Maternal signals help synchronize babies’ circadian rhythms before birth

Humans and most other organisms have internal biological clocks that track the daily cycle of sunrise and sunset. These clocks help time our sleep, metabolism and other essential body functions over the course of a day, creating daily patterns called circadian rhythms. Research shows that when these rhythms are disrupted - by jet lag, lack of sleep or irregular work schedules - people can suffer long-term negative health effects.

Scientists who study daily rhythms have long wondered about when the mammalian circadian clock starts ticking and synchronizes to local time. In a new study published in the Journal of Biological Rhythms, researchers at Washington University in St. Louis reported that a mother helps to set the biological clock for her babies while they are still in the womb.

We know that disrupting circadian rhythms during pregnancy can affect how sleep and daily rhythms develop in infants, and these early disruptions are linked to a higher risk of mood disorders such as anxiety and depression later in life. Understanding when the fetal clock begins to function helps us identify sensitive developmental windows when circadian disruption may have lasting effects and how those effects might be prevented or corrected."

Nikhil Lokesh, study author and research scientist in biology in WashU Arts & Sciences

For this new study, WashU scientists developed a way to observe circadian clock activity in fetuses while they are still developing inside the womb. The scientists used genetically engineered mice in which a luminescent protein called luciferase, the same protein that makes fireflies glow, is attached to a clock protein that drives circadian rhythms.

When a male mouse carrying this modified protein mates with a normal female, the tagged clock protein appears in the developing fetuses but not in the mother's tissues. The pregnant mice were then given drinking water laced with a chemical that reacts with luciferase to produce light. Whenever the clock protein was active in the fetuses, they glowed.

The researchers detected that fetal light using highly sensitive cameras. By recording the glow's timing, they were able to identify clear cyclical patterns of clock protein expression in babies while they developed inside their mothers' womb.

"We found clear day-night rhythms in the pups that synchronized to the mother's rest-activity cycle during the last week of pregnancy, equivalent to the third trimester in humans," Lokesh said. "This suggests that the clock machinery forms early in development and receives entraining cues from mom later."

"Importantly, we found daily rhythms across the placenta from the mother to the baby before the fetus can sense light," said Erik Herzog, the Viktor Hamburger Distinguished Professor in biology, senior author on the study.

The researchers found that circadian synchronization of the pups to the mother coincided with when glucocorticoid hormones from the mother cross the placenta, potentially acting as timing signals for the fetal clock. These stress-related hormones normally rise and fall over the course of the day under the control of the mother's internal clock.

Synthetic glucocorticoids are routinely given to pregnant women at risk of preterm birth, often without considering the time of day when these hormones naturally fluctuate. The authors found that giving these steroids daily to the mother accelerated the synchronization to local time of the daily rhythms in the pups. These findings may be important when considering how and when doctors administer medications to treat pregnancy conditions.

During the study, the researchers also observed a strong association between failure to develop circadian clock gene activity in the fetuses and failure to deliver. "We cannot yet say whether the absence of rhythms contributes to developmental problems or simply reflects them," Lokesh said. "But the observation suggests that circadian clock activity may be closely linked to healthy fetal development."

Lokesh said the findings also highlight the importance of maintaining stable circadian rhythms during pregnancy. "Over 80 percent of the world's population is exposed to artificial light at night that can disrupt daily rhythms, and this includes pregnant people," he said.

"Understanding when and how the body clock starts ticking helps scientists identify sensitive developmental windows when circadian disruption may have lasting effects," Lokesh said. "This knowledge could help guide medical treatments, inform clinical practices and shape public health policies aimed at protecting neonatal circadian health during pregnancy."