Scientific basis:
The neuronal processing that enables us to see and recognise complex visual images like text and faces starts in the retina itself. Diseases leading to photoreceptor death cause irreversible sight loss, and yet the rest of the inner retinal circuitry remains largely intact, offering the prospect of restoring vision, by transplanting new healthy photoreceptors that might form new synaptic connections with the remaining retina. We have recently provided crucial proof-of-concept for this approach, transplanting human stem cell-derived photoreceptors into a mouse model of advanced disease (Ribeiro et al., 2021). Importantly, donor photoreceptors formed new connections in numbers sufficient to drive behavioural responses to simple light stimuli (light flash). However, it is not yet known how accurately these new connections reflect the normal wiring of the retina, or if the retina is able to process more complex visual stimuli.
Aims:
1) Using synaptic tracing techniques, you will map the neuronal connectome that is established following the transplantation of human photoreceptors in the diseased retina and compare this to that of the normal and diseased retina.
2) Using multi-electrode arrays, you will investigate how the physical connectivity established in (1) relates to the processing of patterned visual stimuli.
Techniques:
human stem cell retinal organoid cultures; transplantation; synaptic labelling and tracing techniques; histology; electrophysiology including multi-electrode arrays; programming
Y1: Learn techniques and make synaptic tracing tools
Y2: Map physical a connectome of transplanted, compared to normal, retina
Y3: Establish electrophysiological basis of rescue, compared to physical connectome