Traumatic Brain Injury Neurological Recovery

Scientists from the University of California, Irvine have discovered that the problems for one part of the brain changes the connections between nerve cells over the entire brain. The new research was published now anyway Communications.

Every year in the United States, nearly 2 million Americans sustain a traumatic brain injury . Survivors can accept lifelong physical, cognitive and emotional disabilities. Currently, there are no treatments.

One of the most popular challenges for neuroscientists is to completely understand the way a TBI alters the cross-talk between different cells and brain regions.

In the new study, researchers improved upon a procedure called iDISCO, which utilizes solvents to make biological samples transparent. The procedure results in a completely intact brain that may be illuminated with lasers and imaged in 3D with specialized microscopes.

With the enhanced brain clearing processes, the UCI team mapped neural connections through the entire brain. They centered on connections to inhibitory neurons, since these neurons are incredibly vulnerable to dying following a brain injury. The team first looked at the hippocampus, a brain region responsible for learning and memory. Then, they investigated the prefrontal cortex, a brain region that works together with hippocampus. In the two cases, the imaging demonstrated that inhibitory neurons gain many more connections from neighboring nerve cells after TBI, but they become disconnected from the remaining brain.

“We’ve noted for a long time that the communication between different brain cells can change very dramatically after an injury,” said Robert Hunt, PhD, associate professor of anatomy and neurobiology and director from the Epilepsy Research Center at UCI School of Medicine whose lab conducted the study, “But, we haven’t been able to determine what goes on in the whole brain so far.”

To obtain a closer look at the damaged brain connections, Hunt and the team devised a procedure for reversing the clearing procedure and probing the mind with traditional anatomical approaches.

The findings surprisingly showed that the long projections of distant nerve cells were still present in the damaged brain, however they no more formed connections with inhibitory neurons.

“It looks like the entire mental abilities are being carefully rewired to support for that damage, regardless of whether there is direct injury to the location or otherwise,” explained Alexa Tierno, a graduate student and co-first author from the study. “But different parts of the mind probably aren’t working together as along with they did prior to the injury.”

The researchers then desired to determine if it was possible for inhibitory neurons to become reconnected with distant brain regions. To discover, Hunt and his team transplanted new interneurons into the damaged hippocampus and mapped their connections, based on the team’s earlier research demonstrating interneuron transplantation can improve memory and stop seizures in mice with TBI.

The new neurons received appropriate connections from all over the mind. Although this may mean it may be easy to entice the injured brain to repair these lost connections by itself, Hunt said learning how transplanted interneurons integrate into damaged brain circuits is important for any future make an effort to begin using these cells for brain repair.

“Our study is an extremely important addition to our knowledge of how inhibitory progenitors can one day be utilized therapeutically for the management of TBI, epilepsy or any other brain disorders,” said Hunt. “Some people have proposed interneuron transplantation might rejuvenate the brain by releasing unknown substances to enhance innate regenerative capacity, but we’re finding the new neurons are actually being hard-wired in to the brain.”

Hunt hopes to eventually develop cell therapy for those who have TBI and epilepsy. The UCI team is now repeating the experiments using inhibitory neurons produced from human stem cells.

“The work takes us one step closer to a future cell-based therapy for people,” Hunt said, “Comprehending the types of plasticity that exists after a personal injury will let us rebuild the injured brain with a very high degree of precision. However, it is very important that we proceed step wise toward this goal, which takes time.”

Jan C. Frankowski, PhD; Shreya Pavani; Quincy Cao and David C. Lyon, PhD also led to this research. Funding was provided by the National Institutes of Health.

1. Jan C. Frankowski, Alexa Tierno, Shreya Pavani, Quincy Cao, David C. Lyon, Robert F. Hunt. Brain-wide reconstruction of inhibitory circuits after traumatic brain injury. Nature Communications, 2023; 13 DOI: 10.1038/s41467-022-31072-2