REHOVOT, ISRAEL—December 6, 2023— The images of Israeli child hostages being freed from Hamas captivity are heartwarming, but for most of these children, the release is just the start of a long rehabilitation process. Countless studies have shown that exposure to warfare, abuse and other traumatic events at a young age significantly raises the risk of ill health, social problems and mental health issues later in life. Now, a new study by researchers at the Weizmann Institute of Science published in Science Advances provides a reason for optimism. In research conducted on mice, a team headed by Prof. Alon Chen discovered brain mechanisms that go awry as a result of exposure to trauma in infancy and showed that these changes may be reversible if treated early.
Human brains have a wonderful quality known as plasticity, which is the ability to change throughout life. Peak plasticity occurs in the early years, when the brain is still developing. This manifests in, for example, the aptitude for learning languages. Conversely, this plasticity also leaves young brains with a heightened sensitivity to traumatic events, which many studies have shown are liable to leave scars that only intensify with age. However, very little is known about the way exposure to trauma at a young age affects the different kinds of brain cells and how they communicate in adulthood.
Chen’s laboratory in Weizmann’s Brain Sciences Department focuses on the molecular and behavioral aspects of the response to stress. In previous studies, Chen’s team examined how stress during pregnancy affects mouse offspring when they reach maturity. In their current research, the scientists, led by Dr. Aron Kos, studied how trauma experienced shortly after birth affects mouse pups later in life. To advance the understanding of this topic, the researchers tapped into the strengths of Chen’s lab, including its expertise in exploring the brain’s molecular processes at the highest possible resolution using genetic sequencing on the level of individual cells and its ability to use cameras to track dozens of behavioral variables in a rich social environment intended to recreate natural living conditions. Researchers also took advantage of the lab’s machine learning and artificial intelligence tools to process the massive quantities of data generated in this environment.
This comprehensive behavioral mapping revealed that mice exposed after birth to a traumatic event – in the case of this study, being neglected by their mothers – displayed a variety of behaviors indicating that they found themselves at the bottom of the dominance hierarchy. “Equivalent behaviors in humans might include high levels of introversion, social anxiety and having an avoidant personality, all known to be characteristic of post-trauma,” says Dr. Juan Pablo Lopez, a former postdoctoral fellow in Chen’s joint laboratory at Weizmann and the Max Planck Institute of Psychiatry in Munich, now head of a research group in the Department of Neuroscience at the Karolinska Institute in Stockholm.
In the next stage of the study, the researchers exposed some of the adult mice that had experienced trauma in infancy to a stressful social situation: bullying by other mice. Ultimately, they created four groups: those that had not been exposed to any trauma, those that had not been exposed to trauma in infancy but were subjected to bullying as adults, those that were exposed to trauma only in infancy, and those that were exposed to both trauma in infancy and bullying as adults.
To find out how exposure to early trauma disrupts the brain and what happens in adulthood as a result, the researchers carried out a meticulous comparison of the four groups, using RNA sequencing at the single-cell level in the hippocampus, which plays an important role in social functioning. The comparison revealed that early trauma left a mark on different types of cells, primarily affecting gene expression in the two subpopulations of neurons belonging to the glutamatergic excitatory system and the GABA inhibitory system. This effect was especially strong in mice that had been exposed to both trauma in infancy and bullying as adults.
Cells in the brain communicate with one another by means of electrical signals, which can be excitatory, that is, stimulating, or inhibitory. An excitatory signal encourages communication between brain cells, whereas an inhibitory signal represses it, like the gas and brake pedals in a car. Normal brain functioning requires a balance between the excitatory and inhibitory signals, which is lacking in many psychiatric disorders. One of the ways of assessing the brain’s electrical activity and the balance between excitatory and inhibitory signals is through electrophysiological measurements. Former staff scientist at the Weizmann Institute and now pharmaceutical electrophysiologist Dr. Julien Dine performed such measurements in the hippocampus of the mice, and the results supported the molecular findings: Exposure to trauma in early childhood disrupted the balance between excitatory and inhibitory signals in adulthood.
With these findings in hand, the researchers tried to find a way to fix the imbalance of signals that occurred as a result of early trauma. During a brief treatment window shortly after the early trauma, they gave the mice the well-known antianxiety drug diazepam, known commercially as Valium, which affects the GABA inhibitory system. The results were nothing less than stunning: The treated mice were able to fully or almost fully avoid the behavioral future that awaited them and were no longer at the foot of the social ladder.
“Understanding the molecular and functional mechanisms allowed us to neutralize the negative behavioral impact of trauma with a drug given shortly after exposure to traumatic incidents,” Kos explains. “This certainly should not be seen as a recommendation to treat young trauma patients with drugs, but our findings do highlight the importance of early treatment for successful rehabilitation.”
At any age, intense, ongoing stress can contribute to disease, from psychiatric disorders to obesity and diabetes, but in the womb and the first years of life, such stress can have dramatic ramifications. “The wars in Israel, Ukraine, Sudan and elsewhere, and the unprecedented global refugee crisis that is caused, in part, by climate change, alongside an increased understanding of the long-term harm caused by exposure to war and violence at a young age – all these highlight the need for better rehabilitation capabilities,” says Chen.
“Our new study identifies a key brain mechanism that is especially sensitive to childhood trauma. But the most exciting part is the prospect of using the plasticity of the young brain to help it recover, avoiding the toll this trauma can exact in adulthood.” – Prof. Alon Chen, Weizmann’s Brain Sciences Department
Also participating in the study were Dr. Joeri Bordes, Carlo de Donno, Dr. Elena Brivio, Stoyo Karamihalev, Dr. Alec Dick, Lucas Miranda, Rainer Stoffel, Cornelia Flachskamm and Dr. Mathias V. Schmidt from the Max Planck Institute of Psychiatry; Dr. Malte D. Luecken, Dr. Maren Büttner and Prof. Fabian J. Theis from the Helmholtz Zentrum München; Dr. Suellen Almeida-Correa from Weizmann’s Brain Sciences Department; and Serena Gasperoni from the Karolinska Institute.
Prof. Alon Chen holds the Vera and John Schwartz Professorial Chair in Neurobiology. His research is supported by the Ruhman Family Laboratory for Research on the Neurobiology of Stress; and by the Licht Family.
