At a glance:
Researchers have discovered a new way that brain plasticity is controlled in early life, offering insight into the little-understood phenomenon of critical-period closure.
In the months or years after birth, critical periods of learning in the brain are open, making the organ uniquely sensitive to information coming from the outside world. Experiences during this time can have a lasting impact on the brain by sculpting neural connections that persist into adulthood. As a child or young animal matures, this heightened period of brain plasticity ends as critical periods begin to close through mechanisms that remain largely unclear.
Harvard Medical School researchers have now shown in mice that the stress hormone cortisol plays a key role in this ramp-down. Through a series of experiments, they traced the cascade of brain changes initiated by cortisol that contributes to critical period closure. They also analyzed an existing dataset to determine that the same pathway is present in the human brain.
The findings published May 20 in Nature .
“We think we found a key mechanism that controls the closure of critical periods during development,” said first author Bruno Gegenhuber , research fellow in neurobiology in the lab of Michael Greenberg in the Blavatnik Institute at HMS.
The research could have far-reaching implications for understanding brain plasticity and maturation, including how early-life stress affects the brain, said Greenberg, the Nathan Marsh Pusey Professor of Neurobiology at HMS and senior author of the study.
The work, conducted in collaboration with researchers at Boston Children’s Hospital, could also inform research into various neurodevelopmental and neuropsychiatric conditions linked to timing problems with critical-period closure.
A new plasticity pathway
The Greenberg Lab has spent decades studying basic mechanisms of brain plasticity . Gegenhuber was continuing that research by analyzing cells in the visual region of the mouse brain when he found something unexpected: evidence of an entirely new pathway of brain plasticity.
The researchers were studying the mouse visual cortex to understand how early-life experiences such as vision affect brain-cell maturation and gene expression. They conducted single-cell sequencing of all the cell types in this brain region in a group of young mice exposed to normal light levels and a group of young mice raised in a dark environment.
They found that in the mice exposed to light, corticosterone — the rodent analog of cortisol — is released into the blood by the adrenal glands and selectively activates and binds to glucocorticoid receptors on brain cells called astrocytes. These star-shaped cells are among the first in the brain to receive information from the blood, which they use to support neurons in various ways.
Gegenhuber and colleagues determined that a light-induced change in the level of cortisol initiates a program of more than 100 genes in astrocytes, and this process promotes the maturation of the extracellular matrix around neurons, including structures called perineuronal nets. This finding provides a potential explanation for scientists’ previous observations that maturation of the extracellular matrix — which restricts the formation and turnover of connections between neurons — contributes to critical-period closure.
In mice raised in the dark, the pathway was not activated, and the steps towards critical period closure failed to take place. Moreover, when the researchers removed the glucocorticoid receptors in adult mice, they found evidence that the critical periods that had closed earlier in development reopened, increasing brain plasticity.
The team then analyzed a preexisting single-cell dataset from the human brain and determined that the same pathway emerges during human infancy and peaks around adolescence.
Digging into the details
Now, the team wants to identify and characterize each of the 100-plus genes in the gene program they uncovered to understand how they affect neurons and neural circuits in the brain during development.
“It’s like being a kid in a candy store in terms of figuring out what each gene does and how it contributes to critical period closure,” Greenberg said.
The researchers are also interested in studying how early-life stressors that raise cortisol levels affect mouse brain plasticity through the pathway they discovered.
On the flip side, Greenberg wants to know what happens to the pathway during aging.
The team would also like to explore whether the pathway serves the same function in humans as it does in mice. If it does, then studying how critical periods close in mice could illuminate why these periods sometimes close prematurely or stay open too long in people, as may be the case in conditions such as autism, schizophrenia, and bipolar disorder. Unraveling these mechanisms may eventually help scientists learn how to manipulate the opening and closing of critical periods in ways that are beneficial for human health.
Although the researchers focused on the visual cortex, Greenberg pointed out that cortisol is a blood-based hormone, meaning it may activate the same pathway in other parts of the brain. If that turns out to be the case, he said, then the pathway the team discovered could play a role in development and maturation of other brain regions, including those involved in learning and memory.
“This pathway is very broad, so I think it is going to be important for many aspects of brain maturation and plasticity,” Greenberg said.
Authorship, funding, disclosures
Additional authors on the paper include Takuma Sonoda, Lisa Traunmüller, Christopher P. Davis, Shon A. Koren, Eric C. Griffith, and Chinfei Chen.
Funding for the study was provided by the National Institutes of Health (R35NS143029, T32 NS007473, F32 NS112455), a Harvard Neuroscience Louis Perry Jones Fellowship (F32 NS134623), an EMBO Postdoctoral Fellowship, a Long-Term Human Frontier Science Program Fellowship, the William Randolph Hearst Fund, the Harvard Mahoney Neuroscience Institute, and the NSF Graduate Research Fellowship. The Greenberg Laboratory is also supported by the Yang Tan Collective at Harvard University including the K. Lisa Yang Brain Body Center at Harvard University and the Tan Yang Autism Research Center at Harvard University.
Nature
Astrocyte glucocorticoid receptor signalling restricts neuronal plasticity
20-May-2026