Recent research published in journals nature We reveal how certain stress hormones help solidify the brain’s neural connections during early development. This study provides evidence that star-shaped brain cells called astrocytes sense this hormone and turn off periods of high brain plasticity. These findings suggest new ways to understand how the brain matures and how early-life stress disrupts this natural developmental timeline.
When animals and humans are young, their brains are highly susceptible to mold growth. This flexibility, known as plasticity, allows the brain to learn from sensory experiences and adapt to its surrounding environment. Scientists refer to this period of increased flexibility as the critical period.
During the critical period, brain cells rapidly form connections and rearrange themselves based on what the animal sees, hears, and feels. Eventually, this increased flexibility will diminish. As brain structures mature and become fixed in place, it becomes much more difficult to rewire neural circuits later in life.
The precise environmental signals that signal the brain to end these critical periods are somewhat mysterious. Previous studies have shown that non-neural supporting cells, particularly 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 study. He said the research team started with an “interest in determining whether visual experience causes distinct changes in each cell type in the visual cortex.”
“We employed a new single-cell sequencing technology and were able to address this problem for the first time,” Greenberg said. “Our expectation was that the sensory experience-dependent transcription factor Fos is a mediator of gene expression in each cell type of the visual cortex.”
To see how visual experience shapes the brain, scientists analyzed the visual cortex of mice. This brain area processes information that comes directly through the eyes. The researchers divided the mice into two experimental groups. One group was kept under normal lighting conditions and the other group was kept in complete darkness.
The researchers collected brain tissue from each group of four mice at five different postnatal ages, ranging from 7 days to 35 days. They used advanced genetic sequencing techniques to measure RNA activity and DNA accessibility within more than 70,000 individual brain cells. They found that visual experience induced large changes in gene activity across many cell types, coinciding with the timing of known critical periods.
As Greenberg noted, the research team found that the transcription factor Fos mediates these changes in all different types of neurons. However, this did not occur with astrocytes. “Studies of the transcription factors that mediate changes in astrocytes have revealed a central role for the glucocorticoid receptor,” Greenberg said. “The rest of the research was based on this initial discovery.”
Glucocorticoid receptors act as internal docking stations for stress hormones. The main stress hormone in mice is corticosterone, which is very similar to cortisol in humans. Researchers noticed that the unique response to light associated with this receptor occurs faster than the changes seen in nerve cells.
“The big surprise was the discovery that visual experience activates astrocyte genetic programs via the blood-borne stress hormone cortisol,” Greenberg told PsyPost. “My expectation was that the genetic program induced by light would be similar to that seen 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 normally raised mice and nine mice raised in the dark. They found that exposure to normal light caused circulating corticosterone levels to spike around the 14th day of life. This is exactly the time when the mouse naturally opens its eyes. Mice kept in the dark did not experience this distinct hormonal spike.
The scientists then mapped exactly where the glucocorticoid receptors in astrocytes bind to DNA. They injected a special virus into the brains of infant mice to fluorescently tag the DNA of astrocytes. After isolation of tagged astrocyte nuclei, pooled samples from 3 to 5 mice per group were analyzed.
Sequencing results show that stress hormone receptors bind to thousands of specific spots on astrocyte DNA. This binding activates an extensive genetic program that forces astrocytes to mature. Researchers discovered that this receptor works by working with another specific protein to trigger these maturation genes.
To test what happens if this genetic process is blocked, the scientists used another custom virus to specifically delete glucocorticoid receptors in astrocytes of baby mice. They compared three mice lacking the receptor with three normal mice. The researchers used three-dimensional microscopic imaging to measure the physical size of individual astrocytes.
Astrocytes lacking hormone receptors grew to smaller volumes. There were also few branches extending into surrounding brain tissue. This indicates that stress hormones are required for astrocytes to reach their fully mature physical shape.
The team then investigated how this missing receptor affected neighboring nerve cells. As the brain matures, a specialized structural mesh called perineural nets forms around certain inhibitory neurons. These nets act like physical cages that prevent changes in neural connections.
The researchers examined the brains of five to eight mice lacking astrocyte receptors and compared them to 35-day-old normal mice. They found that mice lacking the receptor had significantly fewer perineural networks. These mice also had fewer inhibitory neural connections, meaning that the structural brakes on brain flexibility were not properly formed.
To test whether the brain is still physically flexible, the researchers performed a visual deprivation test on adult mice. Normally, the adult brain does not rewire visual connections when one eye is temporarily closed. The researchers sutured one eye shut of five adult mice lacking astrocyte receptors and compared them with five normal adult mice.
After visual deprivation for 3 to 4 days, electrical activity in the visual cortex was recorded. No changes in brain wiring were observed in normal adult mice. But adult mice lacking astrocyte receptors rewired their visual circuitry to favor open eyes. This provides evidence that removing stress hormone receptors on astrocytes is sufficient to re-establish juvenile brain plasticity in adult animals.
Finally, the scientists examined a large database of human brain cells to see if this same pathway exists in humans. They examined genetic data from more than 230,000 cells across 38 human tissue samples. These samples ranged from early pregnancy stages to adolescence.
Human genetic data suggest that glucocorticoid receptors become increasingly active within human astrocytes as children grow, reaching a peak at puberty. This timeline coincides with the end of certain critical periods in people. This indicates that the same hormonally driven pathways likely help close critical periods in the human brain.
Although these findings describe key pathways in brain development, this study has several limitations that leave room for future exploration. The experiments rely heavily on mice, and the human brain is much more complex. Although human genetic data is consistent with the findings in mice, scientists cannot directly test this rewiring process in living human brains.
Furthermore, the authors emphasize that more evidence is needed to fully confirm the role of this receptor in normal development. “Our research suggests that the GR pathway is required for the exit of a critical period in postnatal development, but this has not yet been shown,” Greenberg said. “While our paper demonstrated that blocking GR function can restart the visual critical period in adult mice, we need to show that we can block the normal process of critical period exit.”
Future research will focus on identifying specific genes activated by stress hormones in astrocytes. Understanding these individual genes may provide hints on how to safely restart the brain’s plasticity. This knowledge could help treat brain injuries and help older adults learn new skills more easily.
Scientists also plan to study how severe childhood trauma affects this process. Trauma causes the body to release abnormally large amounts of stress hormones, which can cause the critical period to end prematurely. Exploring this connection tends to help researchers explain the causes of certain mental illnesses that develop after severe childhood stress.
“An important next step is to determine whether the effects of early life stress on the brain are mediated by cortisol activation of the astrocyte pathway,” Greenberg said.
Overall, Greenberg hopes the public recognizes the broader implications of these findings. He emphasized that the key point is that “stress hormones in the blood induce changes in the brain that are important for brain plasticity and perhaps learning, memory, and behavior, and that this involves important changes in astrocytes, a relatively understudied brain cell.”
“This study was conducted in collaboration with Dr. Bruno Gegenhuber, an outstanding postdoctoral fellow in my lab, and Dr. Takuma Sonoda in Dr. Qingfei Chen’s laboratory at the FM Kirby Neuroscience Center at Boston Children’s Hospital,” added Professor Greenberg.
The study, “Astrocyte glucocorticoid receptor signaling limits 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.
