Researchers at the National Eye Institute (NEI) have constructed the first detailed three-dimensional map of the neural circuitry underlying S-cone photoreceptors advancing understanding of how the eye processes not only color, but also light cues that influence mood and eye growth.

Studying a field known as retinal connectomics, which combines high-resolution imaging, artificial intelligence, and electrophysiology to map neural networks, the team revealed how S-cones connect with downstream neurons in the retina of a cone-dominant animal model. This work, published on December 1 in Proceedings of the National Academy of Sciences, sheds light on a circuit critical for perceiving short-wavelength (blue) light. 

“The retina is an ideal application for connectomics because it is an accessible part of the brain and because we already have a century of research into its circuits,” said John Ball, PhD, lead investigator and staff scientist in the NEI’s Retinal Neurophysiology Section. 

S-cone photoreceptors make up a small fraction of cones in many mammalian retinas but play an outsized role in visual and non-visual functions. In addition to contributing to color discrimination—especially the perception of blue—S-cone signals are increasingly linked to circadian rhythm regulation and mood, as blue light influences sleep and hormonal cycles. 

Because traditional lab animals like mice have retinas dominated by rod photoreceptors, the NEI team used the 13-lined ground squirrel, which has a cone-rich retina more similar to that of humans. Their connectomic reconstruction not only traced the physical connections between S-cones and other retinal neurons but also incorporated electrophysiology and electroretinography to measure circuit signaling. 

While this study focused on S-cone pathways, researchers emphasize that many aspects of color-vision circuits remain to be mapped. Further research is needed to understand how these circuits operate in other mammals with cone-dominant retinas, including humans, and how they might influence conditions like myopia and mood disorders linked to light exposure. 

The project was supported by the NEI Intramural Research Program.