Overview: A new brain mapping study finds that damage to one part of the brain changes the connections between neurons throughout the brain.
Source: UC Irvine
Scientists at the University of California, Irvine have discovered that an 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. There are currently no treatments.
One of the biggest challenges for neuroscientists has been to fully understand how a TBI changes crosstalk between different cells and regions of the brain.
In the new study, researchers improved a process called iDISCO, which uses solvents to make biological samples transparent. The process leaves a completely intact brain that can be illuminated with lasers and imaged in 3D with specialized microscopes.
With the improved brain-clearing 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 dying after a brain injury. The team first looked at the hippocampus, a brain region responsible for learning and memory.
They then examined the prefrontal cortex, a brain region that interacts with the hippocampus. In both cases, the imaging showed that after TBI, inhibitory neurons become much more connected to neighboring nerve cells, but they become disconnected 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 Epilepsy Research Center at the UCI School of Medicine, whose lab conducted the study. study: “But we haven’t been able to see what’s going on in the whole brain until now.”
To get a closer look at the damaged brain connections, Hunt and his team devised a technique to reverse the purification procedure and examine the brain using traditional anatomical approaches.
The findings surprisingly showed that the long projections from distant nerve cells were still present in the damaged brain, but they no longer formed connections with inhibitory neurons.
“It appears that the entire brain is being carefully rewired to accommodate the damage, regardless of whether there was direct damage to the region or not,” explains Alexa Tierno, a graduate student 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.”
The researchers next wanted to determine whether it was possible to reconnect inhibitory neurons to 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 interneuron transplantation can improve memory and stop seizures in mice with TBI.
The new neurons received appropriate connections from all over the brain. While this may mean it could be possible to trick the injured brain into repairing these lost connections itself, Hunt said it’s essential to learn how transplanted interneurons integrate into damaged brain circuitry for any future attempt to use these cells for brain recovery.
“Our study is a very important addition to our understanding of how inhibitory precursors could one day be used therapeutically to treat TBI, epilepsy or other brain disorders,” Hunt said.
“Some people have proposed that transplanting interneurons could rejuvenate the brain by releasing unknown substances to stimulate its innate regenerative ability, but we find that the new neurons are really stuck in the brain.”
Hunt hopes eventually to develop cell therapy for people with TBI and epilepsy. The UCI team is now repeating the experiments with inhibitory neurons produced from human stem cells.
“This work brings us one step closer to a future cell-based therapy for humans,” Hunt said. “Understanding the types of plasticity that exist after injury will help us rebuild the injured brain with a very high degree of precision. However, it is very important that we move towards this goal step by step, and that takes time.”
Jan C. Frankowski, PhD; Shreya Pavani; Quincy Cao and David C. Lyon, PhD also contributed to this study.
Financing: Funding was provided by the National Institutes of Health.
About this TBI research news
Original research: Open access.
†Brainwide reconstruction of inhibitory circuits after traumatic brain injuryby Robert Hunt et al. nature communication
Brainwide reconstruction of inhibitory circuits after traumatic brain injury
Despite the fundamental importance of understanding the brain’s wiring diagram, our understanding of how neuronal connectivity is rewired through traumatic brain injury remains remarkably incomplete.
Here we use cellular-resolution whole-brain imaging to generate brain-wide maps of the inputs to inhibitory neurons in a mouse model of traumatic brain injury.
We find that somatostatin interneurons are converted into hyperconnected hubs in multiple brain regions, with rich local network connections but reduced long-range input, even in areas not directly damaged.
The loss of input over long distances does not correlate with cell loss in distant brain regions. Interneurons transplanted to the site of injury receive orthotopic local and long-range input, suggesting that the remote connection-making machinery remains intact even after severe injury.
Our results reveal a potential strategy to maintain and optimize inhibition after traumatic brain injury, involving spatial reorganization of the direct inputs to inhibitory neurons in the brain.
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