Classically, photic information was assumed to flow only from rod and cone photoreceptors through bipolar, horizontal and amacrine interneurons to retinal ganglion cells (RGCs), which were assumed to signal only to higher visual centers of the brain. Unexpectedly, the PI and colleagues discovered that a subset of RGCs, namely intrinsically photosensitive retinal ganglion cells (ipRGCs), transmit light-evoked responses intraretinally to several types of amacrine cells (ACs). The functional significance of this counterintuitive retrograde signaling is largely unknown. Since ACs are well-known to regulate the physiology of all classes of retinal neurons, the central hypothesis for this project is that retrograde ipRGC signaling serves to regulate visual processing in the retina, ultimately shaping vision. In the previous funding period the PI?s team identified gap junction (GJ) coupling as one mechanism by which ipRGCs signal to ACs. To begin to assess the roles of retrograde ipRGC signaling, the team genetically knocked out one type of GJ protein specifically in ipRGCs, and an optokinetic behavioral assay showed a reduction in the mice?s ability to track moving stripes of high spatial frequencies or low contrasts. Thus, a functional significance of gap junctional ipRGC-to-AC signaling is that it improves spatial acuity and contrast sensitivity at the behavioral level. The proposed project will test three hypothesized mechanisms by which gap junctional ipRGC-to-AC signaling could enhance acuity and contrast sensitivity.
Aim 1 will test the hypothesis that gap junctional ipRGC-to-AC signaling potentiates retinal light responses. The PI?s team will use field-potential recording of bipolar cells and recording of individual RGCs to measure how these cells? responses to single light pulses are altered when GJ-mediated ipRGC-to-AC signaling is manipulated.
Aim 2 will test the hypothesis that gap junctional ipRGC-to-AC signaling improves the ability of retinal cells to resolve repetitive changes in light intensity. The team will determine whether manipulating GJ-mediated ipRGC-to-AC signaling alters bipolar and ganglion cells? responses to flickering light.
Aim 3 will test the hypothesis that gap junctional ipRGC-to-AC signaling modulates the receptive field properties of RGCs. The team will test whether manipulating GJ-mediated ipRGC-to-AC signaling alters the sizes of RGC receptive fields and the strength of center/surround antagonism in these receptive fields. The research team has strong preliminary data in support of each Aim. The impact of this study will be to: 1) illuminate the roles of a previously overlooked but functionally important retinal signaling pathway; 2) further the appreciation of ipRGCs? contribution to image-forming vision, besides their well-known roles in nonimage-forming photoresponses such as the pupil reflex and circadian photoentrainment; and 3) elucidate the functions of GJ coupling between amacrine and ganglion cells, which remain poorly understood. A potential long-term impact of understanding retrograde ipRGC signaling, which persists following rod/cone degeneration, is to inform new strategies for restoring sight in patients suffering photoreceptor dystrophy.
The applicant and colleagues recently discovered a subset of retinal output cells that transmit light information not only to the brain like all retinal output cells do, but also to other cells within the retina. The applicant?s team has found that this unexpected, backward signaling circuit is important for light-adapted vision, and the proposed work will elucidate the mechanisms by which this circuit enhances visual acuity and contrast sensitivity. Because this novel visual pathway remains light-sensitive in rod/cone-dystrophic retinas, studies of its properties could lead to innovative strategies for restoring sight in patients suffering photoreceptor degeneration.
