Every year, over two million Americans suffer a traumatic brain injury in the United States (TBI). Survivors may be left with physical, cognitive, and emotional problems for the rest of their lives. There are currently no therapies. One of the most difficult issues for neuroscientists has been determining how a TBI affects the cross-talk between different cells and brain areas.
The current study is based on the iDISCO technique, which employs solvents to make biological samples transparent. The procedure results in a completely intact brain that can be lit with lasers and examined in 3D using specialized microscopes. The UCI team used the improved brain clearing mechanisms to map neuronal connections throughout the whole brain.
The researchers concentrated on connections to inhibitory neurons because these neurons are more prone to death following a brain injury. The researchers began by examining the hippocampus, a brain area crucial for learning and memory.
They then looked at the prefrontal cortex, a brain area that collaborates with the hippocampus. In both cases, imaging revealed that following TBI, inhibitory neurons form many more connections with neighboring nerve cells, but they become separated from the rest of the brain. “We’ve known for a long time that 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 the University of California, Irvine, whose lab conducted the study. However, until today, we haven’t been able to view what happens in the entire brain.
Hunt and his colleagues discovered a method for reversing the cleaning procedure and exploring the brain with traditional anatomical ways to gain a better look at the disrupted brain connections. Surprisingly, the data revealed that long projections of distant nerve cells remained in the damaged brain, but they no longer formed connections with inhibitory neurons. The researchers then wanted to see if inhibitory neurons could be joined to distant brain regions. To discover out, Hunt and his colleagues transplanted new interneurons into the injured hippocampus and mapped their connections, building on previous research showing that interneuron transplantation can enhance memory and reduce seizures in TBI animals.
The new neurons were given connections from everywhere around the brain. While this suggests that the injured brain may be able to repair these missing connections on its own, Hunt believes that understanding how transplanted interneurons integrate into damaged brain circuits is critical for any future attempts to use these cells for brain healing.
“Our research adds to our understanding of how inhibitory progenitors can one day be employed therapeutically to treat TBI, epilepsy, and other brain illnesses,” Hunt said. “Some have claimed that interneuron transplantation could revitalize the brain by releasing unknown compounds to improve natural regenerative potential, but we’ve discovered that the new neurons are actually hard wired into the brain.”
Hunt aims to one day develop cell treatments for those suffering from TBI and epilepsy. The UCI researchers are currently replicating the findings with inhibitory neurons derived from human stem cells. “This discovery brings us one step closer to a future cell-based therapy for patients,” Hunt said, adding that “understanding the types of plasticity that exist after an injury will allow us to reconstruct the broken brain with a very high degree of accuracy.” However, it is critical that we take small steps toward this goal, which takes time. “
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