Recovery of Retinal Terminal Fields after Traumatic Brain Injury: Evidence of Collateral Sprouting and Sexual...

The central nervous system is characterized by its limited regenerative potential, yet striking examples of functional recovery after injury in animal models and humans highlight its capacity for repair. Little is known about repair of pathways/circuits after traumatic brain injury (TBI), which results in disruption of connectivity. Here we utilize a mouse model of diffuse traumatic axonal injury (impact-acceleration TBI) in order to explore, for the first time, the evolution of structural and functional changes in the terminal fields of the injured visual system. Retinal ganglion cell (RGC) axons and synapses were genetically labeled via AAV transduction, while anterograde and transsynaptic tracers were used to mark terminals and postsynaptic cells. Functional connectivity and visual integrity were assessed by monitoring c-Fos expression following light stimulation and pattern-reversal visual evoked potentials (pVEPs). Our findings demonstrate that, although TAI results in an ∼50% loss of RGC axons and terminals, surviving RGCs undergo collateral sprouting, a form of compensatory branching of surviving axons, that restores terminal density to preinjury levels. Transsynaptic tracing and c-Fos mapping confirmed the reestablishment of connectivity, which was also associated with significant improvements in visual function as measured by pVEPs. Interestingly, the recovery process exhibited sexual dimorphism, with female mice showing delayed or incomplete repair. Moreover, collateral sprouting proceeded normally in Sarm1 knock-out mice, evidence of some independence from Wallerian degeneration. Our findings show that collateral sprouting may be an important mechanism of circuit repair in TAI and may represent a promising target for therapeutic interventions.