Important New Maps Reveal That Head Injuries Can Rewire Whole-Brain Networks in Mice

Important New Maps Reveal That Head Injuries Can Rewire Whole-Brain Networks in Mice ...

After a trauma, we know that the brain changes, and now we have mouse maps showing how that change functions.

A team of researchers has traced connections between mouse nerve cells throughout the entire brain, demonstrating that distant parts of the brain become disconnected following a head injury.

Scientists might be interested in how a traumatic brain injury (TBI) alters cross-talk between different cells and brain regions, first in mice and then in humans.

"We've known for a long time that the communication between different brain cells can vary dramatically after an injury," says neuroscientist and study author Robert Hunt of the University of California, Irvine, who proposed the project a decade ago.

"But until now, we've not been able to see what happens in the whole body."

traumatic brain injuries are still unexplored, and can leave people with lifelong disabilities, feeling like shadows of their former self and almost unrecognizable to their families.

TBI occurs when a blow to the head, often from a car accident, sports collision, or physical assault, sends the brain ricocheting around the skull, causing permanent damage.

Professional athletes have long documented head traumas that resulted in a severe illness called chronic traumatic encephalopathy. However, even minor head traumas, such as concussions, can cause damage years later, according to new research.

No two head injuries are usually the same, making them difficult to diagnose, although there are common symptoms: memory difficulties, communication difficulties, attention deficits, depression, and emotional instability to name a few.

Nonetheless, integrating behavioral, emotional, and brain function changes to variations in specific brain cells or larger neural networks is one of the most pressing tasks at hand, as researchers aim to better understand how brain damage develops and whether or not its onset may be prevented.

Hunt and his team, led by Jan Frankowski, a fellow neuroscientist and UCI researcher, developed a few new and improved methods to map nerve connections across the entire brain in a mouse model reimagining TBI using a stunning array of laser-illuminated fluorescent tags.

iDISCO was well-established at the time, and we modified the clearing protocols to achieve strong immunoslabeling across an entire injured brain, without splitting the brains into two halves as is often done.

A group of neurons called somatostatin interneurons, which control the input and output of local brain circuits, are among the most susceptible to cell death as a result of brain injury.

The trick was to infuse whole mouse brains with chemicals to make the fully intact, jelly-like organs transparent, and then photographing them before cutting the tissue into thin sections for further examination under microscopes.

What the researchers discovered was astonishing. Two months after an injury to the hippocampus, a brain region involved in learning and memory, neural circuits in the mice's brains had reconfigured themselves.

Fragkowski et al., Nat Commun., 2022) Stained tissue sections of an uninjured and injured brain region

Somatostatin interneurons in the hippocampus became "hyperconnected hubs," rich with close-range connections but disconnected from long-range inputs; the same connectivity changes were also seen in distant areas of the brain, although they were not directly injured.

"It appears like the whole brain is being carefully rewired to accommodate for the damage, regardless of whether there was direct damage to the region or not," says Alexa Tierno, a neuroscience graduate student at UCI who was the first author of the research.

"But different parts of the brain may not be working quite as efficiently as they did before the injury."

The team found signs that the neural machinery that is used to make distant connections remained intact after a severe injury, which they believe is beneficial for recovery because it suggests there may be a way to entice the injured brain to repair lost connections on its own.

Researchers grafted new neurons into animals' brains at the injury site, and found that newly transplanted cells were capable of intertwining with existing, injured circuits and receiving input from all over the brain.

So, we transplanted SST interneurons into a brain-damaged hippocampus and mapped their connections. The new SST interneurons received appropriate connections from all over the brain, providing a potential circuit basis for interneuron cell therapy

"Some people have suggested that [brain cell] transplantation might revitalize the brain by releasing unknown substances to boost the body's inherent regeneration potential," says Hunt. "But we're also discovering that new neurons are really being hard-wired into the brain."

Nonetheless, this isn't the only approach. Other fields are considering the possibility that improving existing connections through learning might help restore brain function following injury, and thus might stimulate new brain cells to mature, a process that slows with age.

The researchers behind this new study believe their next steps will be to investigate what might be happening with other cell types (they only studied one) and in other brain regions after injury.

Another interesting exercise will be to see if the brain-wide circuit changes observed in mice are also apparent in people who have suffered a traumatic brain injury. They may also play a role in disabilities and epilepsy.

Hunt states, "Understanding the kinds of plasticity that exist after an injury will allow us to rebuild the brain with a very high degree of precision." However, it is very important that we proceed step-wise towards this goal, and that takes time."

The investigation has been published in Nature Communications.

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