Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a key role in transmitting non-image-forming visual information to the brain. Recent evidence has implicated ipRGCs in conscious vision as well as in serious conditions such as migraine pain and seasonal affective disorder. Despite the fundamental importance of ipRGCs in the visual process, the underlying synaptic mechanisms and circuits that control ipRGC function are unknown. IpRGCs express their own photopigment - melanopsin and, at high light intensities, intrinsic responses drive ipRGC function. However, surprisingly, at lower intensities, even in the photopic range, ipRGCs are predominantly driven by rods and not cones. These data suggest that a sustained signal originating from rods must travel through the retina to carry information about irradiance to ipRGCs. In this proposal, we will test the primary hypothesis that the irradiance pathway through the mammalian retina is driven via rod-to-cone gap junctions. Our preliminary studies provide evidence that a novel irradiance pathway contains the following elements: rod?rod/cone gap junction?cone?ON cone bipolar cell?ectopic synapse?M1-type ipRGCs and dopaminergic amacrine cells (DACs). In turn, M1 ipRGCs drive non-image-forming visual behavior such as the pupillary light reflex and circadian photoentrainment, while dopamine release may control network adaptation in the retina. To test these hypotheses, we have developed and validated several mouse lines in which Cx36 has been conditionally deleted in either rods or cones, and therefore lack rod/cone gap junctions.
In Aim 1, we will test the hypothesis that rod/cone gap junctions are required to drive the PLR, circadian photoentrainment and negative masking, non-imaging-forming visual functions also driven by M1 ipRGCs.
In Aim 2, we will test the hypothesis that rod/cone gap junctions are also essential for the release of dopamine, in the mammalian retina. Furthermore, we will test the hypothesis that dopamine-dependent network adaptation relies on the irradiance pathway via rod/cone gap junctions.
In Aim 3, we will test the function of the irradiance pathway at two key points: rod/cone gap junctions and ectopic bipolar synapses in the inner plexiform layer. In summary, we propose that rod/cone coupling generates an irradiance signal transmitted via ipRGCs that not only controls the pupillary light reflex, it also entrains the circadian clock every day. The biological influence of the circadian clock is pervasive yet it may be driven via gap junctions between the first two cell types in the visual system. Furthermore, there is a link between dopamine and myopia. If, in turn, the irradiance pathway controls dopamine release, this may inform a new approach to myopia.
A key function of the retina is to obtain global measures of ambient light. This irradiance signal is critical to adjust our vision in response to varying ambient light, organize our daily functions and control eye development in early life. Yet we don't know how the visual system extracts this data. The proposed project will significantly advance our understanding of irradiance signals in the retina and will contribute to the overall goal of preserving normal visual function and eye development.
