Interhemispheric axonal sprouting occurs after pial removal in mice

White matter lacks the kind of plasticity that is present in the cortex, and subcortical injuries often result in permanent neurological deficits. Because cortical regions share common subcortical nuclei, creating new intergyral connections may allow for the bypass of subcortical damage. In this manuscript, a surgical interhemispheric bridge is created in mice, providing a model for an intercortical transpial bypass. To model this bypass, a midline craniotomy followed by interhemispheric (IH) pial removal was performed in C57BL/6 mice, allowing for the juxtaposition of the right and left prefrontal cortices. Adeno-associated virus (AAV) expressing tdTomato under a neuronal-specific promoter were injected into the right hemisphere. Animals were sacrificed two and four weeks after surgery, and axonal sprouting and glial changes were assessed in the "bypass" (BP) operation and sham surgery. Surgery did not result in any clear functional impairments. Removing the pia resulted in the formation of a physical connection between the hemispheres and the loss of the normal pial IH barrier. Cortical layer I became thinner with neuronal bodies in closer proximity than in the sham group. New interhemispheric axonal crossings were visible at two and four weeks in the BP group but not in the sham mice. These findings constitute the first step in the development of a cortico-cortico transpial bypass, allowing us to test a new way to surgically restore neurological function.