A study of the molecular mechanism which induces the remodeling of cortico-mesencephalic tract after brain injury

概要

Neural circuits are known to be reorganized after brain injury, contributing to functional recovery. It is known that after the unilateral cortical lesion axons from the intact cortex sprout and project to the denervated midbrain to establish a compensatory neural circuit. However, the underlying molecular mechanisms remain largely unknown. A hypothesis is that the molecules to induce axonal sprouting and projection are expressed in the denervated targets. To address this issue, the gene expression profiles were examined in the denervated and intact mice midbrains after the hemispherectomy at P6, when the ectopic axonal projection robustly occurred. The analysis showed that various genes were significantly upregulated in the denervated midbrain, and were mostly found to be expressed by astrocytes or microglia. To identify the underlying molecules, I knocked-out their receptors in layer V projection neurons in the intact cortex using the CRISPR/Cas9 mediated method, and studied axonal projection from the knocked out cortical neurons. The result showed that the ectopic projection was significantly reduced when Integrin beta 3 (Itgb3) or Neurotrophic receptor tyrosine kinase 2 (Ntrk2, also known as TrkB) was knocked out. Taken together, the present study suggests that after unilateral cortical injury, the midbrain-derived factors are involved in the remodeling of the cortico-mesencephalic tract.