live imaging of tbi

TBI poses a significant socio-economic burden and currently there are no clinical therapeutics for it. In contrast to mammals, zebrafish are able to efficiently repair their central nervous system: after a spinal cord injury, adult fish regain full swimming activity within 6 weeks; likewise, brain injuries are rapidly resolved in zebrafish and functional integration of newborn neurons occurs.

Several wound healing paradigms have revealed that the early phase after an injury is critical for later regenerative and reparative success. For instance, an early calcium wave instructs neighbouring cells to initiate the wound repair process. We hypothesised that this may also happen in the brain. I developed a novel brain injury model in optically transparent larval zebrafish. Using fluorescent genetic reporter lines for calcium (to assess calcium waves and neuronal activity), nuclei (to assess tissue architecture) and microglia/macrophages (to assess immune recruitment), I found that:

• larval zebrafish are able to repair brain injuries within 2 days
• injury elicits an early calcium wave followed by persistent neuronal activity
  • the early calcium wave is important for later recovery, while the latter mimicks excitotoxicity in the mammalian brain and contributes to secondary neuronal cell death
• microglia/macrophages are recruited to the injury rapidly and phagocytose dead cells
• if phagocytosis of dead cells is disrupted genetically or pharmacologically after an injury, secondary cell death is exacerbated

Thus, the results of this project suggest a neuroprotective role for early phagocytosis of dead cells after an injury, which we hypothesized may help to shift microglia/macrophages to a pro-regenerative phenotype (see follow-up project).

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