Interplay between retinal light responses and the circadian clock, and their implications for retinal degenerative diseases

• Main Author: Palumaa, Teele
• Format: Dissertation
• Language: English
• Published: University of Oxford 2021
• Subjects: Circadian rhythms; Retina

Multiple aspects of mammalian physiology display circadian rhythms, which allow the organism to better adapt to the external environment. Several circadian rhythms, such as the sleep-wake cycle and the retinal function, are primarily regulated by light detection in the retina. The molecular properties of melanopsin, a blue light sensitive photopigment expressed in a subset of retinal ganglion cells, make it ideal for encoding environmental light levels. Indeed, melanopsin has been shown to regulate several aspects of the retinal circadian function. However, the molecular mechanisms underpinning melanopsin's role in retinal circadian rhythms remain unknown. By analysing the circadian transcriptome of wild-type and melanopsin-null retinas, I discovered that the absence of melanopsin leads to dampened rhythmicity in the expression of core clock genes. Furthermore, while the melanopsin-null retinas retained the rhythmic expression of dopamine- related and gap junction genes, the circadian rhythmicity of sphingolipid and phototransduction pathways were aberrant. Alongside its role in the retinal circadian clock, melanopsin is also modulat- ing functional aspects of retinal light adaption, and it has been suggested that melanopsin may mediate retinoprotection in response to bright light exposure. However, using a mouse model of light-induced retinal damage, I did not detect an increased susceptibility to light damage in animals lacking melanopsin. I further studied how well the mouse model of retinal light damage mirrors the human retinal degenerations. I conducted a meta-analysis of all available datasets probing retinal transcriptome changes in this model and discovered that the genes affected by light damage were enriched for genes implicated in human retinal degenerations, indicating that the model indeed mimics the molecular aspects of human diseases. Finally, melanopsin signalling also regulates the central light responses in the suprachiasmatic nucleus (SCN), but several reports on its role in retinal light sensitivity are conflicting. Therefore, I further researched how retinal and SCN responses to light are regulated. I found that the retinal light responses of animals lacking melanopsin were slightly attenuated, similarly to what is known about their SCN light responses. However, in a mouse model showing increased SCN light sensitivity, the retinal responses were not enhanced, suggesting differential regulation of the retinal and SCN light sensitivity. These results provide valuable insights into the molecular and functional aspects of retinal light responses in both local and central circadian rhythms, and dissect their implications for retinal degenerative diseases, together providing a wealth of avenues for future research.