Restoration of Higher-Order Cortical Processing in Rat V2 by Retinal Sheet Transplants in Degenerated Rats

Abstract

Age-related macular degeneration (AMD) is a leading cause of central vision loss, and effective treatment options are limited once photoreceptors and the retinal pigment epithelium (RPE) are lost. In advanced stages, vision restoration requires strategies that replace or bypass degenerated retinal circuitry. Retinal sheet transplantation using fetal neural retinal tissue has emerged as a promising intervention, demonstrating long-term survival, integration with the host retina, and partial restoration of light-driven responses. We previously showed that such transplants can restore fundamental visual response properties in the primary visual cortex (V1) of rapidly degenerating rats. However, it remains unclear whether restored retinal input can support higher-order cortical computations that depend on the integration of classical and extra-classical receptive field mechanisms. In this study, we extend this investigation by evaluating whether fetal retinal sheet transplants can restore extra-classical surround modulation in neurons of higher visual areas (V2). Fetal retinal sheets (E18-E19) derived from donor rats were transplanted into one eye of Rho-S334ter line-3 rats at ages P41-P78, when rod degeneration is nearly complete and cones are largely nonfunctional. Animals were assessed 2.2-9.3 months post-surgery using in vivo extracellular single-unit recordings from V2, optokinetic testing, OCT imaging, and histology. Control groups included normal-vision rats, age-matched degenerated rats (AMC), and sham-operated line-3 rats. Transplants survived long term, developed laminated and rosetted photoreceptor structures, and integrated with the host retina. Optokinetic testing revealed significant improvement in spatial acuity in transplanted eyes compared with degenerated controls beginning at three months post-surgery. Transplanted rats exhibited a markedly higher proportion of visually responsive V2 neurons than degenerated animals (21.0% vs. 8.2%). They also showed significantly shorter response latencies and larger visually evoked response amplitudes, indicating improved transmission of retinal signals to the cortex. To quantify surround suppression, neurons were tested with sinusoidal gratings confined to the classical receptive field and gratings extended to full-field size. Transplanted rats displayed robust surround suppression properties similar to normal controls, including significantly reduced firing rates and narrower tuning under full-field conditions. A Support Vector Machine (SVM) classifier trained on net responses to CRF and FF stimulus sizes reliably distinguished control and transplanted neurons from degenerated ones but could not separate control from transplant, further indicating similar response properties in these two groups. These findings provide the first demonstration that retinal sheet transplants restore not only basic visual responses but also higher-order cortical mechanisms involving extra-classical surround suppression. This recovery of surround suppression in V2 suggests that transplanted retinal tissue can re-establish functionally meaningful circuits capable of supporting complex visual processing. The results underscore the therapeutic potential of retinal sheet transplantation for advanced retinal degenerative disease and provide the first evidence of surround suppression in the rat V2.