Development and regeneration of neuronal circuits in the vertebrate retina

Thesis (Ph.D.)--University of Washington, 2016-08

Like in other parts of the central nervous system (CNS), information processing in the retina depends upon the exquisite organization of synaptic connectivity amongst diverse neuronal cell types. Assembly of neuronal circuits during retinal development is highly orchestrated. Recapitulating the precision of this process presents a major challenge for therapeutic efforts to repair the retina after injury or disease in mammals. Whereas mammals cannot replenish lost neurons in their retinas, zebrafish show an innate ability to regenerate their retinas. In this work, I sought to advance our understanding of the restorative potential of retinal regeneration. I capitalized on the native regenerative capacity of the zebrafish to provide some of the first insights into the fidelity of neuronal replacement and integration in the retina. In Chapter 1, I review the factors and mechanisms that shape organized circuitry during retinal development, as well as summarize the current state of the field in teleost and mammalian retinal regeneration research. In Chapters 2 and 3, I investigate bipolar cells, interneurons that convey light signals from photoreceptors to the retinal output neurons. In Chapter 2, I explore the cellular strategies that functionally distinct bipolar cell types undertake during retinal development to attain their characteristic morphologies and dendritic wiring patterns. I use this knowledge in Chapter 3 as a framework to assess the ability of regenerated circuits to engage developmental mechanisms to re-establish their original patterning. I utilize a genetically targeted cell ablation technique to trigger regeneration of bipolar cells in situ, and investigate the precision with which regenerated cells integrate into a mature retinal network. In Chapter 4, I examine the specificity of endogenous neuronal replacement by comparing the composition of regenerated cone photoreceptor populations after ablation of distinct cone types. Lastly, in Chapter 5 I summarize my findings and discuss future directions to address questions raised by this work.