Axonal regrowth and restoration of visual function were studied in adult rats. The optic nerve was completely cut behind the eye. The proximal and distal nerve stumps were realigned and the meninges sutured back together. During the same surgical procedure, the lens was lesioned in order to induce secondary cellular cascades, which are known to strongly support the survival of retinal ganglion cells (RGCs) and to promote axonal regeneration. The anatomical and topographic restoration of the visual pathway was assessed neuroanatomically with the aid of anterograde and retrograde tracing using fluorescent dyes. It appeared that the axons formed growth cones at the junction of the suture soon after injury, before glial cells and extracellular matrix proteins were able to cause local scar formation. Growth cones first entered the distal optic nerve stump 3 days after injury, grew through it to reach the optic chiasm approximately 3 weeks after the lesion was made, and terminated within the retinoreceptive layers of the superior colliculus 5 weeks after lesioning. Quantification of the retrogradely labeled cell bodies within the regenerating retina revealed that up to 30% of the RGCs, which includes all major cell types, were capable of regenerating their axons along the entire visual pathway. To assess whether topography was restored, double-labeling experiments were performed, revealing only crude topographic restoration during the initial stages of regeneration. However, visual-evoked potentials could be recorded, indicating that synaptic transmission in higher visual areas was relatively intact. The data show, in principle, that cut axons can regenerate over long distances within the white matter of a central nerve like the adult optic nerve, spanning over 11 mm to the chiasm and between 12 and 15 mm to the thalamus and midbrain. The findings suggest, for the first time, that lentogenic stimulation of RGCs is sufficient to induce the formation of growth cones that can override inhibitors at the site of injury, grow through the white matter of the optic nerve, pass through the optic chiasm, and make synaptic connections within the brain. (c)2001 Elsevier Science.