We know that the brain changes after traumatic injury, and now we have mouse maps showing what that change looks like.
A team of scientists has traced connections between nerve cells throughout the brains of mice, showing that distant parts of the brain become detached after a head injury.
The stunning visualizations of brain-wide connectivity could help scientists understand how a traumatic brain injury, or TBI, changes crosstalk between different cells and regions of the brain, first in mice and then in humans.
“We have known for a long time that the communication between different brain cells can change very drastically after an injury,” say neuroscientist and study author Robert Hunt of the University of California, Irvine (UCI), who envisioned the project ten years ago.
“But we haven’t been able to see what’s happening in the whole brain until now.”
There’s still so much we don’t quite understand traumatic brain injuryallowing people with lifelong disabilities to feel like shadows of their former selves and almost unrecognizable to family.
A TBI occurs when a blow to the head — often from a fall, car accident, sports collision, or physical assault — causes the brain to bounce inside the skull, causing permanent damage.
Repeated head trauma leading to a serious condition known as chronic traumatic encephalopathy include: well documented in professional athletes. But even “mild” head jerks called concussions can… manifest damage years lateraccording to recent research.
No two head injuries are usually the same, making them challenging to study, although there are common symptoms: memory problems, communication problems, attention deficits, depressionand emotional instability, just to name a few.
However, linking behavioral, emotional and brain function changes to changes in specific brain cells or broader neural networks is one of the important tasks as researchers hope to better understand how brain damage develops and whether its onset can be prevented.
In this study, Hunt and the team, led by fellow neuroscientist and UCI researcher Jan Frankowski, devised a few new and improved techniques to map connections between nerve cells throughout the brain in a mouse model that replicates TBI using a dazzling array of laser-illuminated fluorescent labels.
By this time, iDISCO was well established and we modified the clearing protocols to achieve strong immunolabeling in an entire injured brain, without separating the brain into two hemispheres as is usually done. pic.twitter.com/5qborRCuNN
— robert hunt 🔥 (@hunt_lab) June 14, 2022
Of particular interest was a group of neurons called somatostatin interneurons, which control the input and output of local brain circuits and are among the most vulnerable to cell death following brain injury.
The trick was to inject whole mouse brains with chemicals to make the fully intact, jelly-like organs transparent and image them before cutting the tissue into thin sections for further inspection under microscopes.
What the researchers saw was striking. Two months after an injury to the hippocampus, a brain region involved in learning and memory, neural circuits in the brains of mice had reconfigured themselves.
Surviving somatostatin interneurons in the hippocampus became ‘hyperconnected hubs’, rich in short-range connections but disconnected from long-range inputs; the same connectivity changes were also seen in distant regions of the brain, not directly injured.
“It appears that the whole brain is being carefully rewired to accommodate the damage, regardless of whether there was direct injury to the region or not,” explains Alexa Tierno, a neuroscience graduate student at UCI and co-first author of the study.
“But different parts of the brain probably don’t work together as well as they did before the injury.”
In their imaging studies, the team also found signs that the machine brain cells used to establish distant connections remained intact after severe injury. This bodes well for recovery because, Hunt says, it suggests there’s a way to trick the injured brain into repairing lost connections on its own.
Based on previous workthe researchers grafted new neurons into the animals’ brains, at the site of injury, and found that newly transplanted cells were able to intertwine with existing, damaged circuitry and receive input from all over the brain.
So we transplanted SST interneurons into the brain-injured hippocampus and mapped their connections. The new SST interneurons received appropriate connections from all parts of the brain, providing a potential circuit base for interneuron cell therapy pic.twitter.com/MPATNJn6fv
— robert hunt 🔥 (@hunt_lab) June 14, 2022
“Some people have suggested [brain cell] transplantation can rejuvenate the brain by releasing unknown substances to stimulate its innate regenerative capacity,” say Hunt. “But we find that the new neurons really do connect in the brain.”
However, it is not the only approach. Other research considers the possibility that strengthening existing connections through learning could help restore brain function after injury, and it could. encourage new brain cells to growa process that slows down with age.
With cell-based therapies still a long way off, the researchers behind this latest study say their next steps will be to look at what can happen to other cell types (they’ve only studied one) and in other brain regions after injury.
Examining whether the brain-wide circuit changes seen in mice are also evident in people who have suffered a traumatic brain injury, and whether they may contribute to disability and epilepsy, will be another real test further on.
“Understanding the types of plasticity that exist after injury will help us rebuild the injured brain with a very high degree of precision,” say Hunt. “However, it is very important that we move towards this goal step by step, and that takes time.”
The study is published in Nature Communication.
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