Melanopsin signalling: phototransduction, behavioural regulation and clinical relevance.

The first phase of funding of our WTPG contributed greatly to the discovery and initial characterisation of Opn4-based photosensitive retinal ganglion cells (pRGCs). However, there is much still to understand about this novel signalling pathway. Three key questions are addressed in our renewal: (i) How do melanopsin pRGCs signal light and what is the basis for their varied responses? The central aims in this part of the proposal are to test and extend our working model of Opn4 phototransduction and link specific elements of the pathway to the physiological diversity of pRGC responses to light; (ii) How do pRGC brain targets respond to light? The central aims here are to determine the contribution of pRGCs and rods/cones to the regulation of molecular, cellular and behavioural responses to light at the level of the brain; (iii) What is the impact of eye disease on pRGC function and the ability of human subjects to time their sleep and circadian systems? Here we wish to understand the co nsequences of common ocular diseases on pRGC photoreception and assess the impact of these deficits on human sleep, circadian timing, alertness and performance. Such information will permit the development of evidence-based guidelines for ophthalmologists.