Head Injuries Can Rewire Whole-Brain Networks in Mice

We know that the brain changes after severe damage, and we now have maps from mice that depict how that change looks.

A team of scientists tracked nerve cell connections throughout the whole brain of mice, demonstrating that following a head injury, distant areas of the brain become unconnected.

The remarkable visualizations of brain-wide connectivity might aid scientists in understanding how traumatic brain injury (TBI) modifies cross-talk between various cells and brain areas, first in mice and later in humans.

"We've known for a long time that the communication between different brain cells can change very dramatically after an injury," explains neuroscientist and study author Robert Hunt of the University of California, Irvine (UCI), who conceived of the experiment more than a decade ago.

"But we haven't been able to see what happens in the whole brain until now."

There is still a lot we don't know about traumatic brain injuries, which may leave people with permanent problems, feeling like shadows of their former selves, and being nearly unrecognizable to relatives.

A traumatic brain injury (TBI) occurs when a blow to the head, such as from a fall, automobile accident, sports collision, or physical attack, sends the brain ricocheting about inside the skull, causing permanent damage.

Repeated head blows have been linked to a serious illness known as chronic traumatic encephalopathy in elite sports. Recent study suggests that even'mild' head blows known as concussions can cause long-term harm.

Because no two brain injuries are the same, they are difficult to investigate, even if there are some similar symptoms: memory impairments, communication difficulties, concentration deficiencies, depression, and emotional instability, to mention a few.

However, researchers seek to better understand how brain damage develops and if it may be prevented by correlating changes in behavioral, emotional, and mental function to changes in specific brain cells or larger neural networks.

In this work, Hunt and his colleagues, lead by fellow neuroscientist and UCI researcher Jan Frankowski, used a dazzling array of laser-illuminated fluorescent tags to map connections between nerve cells throughout the whole brain in a mouse model of TBI.

Somatostatin interneurons, which govern the input and output of local brain circuits and are among the most sensitive to cell death after brain damage, were of special interest.

The secret was to inject chemicals into complete mouse brains to make the totally intact, jelly-like organs transparent, then image them before dissecting the tissue into small slices for further examination under microscopes.

What the researchers discovered was startling. Neural networks in mouse brains have reorganized themselves two months following a damage to the hippocampus, a brain area crucial in learning and memory.

Surviving somatostatin interneurons in the hippocampus formed 'hyperconnected hubs,' rich in close-range connections but isolated from long-range inputs; similar connectivity alterations were observed in distant parts of the brain that were not physically harmed.

"It looks like the entire brain is being carefully rewired to accommodate for the damage, regardless of whether there was direct injury to the region or not," says Alexa Tierno, a neuroscience graduate student at UCI and the study's co-first author.

"But different parts of the brain probably aren't working together quite as well as they did before the injury."

The scientists discovered evidence that the machinery brain cells employ to make distant connections remained intact despite a severe lesion during their imaging examinations. This is encouraging for rehabilitation, according to Hunt, since it shows that there may be a method to persuade the wounded brain to rebuild missing connections on its own.

Based on previous study, the researchers grafted new neurons into the wounded animals' brains and discovered that freshly transplanted cells were capable of tangling with existing, injured circuits and receiving input from all throughout the brain.

"Some people have proposed [brain cell] transplantation might rejuvenate the brain by releasing unknown substances to boost innate regenerative capacity," Hunt explains. "But we're finding the new neurons are really being hard-wired into the brain."

It is, however, not the only approach. Other study is looking at whether strengthening existing connections via learning might assist restore brain function after damage, as well as boosting new brain cell growth, which declines with age.

With cell-based treatments still a long way off, the researchers behind this recent study said their next steps will be to look at what happens after damage with different cell types (they only analyzed one) and in other brain locations.

Exploring whether the brain-wide circuit abnormalities shown in mice are also seen in people who have had a traumatic brain injury, and if they may lead to disability and epilepsy, will be an important next step.

"Understanding the kinds of plasticity that exists after an injury will help us rebuild the injured brain with a very high degree of precision," Hunt adds. "However, it is very important that we proceed step-wise toward this goal, and that takes time."

The study was published in Nature Communications.