Region-specific Brain Targets Drive Circuit Formation and Maturation of Human Retinal Ganglion Cells

Human vision relies on retinal ganglion cells (RGCs), and their connectivity with distinct brain regions enables higher order visual processing. RGCs vary considerably between species, and small model organisms display distinct RGC innervation patterns from that in humans. There is thus a need for robust models of human RGC circuit formation that preserves innervation specificity. Here, we developed an in vitro microfluidics eye-to-brain connectivity model using human pluripotent stem cell (hPSC)-derived RGCs to assess brain region-specific connectivity features. We find that cultured human RGCs segregate their dendrites and axons and display axonal features that align with that of their in vivo human RGC counterparts. The addition of region-specific brain targets to human RGC axons terminals resulted in differential RGC connectivity with distinct retinorecipient brain regions. Increased synapse formation occurred between RGCs and lateral geniculate neurons relative to that with superchiasmatic nucleus neurons, mirroring in vivo innervation differences. Both retinorecipient partners induced the formation of more synapses relative to non-retinorecipient brain target controls. These results suggest that human RGC innervation properties are preserved in culture systems and that human RGCs can differentially sense and respond to retinorecipient targets to control wiring outcomes. These systems may aid in the discovery of human-specific wiring factors for potential therapeutic applications.

This study presents a novel in vitro model to investigate human retinal ganglion cell (RGC) connectivity, using human pluripotent stem cell-derived RGCs. By modeling human eye-to-brain connections in a microfluidic devise, this system reveals how human RGCs form selective, region-specific synapses with brain areas like the lateral geniculate nucleus and the suprachiasmatic nucleus. The findings demonstrate that human RGCs retain their innervation specificity presences in culture, mimicking in vivo human connectivity patterns. This model provides a powerful tool for understanding the factors controlling human-specific brain wiring, with potential applications in therapies for visual and neurological disorders.