Nrg1 regulates cortical wiring and motor recovery upon traumatic injury

Traumatic brain injury (TBI) is a leading cause of disability, yet molecular mechanisms supporting cortical repair remain poorly defined. While Neuregulin-1 (Nrg1) is essential for cortical development, its role in traumatic cortical injury in adults is unclear. To circumvent developmental confounds, we used an inducible conditional Nrg1 knockout in the adult mouse and subjected it to controlled cortical damage (CCD) in the motor cortex. We combined high-resolution adeno-associated viral tracing of callosal projections with comprehensive behavioral, histological, and molecular analyses. Nrg1 deletion led to significant impairments in structural connectivity and long-term motor recovery, which were markedly exacerbated in aged mice, indicating a critical role for Nrg1 in adult cortical repair. Mechanistically, our data indicated that Nrg1 promoted this plasticity through its intracellular domain (ICD) signaling, acting cell-autonomously to enhance axonal outgrowth. Furthermore, loss of Nrg1 was associated with altered structure of perineuronal-nets (PNN) and increased neuroinflammation at the lesion site. Our findings identify endogenous Nrg1 as a key regulator of structural preservation and functional recovery, highlighting the Nrg1 signaling as a potential target to enhance cortical plasticity after trauma.