Scientists at the University of California at Irvine have found that injury to one part of the brain changes the connections between nerve cells throughout the brain. The new research was published this week in Nature Communication.
Each year in the United States, nearly two million Americans suffer a traumatic brain injury (TBI). Survivors can live with lifelong physical, cognitive and emotional disabilities. Currently, there is no treatment.
One of the biggest challenges for neuroscientists has been to fully understand how a TBI alters crosstalk between different brain cells and regions.
In the new study, the researchers improved a process called iDISCO, which uses solvents to make biological samples transparent. The process leaves behind a fully intact brain that can be illuminated with lasers and imaged in 3D with specialized microscopes.
Using enhanced brain-cleansing processes, the UCI team mapped neural connections throughout the brain. The researchers focused on connections to inhibitory neurons because these neurons are extremely vulnerable to death after brain injury. The team first looked at the hippocampus, a region of the brain responsible for learning and memory. Next, they studied the prefrontal cortex, a region of the brain that works with the hippocampus. In both cases, imaging showed that inhibitory neurons gain significantly more connections with neighboring nerve cells after TBI, but disconnect from the rest of the brain.
“We’ve known for a long time that communication between different brain cells can change very dramatically after injury,” said Robert Hunt, PhD, associate professor of anatomy and neurobiology and director of the Center for Epilepsy Research at the University. ‘UCI School of Medicine whose lab conducted the study, “But, we haven’t been able to see what’s going on in the whole brain so far.”
To take a closer look at damaged brain connections, Hunt and his team developed a technique to reverse the cleaning procedure and probe the brain with traditional anatomical approaches.
The results surprisingly showed that the long distant nerve cell projections were still present in the damaged brain, but no longer formed connections with the inhibitory neurons.
“It appears that the entire brain is carefully rewired to accommodate the damage, whether or not there was direct injury to the region,” explained graduate student and study co-first author Alexa Tierno. “But different parts of the brain probably don’t work as well together as they did before the injury.”
The researchers then wanted to determine whether it was possible to reconnect inhibitory neurons with distant brain regions. To find out, Hunt and his team transplanted new interneurons into the damaged hippocampus and mapped their connections, based on the team’s previous research showing that transplanting interneurons can improve memory and stop seizures in mice with TBI.
The new neurons received appropriate connections from across the brain. While this may mean it might be possible to trick the injured brain into repairing those lost connections on its own, Hunt said learning how transplanted interneurons fit into damaged brain circuitry is essential for any future attempts. to use these cells for brain repair.
“Our study is a very important addition to our understanding of how inhibitory progenitors may one day be used therapeutically for the treatment of TBI, epilepsy, or other brain disorders,” Hunt said. “Some people have proposed that transplanting interneurons might rejuvenate the brain by releasing unknown substances to stimulate innate regenerative capacity, but we’re seeing that the new neurons are really hard-wired into the brain.”
Hunt eventually hopes to develop a cell therapy for people with TBI and epilepsy. The UCI team is now repeating the experiments using inhibitory neurons produced from human stem cells.
“This work brings us closer to a future cell therapy for people,” Hunt said, “Understanding the types of plasticity that exist after injury will help us reconstruct the injured brain with a very high degree of precision. However, it is very important that we move step by step towards that goal, and that takes time.
Jan C. Frankowski, Ph.D.; Shreya Pavani; Quincy Cao and David C. Lyon, PhD also contributed to this study. Funding was provided by the National Institutes of Health.
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