In the mammalian retina, a small population of retinal ganglion cells are intrinsically photosensitive due to the expression of the photopigment melanopsin. These intrinsically photosensitive retinal ganglion cells (ipRGCs) integrate their own intrinsic light response with that of rod and cone photoreceptors to drive a variety of physiological and behavioural responses to light. Recently, however, a subset of these cells have been shown to project to the dorsal Lateral Geniculate Nucleus (dLGN) of the visual thalamus, where they directly contribute to visual perception. In the case of retinal degenerations (the most common being retinitis pigmentosa which affects up to 1:2000 people worldwide), the death of the rod and cone photoreceptors results in complete visual blindness with no available treatment. At least some ipRGCs survive retinal degeneration and can continue signalling light information to the dLGN, suggesting that these cells could support some form of visual perception. However, to-date little is known about this projection during retinal degeneration. Thus, characterising its anatomy and physiology is key to determining the quality of visual information that is conveyed to the dLGN during retinal degeneration and what prevents these cells supporting behaviourally relevant vision. A subset of ipRGCs target the dLGN and continue signalling light information even at advanced stages of retinal degeneration. However, it is unknown whether all ipRGC subtypes survive following the death of rod and cone photoreceptors, and whether they retain normal dendritic architecture following reorganisation of the remnant neural retina. We set out to answer these questions using the multi-colour labelling technique Brainbow. In doing so, we design and describe a unique methodology and toolset, based on Principal Component Analysis (PCA), to analyse 3-Dimensional (3D) multi-colour images. We then demonstrate its utility by identifying, isolating and reconstructing the 3D morphology of individual ipRGCs from a population of labelled cells in the degenerate retina and quantitatively characterise their dendritic architecture. The results indicate that all known ipRGC subtypes are resilient to the effects of outer photoreceptor degeneration. Melanopsin responses in the dLGN have been shown to support global brightness perception in mice with advanced retinal degeneration. However, to-date, it is unknown whether these cells can encode spatial information. Using in-vitro and in-vivo electrophysiological recordings from mice in advanced stages of retinal degeneration, we demonstrate for the first time that ipRGCs in the retina, and their target neurones in the dLGN, possess discrete spatial receptive fields. These receptive fields are large and lack a centre-surround organisation. The retinotopic organisation of these cells' projections would suggest they could support spatial vision. However the poor temporal resolution of the deafferented melanopsin response is the most significant limitation precluding melanopsin signalling from supporting behaviourally relevant vision under naturalistic viewing conditions. Considering these temporal limitations, we finally investigated if melanopsin could contribute to visual perception at earlier stages of degeneration which is more representative of clinical conditions in humans. Here, vision can rely on both the intrinsic melanopsin-driven light response and residual cone function. Using silent substitution in combination with in-vivo electrophysiological recordings from the dLGN of mice in early-stage degeneration, we identify a number of cone-driven responses which could support normal visual function. However, we were unable to detect a significant and robust contribution of melanopsin signalling to these residual light-responses using our silent substitution stimuli in both retinally degenerate and wildtype mice at these age. However, we did find a significant contribution to the Olivary Pretectal Nucleus (OPN) of visually intact mice at equivalent ages, and to the adult dLGN. Supported by anatomical data, this suggests that there is a specific temporal delay in the maturation of ipRGCs which project to the dLGN during development of the visual system.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:713590 |
| Date | January 2017 |
| Creators | Procyk, Christopher |
| Contributors | Lucas, Robert |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/the-contribution-of-melanopsin-signalling-to-imageforming-vision-during-retinal-degeneration(6013b730-e5ed-43b3-abff-81c9ca354935).html |
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