NeuFRO · Inducing functionality in retinal organoids with electrical activities derived from developing retina

Deriving mammalian retina from stem cells has had a large impact on the study of the biology of vision and is called organoid. Compared to in vivo retina, retinal organoids are far less functionally sophisticated in terms of their synapses, connectivity, discrimination between different light stimuli and their electrical action potentials. This project will overcome this functional constraint of retinal organoids by studying electrophysiological events-derived functional maturation of mouse retina during retinal development and then stimulating those events with the help of mathematical models in order to induce the same functionality in mouse and human retinal organoids. NeuFRO will achieve a resonance in the field by generating retinal organoids with the neuronal connectivity and the natural diversity of functions using interdisciplinary fields including electrophysiology, developmental biology, and computationally-derived electrical stimulation. Initially, I will create a holistic roadmap of the electrical features of immature mouse retina during development that shows self-organization through electrophysiology. With milli- to nanometer imaging precision, electrical activities derived the circuit formation will be spatiotemporally documented. Then I will decode this space-time code of intrinsic electrical patterns and neuronal connectivity using an ambitious strategy incorporating Hodgkin-Huxley and linear-nonlinear models. Next, such electrical response models will be applied to immature retinal organoids (mouse and human) by an innovative ‘sandwich’ electrophysiology technique during the development in vitro. With this approach, I will induce naturalistic electrical features in the retinal organoid, allowing the functional neurons to wire and fire appropriately into retinal organoids, particularly visual circuits. This ground-breaking approach will advance techniques for generating functional human retina.