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• Injuries to the brain of laboratory mice activate oligodendrocyte progenitor cells (OPCs), which are responsible for forming the myelin sheath.
• Activated OPCs produce the stress hormone corticotropin-releasing hormone (CRH), which plays a crucial role in the wound healing process.
• CRH receptor 1 influences the myelination of the brain, which has long-term consequences on brain structure.
• Stress in early development could activate the CRH system in OPCs and thus play a role in psychiatric disorders such as depression.
When laboratory mice suffer brain damage, e.g. from an injection, research group leader Jan Deussing has observed that a certain type of cell always appears and is activated in the immediate vicinity of the injury site. However, the experienced neurobiologist was unable to explain what kind of cells these were. This was a good project for a master's student to take a closer look at. This is how Clemens Ries came into play, who had joined the Max Planck Institute of Psychiatry for an internship shortly before completing his biology degree.
Ries began systematically testing all known cell types in a mouse model. The only marker that responded was the one for oligodendrocyte progenitor cells (OPCs). OPCs develop into oligodendrocytes, whose task is to form the myelin sheath around the axons. Axons are extensions that all nerve cells possess and through which they communicate with each other. The myelin that coats the axons is comparable to the insulation layer of an electrical cable and, in addition to transmitting information, also serves to supply nutrients, making it extremely important. In autoimmune diseases such as multiple sclerosis (MS), this protective layer dissolves. Injuries also damage the myelin layer, causing entire neurons to die in extreme cases. It is therefore important that the myelin layer is rebuilt at this point.
Cells identified and new mechanism discovered
Ries first wrote his master's thesis on the initial characterization of these cells. “The topic remained so exciting that it became my doctoral thesis,” says the biologist. In it, he was able to prove that the precursor cells proliferate massively at the edges of wounds, mature further for the most part, and develop into myelin-forming oligodendrocytes. Ries and his supervisor Deussing discovered something else completely new: in the vicinity of wounds, about one-third of all OPCs activate corticotropin-releasing hormone (CRH), which is crucial for the body's stress regulation. Until then, it was unknown that OPCs could produce neuropeptides such as CRH. This has now been published in the renowned journal “Cell Reports.”
CRH production occurs very rapidly and can be detected within a few hours as an immediate response to injury, but stops again after about three days. This acute response indicates an important function in early wound healing processes.
One of the two known CRH receptors also appears to play an important role in this process. CRH receptor 1, which is found in another population of OPCs, exerts the effect of released CRH. Without CRHR1, OPCs proliferate more rapidly as a result of injury, but ultimately fewer mature oligodendrocytes are produced and persist. CRH clearly plays a crucial role in the correct timing of OPC maturation to ensure restoration of the myelin sheath.
What happens after birth?
OPCs also play an important role in myelination during brain maturation. This occurs mainly after birth and is completed in young adulthood. Since CRH receptor 1 is also present on OPCs independently of injury, the two scientists wondered whether the receptor also plays a role in myelination during brain maturation. They consulted other colleagues and took a close look at the process of myelination in other mouse models using various methods. Here, they observed that without CRH receptor 1, more OPCs are formed in early stages of development, which has long-term consequences on the structure of the brain. In the adult brain, the experts were able to detect changes in myelination that are attributable to a thickening of the myelin sheath, particularly of thin axons.
The CRHR receptor 1 on OPCs therefore also plays a crucial role in myelination during brain development. When injured, OPCs respond by producing and releasing CRH. But where does the stress hormone CRH come from during brain maturation? The scientists' hypothesis is that during development, CRH is released by neurons and modulates the proliferation of OPCs and their maturation into myelin-producing oligodendrocytes.
Significance for psychiatric disorders
It is well known that CRH is released by neurons, especially under stressful conditions. Stress during early childhood development is one of the risk factors for psychiatric disorders. “Our current findings suggest that in stress-associated psychiatric disorders such as depression, the CRH system in OPCs may play a greater role than previously known,” Deussing speculates. In the long term, this could lead to completely new therapeutic approaches.
Dr. Jan Deussing
Cell Reports, 2025
https://doi.org/10.1016/j.celrep.2025.116474
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