate future brain health, Dr. Penn has been studying what happens when these hormone levels are altered during gestation. Her research demonstrates that when exposure to key hormones is abbreviated or missed altogether—through days or weeks of gestation missed when a baby is born prematurely, for example—long-term injury or dysfunction is much more likely. If the interplay between the developing brain and the placenta is disrupted, disorders such as cerebral palsy, autism, and schizophrenia can result, she says. “As we learn more, these disorders could be redefined as disorders of the placenta.”

Dr. Penn has dubbed the study of the placenta’s role in protecting and shaping the fetal brain, neuroplacentology. “When I started this work I made a list of 104 really critical neuroendocrine factors made by the placenta that should be investigated,” she says. The hormone she chose to look at most closely is allopregnanolone (ALLO). Levels of this hormone rise late in gestation, when it is generated in the placenta from progesterone, and are highest at the end of pregnancy. “If you're born preterm, you can lose up to 16 weeks of exposure to ALLO,” she says, “and it's a huge loss.”

Her research initially focused on why male preterm infants are at much higher risk for poor neurologic outcome than females. To understand more, Dr. Penn and her lab members created a mouse model in which progesterone could not be converted into ALLO. In a 2021 publication in Nature Neuroscience, they showed that in the absence of ALLO, the cerebellum, a brain region important for motor activity and emotional control, developed differently. Males had higher than normal levels of myelin, the insulating sheath that forms around nerves, than mice that had a placenta that made normal amounts of ALLO. Males were also less likely to interact with other mice and showed increases repetitive behaviors. “The most exciting thing is that when we gave a single dose of allopregnanolone during late pregnancy, we could shift their behavior back into the normal range,” she says. “This is the first strong example of a hormone that alters late fetal neurodevelopment in such a striking way.”

In a 2022 study in Frontiers in Endocrinology her team showed that development of a different brain region, the sensory cortex, was altered in females exposed to low levels of the same hormone. Her future work will continue this focus on sex-linked differences in brain development, and therapeutic strategies that could prevent devastating neurodevelopmental disorders linked to loss of placental function.