Traumatic brain injury changes the connections between nerve cells across the entire brain.
Scientists from the University of California, Irvine have
discovered that an injury to one part of the brain changes the connections
between nerve cells across the entire brain. The new research was published
this week in Nature Communications.
Every
year in the United States, nearly two million Americans sustain a traumatic
brain injury (TBI). Survivors can live with lifelong physical, cognitive and
emotional disabilities. Currently, there are no treatments.
One
of the biggest challenges for neuroscientists has been to fully understand how
a TBI alters the cross-talk between different cells and brain regions.
In
the new study, researchers improved upon 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.
With
the enhanced brain clearing processes, the UCI team mapped neural connections
throughout the entire 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. Then, they investigated the prefrontal
cortex, a brain region that works together with hippocampus. In both cases, the
imaging showed that inhibitory neurons gain many more connections from
neighboring nerve cells after TBI, but they become disconnected from the rest
of the brain.
"We've
known 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 of the Epilepsy
Research Center at UCI School of Medicine whose lab conducted the study,
"But, we haven't been able to see what happens in the whole brain until
now."
To
get a closer look at the damaged brain connections, Hunt and his team devised a
technique for reversing the clearing procedure and probing the brain with
traditional anatomical approaches.
The
findings surprisingly showed that the long projections of distant nerve cells
were still present in the damaged brain, but they no longer formed connections
with inhibitory neurons.
The researchers then wanted to determine if it was possible for
inhibitory neurons to be reconnected 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 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 brain. While
this may mean it could be possible to entice the injured brain to repair these
lost connections on its own, Hunt said learning how transplanted interneurons
integrate into damaged brain circuits is essential for any future attempt to
use these cells for brain repair.
"Our
study is a very important addition to our understanding of how inhibitory
progenitors can one day be used therapeutically for the treatment of TBI,
epilepsy or other brain disorders," said Hunt. "Some people have
proposed interneuron transplantation might rejuvenate the brain by releasing
unknown substances to boost innate regenerative capacity, but we're finding the
new neurons are really being hard wired into the brain."
Hunt
hopes to eventually develop 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 takes us one step closer to a future cell-based therapy for people,"
Hunt said, "Understanding the kinds of plasticity that exists after an
injury will help 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, and that takes time."
