A chance observation in injured mouse brains has led scientists to uncover a surprising connection between stress biology and the repair of nerve fibers.
Cells that help rebuild the brain’s protective insulation appear to use a hormone normally associated with the body’s stress response.
The discovery came from researchers at the Max Planck Institute of Psychiatry. Their findings were published in the journal Cell Reports.
Research group leader Jan Deussing had repeatedly seen unusual cell activity around areas of brain damage in laboratory mice. Whenever the brain was injured experimentally, cells seemed to gather and become active near the wound.
He knew the response was consistent, but he did not initially know which cells were responsible. Biology student Clemens Ries took on the question during a research internship and began testing markers used to identify different types of brain cells.
One marker finally provided the answer. The mysterious cells were oligodendrocyte progenitor cells, or OPCs, which are immature cells capable of becoming myelin-producing oligodendrocytes.
Myelin is a fatty protective layer around many nerve fibers in the brain and spinal cord. It allows electrical messages to travel efficiently and also helps keep nerve fibers healthy.
Loss of myelin can have serious consequences. Multiple sclerosis is perhaps the best-known example because the immune system damages myelin, interfering with signals between the brain and the rest of the body.
Brain injuries can damage myelin too. If the damage becomes severe enough, nerve fibers and eventually entire nerve cells may be lost, making the body’s ability to rebuild myelin an important part of recovery.
Ries found that OPCs rapidly increased around injured brain tissue. Many of these cells later developed into mature oligodendrocytes, giving the brain new cells capable of replacing damaged myelin.
Then the researchers noticed something much less expected. Around one third of OPCs close to the injury switched on production of corticotropin-releasing hormone, better known as CRH.
CRH is famous for its role in stress. It helps start a chain of biological responses that prepare the body to deal with threatening or demanding situations.
Finding it in OPCs was surprising because these cells are usually discussed in relation to myelin rather than stress hormones. The study suggests they may have a more active communication role in the injured brain than scientists previously appreciated.
The CRH signal appeared very soon after damage. Researchers could detect it within hours, but after roughly three days it faded again.
Such a short burst could be important because repair requires precise timing. Cells need to multiply enough to provide replacements, but they also need to stop dividing and mature at the right moment.
To investigate this idea, the team examined CRH receptor 1, or CRHR1. This receptor allows cells to receive the message carried by CRH.
Some OPCs carried CRHR1, while nearby OPCs produced CRH. This created a possible communication system between different groups of precursor cells at the site of injury.
When the receptor was missing, OPCs multiplied more rapidly at first. However, this early increase did not improve the final repair response because fewer cells ultimately became mature oligodendrocytes and remained available to produce myelin.
The result suggests that faster cell growth is not necessarily better. CRH may act partly as a brake that prevents precursor cells from rushing through the repair process in a poorly coordinated way.
The researchers then looked beyond injury. OPCs are essential during normal development because the brain continues building and adjusting its myelin network from childhood into young adulthood.
Mice without CRHR1 had more OPCs early in development. Even after the animals reached adulthood, their brains still showed differences, including thicker myelin around particularly thin axons.
This means the CRH system appears to influence how much myelin is produced and where it is placed. The same signaling pathway may therefore help organize both normal brain development and repair after damage.
One question remains: where does CRH come from during healthy development when there is no injury? The researchers suggest neurons may release it and use the hormone as a signal to influence nearby OPCs.
That possibility creates an intriguing link with psychological stress. Neurons already release CRH under stressful conditions, and early-life stress has long been studied as a factor that can influence later mental health.
The researchers speculate that CRH effects on OPCs and myelin could be relevant to stress-related psychiatric disorders such as depression. This does not mean that changes in myelin cause depression, but it identifies a biological pathway worth investigating.
The study broadens the way scientists can think about brain cells. OPCs may not be passive waiting cells whose only purpose is to become oligodendrocytes; they may actively sense their environment, send chemical signals, and help coordinate the response to damage.
There are important limits to the findings. Most of the work was performed in mouse models, and human brains may respond differently, so the research does not yet point to a treatment for multiple sclerosis, brain injury, or depression.
Still, the study provides a strong reason to investigate CRH signaling more closely. Its most interesting finding is that a chemical associated with stress appears to control the timing of cells needed to build and repair myelin.
If the mechanism is eventually confirmed in people, scientists could explore whether carefully changing this signaling pathway might improve myelin repair. The discovery is therefore less a ready-made therapy than a new map showing researchers where an important part of the brain’s repair system may be hiding.
Source: Max Planck Institute of Psychiatry.
