Summary: A developmental neurobiology breakthrough uncovered a previously unmapped molecular pathway that regulates brain plasticity in early life, solving the long-standing mystery of critical-period closure. The study demonstrates that the stress hormone cortisol acts as a biological clock to wind down heightened periods of infant learning.
By triggering a massive gene expression program inside star-shaped brain cells called astrocytes, the hormone accelerates the maturation of the protective scaffolding around neurons, locking neural connections into place and establishing a permanent template for adult brain architecture.
Key Facts
- The Critical-Period Enigma: In the months or years following birth, critical windows of development open, making the brain uniquely sensitive to external sensory information. As an organism matures, this heightened plasticity closes through mechanisms that have historically remained unclear.
- The Astrocytic Cortisol Catalyst: Conducting single-cell sequencing in the visual cortex of young mice, researchers discovered that exposure to environmental light stimulates the adrenal glands to release corticosterone, the rodent analog of cortisol. This blood-borne hormone binds selectively to glucocorticoid receptors on astrocytes.
- The Perineuronal Net Lock: Once activated, the cortisol receptor triggers a cascade of more than 100 genes inside astrocytes. This program promotes the rapid maturation of the extracellular matrix around neurons, forming rigid physical structures called perineuronal nets that permanently restrict the turnover of neural connections.
- Reopening Closed Windows: In dark-reared mice, the light-induced pathway failed to activate, delaying critical-period closure. Remarkably, when researchers genetically removed glucocorticoid receptors from adult mice, the closed critical periods reopened, successfully restoring youthful brain plasticity.
- Human Lifespan Validation: By evaluating a preexisting single-cell human brain dataset, the Harvard team verified that this identical astrocytic pathway emerges during human infancy and reaches its peak activity around adolescence.
- Clinical and Aging Implications: Co-senior author Dr. Michael Greenberg and first author Dr. Bruno Gegenhuber note that because cortisol travels globally through the bloodstream, this pathway likely impacts learning, memory, and timing anomalies tied to neurodevelopmental conditions like autism, schizophrenia, and bipolar disorder.
Source: Harvard
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: 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.
Key Questions Answered:
A: By forcing supportive brain cells to lock down the spaces between neurons. When external experiences like light trigger the release of cortisol, the hormone binds to receptors on astrocytes, activating a program of over 100 genes. This gene cascade hardens the matrix around neurons into rigid nets, stopping the rapid creation of new connections and closing the critical window.
A: Yes, the Harvard team proved this reversal is biologically possible in mouse models. When researchers deliberately removed glucocorticoid receptors from fully mature adult mice, the rigid extracellular locks vanished, allowing previously closed critical periods to reopen and experience-driven plasticity to return.
A: Because these conditions are deeply linked to timing problems with how the brain matures. If this blood-borne hormone pathway behaves the same way in humans as it does in mice, understanding it will clarify why critical learning periods close prematurely or stay open too long, handing science a tool to manipulate these windows to improve health.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neurodevelopment and brain plasticity research news
Author: Katie Brace
Source: Harvard
Contact: Katie Brace – Harvard
Image: The image is credited to Greenberg Lab
Original Research: Open access.
“Astrocyte glucocorticoid receptor signalling restricts neuronal plasticity” by Bruno Gegenhuber, Takuma Sonoda, Lisa Traunmüller, Christopher P. Davis, Shon A. Koren, Eric C. Griffith, Chinfei Chen & Michael E. Greenberg. Nature
DOI:10.1038/s41586-026-10512-9
Abstract
Astrocyte glucocorticoid receptor signalling restricts neuronal plasticity
Sensory experience refines neural circuits during critical periods of postnatal development. Although neuronal activity is known to orchestrate the circuit wiring that underlies this process, the environmental cues that restrain developmental plasticity as animals mature are less clear.
Here we examine the experience-dependent maturation of the mouse primary visual cortex across postnatal development using paired single-cell transcriptomic and chromatin accessibility sequencing.
In addition to identifying the activity-dependent gene programs that emerge within each cortical cell type, we find that light exposure drives astrocyte maturation through cell-type-specific recruitment of the glucocorticoid receptor (encoded by Nr3c1) to chromatin.
Astrocyte glucocorticoid receptor signalling activates an extensive gene regulatory program that is partially conserved in human brain development and promotes maturation processes that may regulate critical period closure. Collectively, these findings reveal that astrocyte glucocorticoid receptor signalling restricts neuronal plasticity.
Glucocorticoid regulation of astrocyte maturation may also contribute to the effects of early-life stress across the brain, and the disruption of this process may increase susceptibility to neuropsychiatric disease.
