We know how important oxygen is for life, but we’re now finding out how critical oxygen is for neuron development in newborns. Our studies have revealed a pathway that functions as a master regulator of this development, and its activity is dependent upon oxygen levels in the brain.
As a developmental neurobiologist, I study how the brain wires itself before and after birth. In that wiring, neurons have to migrate to their final position in the brain’s network. But how do environmental cues control the onset of differentiation and migration? We are researching this question, as well as how that process drives overall brain maturation.
In part, this question has been unanswered due to a historical quirk in our field. For the last several decades, researchers have concentrated on how genes control the maturation of neurons and guide them to their final position. Environmental influences have been relatively overlooked. Researchers have been so focused on genetic mechanisms that affect neuronal maturation that they didn’t really think about how the air we breathe could be an important developmental trigger.
Our latest findings, published in Neuron, have revealed for the first time the surprising mechanism by which oxygen levels trigger neurons to mature and migrate. The results have important clinical implications because we know that babies born prematurely have problems with the oxygen levels in their brain, a condition called hypoxic insults.
It’s been known for a number of years that hypoxic insults are associated with congnitive deficiency and delayed brain development in pre-term children. While some basic scientists had previously noted a delay in neuron maturation in hypoxia, no one had implicated precise molecular mechanisms to understand how this occurs.
The oxygen-dependent mechanism we discovered not only changed neurons ability to mature but also migrate to a final position in the developing brain. Thus, lack of oxygen in the brains of preterm infants could be a major underlying cause for disruption of neuron or circuit function.
The discovery began in mice. It’s well known that oxygen concentrations in the fetus (mice or humans) are low (hypoxic). That is expected because the fetus has not begun to breathe. Surprisingly, the mouse cerebellum remains hypoxic for about nine days after birth. The discovery gave us an opportunity to explore how oxygen levels govern brain development.
Our studies revealed that rising oxygen levels in the developing cerebellum dial down a biological mechanism called the Hif1α pathway. At low oxygen levels, this pathway inhibits neurons from maturing and migrating, but turning it down essentially kick-starts their development. We showed that hypoxia and the Hif1α pathway inhibits a critical process called polarization that is essential both for neurons prepare to differentiate and kick-off migration.
As oxygen levels increase in the developing brain, Hif1α pathway inhbition recedes, allowing developing neurons to accelerate their maturation programs prior to migration. This finding of the link between oxygen levels, maturation and migration, we believe, is an important conceptual shift in the field.
To explore the mechanism, we used sophisticated genetic tools and imaging technologies called macro light sheet microscopy and lattice light-sheet microscopy. The former lets us take 3-D images of the blood vessels permeating the developing cerebellum and compare them with images of neighboring brain tissue that is not hypoxic. The latter lets us take high-resolution images of samples about the size of a single cell. Lattice light sheet microscopy showed us at the subcellular level that Hif1α changes the types of cell adhesive interactions that happen in developing neurons that are critical to start their migratory journey.
This work is the epitome of team science: a group of developmental neurobiologists in my lab worked for nearly eight years on the genetic and cellular biological aspects of the study (co-authors Jan Kullmann, PhD, Niraj Trivedi, PhD, Danielle Wong, MS, and Christophe Laumonnerie, PhD). Our department is fortunate to have optics specialists led by co-author Daniel Stabley, PhD, to employ advanced microscopy. We are also fortunate to have computational expert and co-author Abbas Shirinifard, PhD, to extract the data from these images and give us quantifiable results.
Although our findings are basic, we hope that they can lead to treatments that would enhance the Hif1α-control mechanism in preterm infants, both to help their neurons properly mature and migrate.