A recent study published in the journal * Nature* reveals how a specific stress hormone helps the brain lock in its neural connections during early development. The research provides evidence that star-shaped brain cells called astrocytes sense this hormone to turn off periods of high brain flexibility. These findings suggest new ways to understand how the brain matures and how early life stress might disrupt this natural developmental timeline.
When animals and humans are young, their brains are highly moldable. This flexibility, known as plasticity, allows the brain to learn from sensory experiences and adapt to the surrounding environment. Scientists refer to these windows of heightened flexibility as critical periods.
During a critical period, brain cells rapidly form and rearrange their connections based on what the animal sees, hears, and feels. Eventually, this heightened flexibility ramps down. The brain structures mature and lock into place, making it much harder to rewire neural circuits later in life.
The exact environmental cues that signal the brain to close these critical periods have remained somewhat mysterious. Prior research indicates that non-neuronal support cells, specifically astrocytes, help manage this closure. Astrocytes are star-shaped cells that wrap around blood vessels and interact directly with nerve cells.
Michael E. Greenberg, Nathan Marsh Pusey professor of neurobiology at Harvard Medical School and senior author of the study, explained the motivation behind the research. He noted the team started with “an interest in determining if visual experience causes distinct changes in each cell type of the visual cortex.”
“We employed new single cell sequencing techniques that allowed this question to be addressed for the first time,” Greenberg said. “Our expectation was that the sensory experience-dependent transcription factor Fos would be the mediator of gene expression in each cell type in the visual cortex.”
To observe how visual experience shapes the brain, the scientists analyzed the visual cortex of mice. This brain region processes information coming directly from the eyes. The researchers separated mice into two experimental groups. One group was raised in normal lighting conditions, while the other group was raised in complete darkness.
The scientists collected brain tissue from four mice in each group at five different postnatal ages, ranging from seven days to thirty-five days old. They used an advanced genetic sequencing technique to measure the RNA activity and DNA accessibility inside more than seventy thousand individual brain cells. They found that visual experience caused massive shifts in gene activity across many cell types, matching the known timing of critical periods.
Add PsyPost to your preferred sources As Greenberg mentioned, the team found that the transcription factor Fos mediated these changes in all the different types of neurons. However, this did not happen in the astrocytes. “Investigation of the transcription factor that mediates changes in the astrocytes revealed a central role for the glucocorticoid receptor,” Greenberg said. “The rest of the study emerged from this initial finding.”
The glucocorticoid receptor acts as an internal docking station for stress hormones. In mice, the main stress hormone is corticosterone, which is very similar to human cortisol. The researchers noticed a unique response to light involving this receptor that happened earlier than the changes seen in nerve cells.
“The big surprise was the finding that visual experience activates a gene program in astrocytes via a blood-borne stress hormone, cortisol,” Greenberg told PsyPost. “My expectation was that the light-induced gene program would be similar to that found in neurons where the transcription factor Fos mediates experience-dependent changes in gene expression.”
To see if light actually changes stress hormone levels in the body, the researchers tested the blood of nine normal reared mice and nine dark reared mice. They found that normal light exposure caused circulating corticosterone levels to spike right around postnatal day fourteen, which is exactly when mice naturally open their eyes. The mice raised in the dark did not experience this distinct hormone spike.
Next, the scientists mapped exactly where the glucocorticoid receptor binds to DNA inside the astrocytes. They injected a specialized virus into the brains of infant mice to place a fluorescent tag on the DNA of astrocytes. After isolating the tagged astrocyte nuclei, they analyzed samples pooled from three to five mice per group.
The sequencing results show that the stress hormone receptor attaches to thousands of specific spots on the astrocyte DNA. This binding activates a massive program of genes that forces the astrocyte to mature. The researchers found that the receptor works by partnering with another specific protein to trigger these maturation genes.
To test what happens when this genetic process is blocked, the scientists used another custom virus to delete the glucocorticoid receptor specifically in the astrocytes of infant mice. They compared three mice lacking the receptor to three normal mice. Using three-dimensional microscopic imaging, the researchers measured the physical size of the individual astrocytes.
Astrocytes lacking the hormone receptor grew to a smaller volume. They also had fewer branches extending into the surrounding brain tissue. This indicates that the stress hormone is necessary for astrocytes to reach their full mature physical shape.
The team then looked at how this missing receptor affected the neighboring nerve cells. As the brain matures, special structural meshes called perineuronal nets form around certain inhibitory nerve cells. These nets act like a physical cage that prevents nerve connections from changing.
The researchers examined the brains of five to eight mice lacking the astrocyte receptor and compared them to normal mice at thirty-five days old. They found that mice without the receptor had significantly fewer perineuronal nets. These mice also had fewer inhibitory nerve connections, meaning the structural brakes on the brain’s flexibility had failed to form properly.
To test if the brain was still physically flexible, the researchers conducted a visual deprivation test on adult mice. Normally, adult brains do not rewire their visual connections if one eye is temporarily closed. The researchers sutured one eye shut in five adult mice lacking the astrocyte receptor and compared them to five normal adult mice.
After three to four days of visual deprivation, they recorded the electrical activity in the visual cortex. The normal adult mice showed no changes in their brain wiring. But the adult mice lacking the astrocyte receptor rewired their visual circuits to favor the open eye. This provides evidence that removing the stress hormone receptor in astrocytes is enough to reopen a state of juvenile brain flexibility in adult animals.
Finally, the scientists looked at a large database of human brain cells to see if this same pathway exists in people. They examined genetic data from over two hundred and thirty thousand cells across thirty-eight human tissue samples. These samples ranged from early pregnancy stages to adolescence.
The human genetic data suggests that the glucocorticoid receptor becomes increasingly active in human astrocytes as children grow, peaking during adolescence. This timeline aligns with the closure of certain critical periods in people. It indicates that the same hormone-driven pathway likely helps close critical periods in the human brain.
While these findings explain a major pathway in brain development, the study has some limitations and leaves room for future exploration. The experiments rely heavily on mice, and human brains are much more complex. Although the human genetic data aligns with the mouse findings, scientists cannot directly test this rewiring process in living human brains. Additionally, the authors emphasize that more evidence is needed to fully confirm this receptor’s role during normal development. “We suggest in the study that the GR pathway is required for the closure of critical periods during postnatal development however this has not yet been shown,” Greenberg said. “In our paper we demonstrate that blocking GR function can reopen the visual critical period in adult mice but it still needs to be shown that the normal process of critical period closure can be blocked.”
Future studies will focus on identifying the specific genes activated by the stress hormone in astrocytes. Understanding these individual genes might offer hints on how to safely reopen brain flexibility. This knowledge could be useful for treating brain injuries or helping older adults learn new skills more easily.
Scientists also plan to study how severe early life trauma affects this process. Because trauma causes the body to release abnormally high amounts of stress hormones, it might force critical periods to close too early. Exploring this connection tends to help researchers explain the origins of certain psychiatric conditions that develop after severe childhood stress.
“An important next step is to determine if the effects of early life stress on the brain are mediated by cortisol activation of the astrocytic pathway,” Greenberg said.
Overall, Greenberg hopes the public recognizes the broader implications of these findings. He emphasized the key takeaway is “that stress hormones in the blood cause changes in the brain that are critical for brain plasticity and likely learning, memory and behavior. And that this involved key changes in astrocytes, a relatively understudied brain cell.”
“This work was carried out by an outstanding postdoctoral fellow in my laboratory Dr. Bruno Gegenhuber in collaboration with Dr. Takuma Sonoda in the laboratory of Dr. Chinfei Chen within the F.M. Kirby Neuroscience Center of Boston Children’s Hospital,” Greenberg added.
The study, “Astrocyte glucocorticoid receptor signalling restricts neuronal plasticity,” was authored by Bruno Gegenhuber, Takuma Sonoda, Lisa Traunmüller, Christopher P. Davis, Shon A. Koren, Eric C. Griffith, Chinfei Chen, and Michael E. Greenberg.