Photoreception in ipRGCs and Their Developmental Roles in Neural Circuit Formation and Refinement

Neuroscience;Circadian;Development;Neuroscience

Chew, Kylie ShannonHattar, Samer ;

Johns Hopkins University

关键词: Neuroscience;    Circadian;    Development;    Neuroscience;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39287/CHEW-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

During development, neurons must form a precise network in order to generate a variety of complex behaviors. It is critical for many neurons to accurately achieve both local and long-distance connections. Retinal ganglion cells (RGCs) must both be integrated into the network of retinal neurons and form precise long-distance connections with a variety of different brain nuclei. Thus, these cells provide an excellent system to investigate the mechanisms underlying key processes of neural development.My thesis work has focused on intrinsically photosensitive retinal ganglion cells(ipRGCs) because these cells are one of the few RGC subtypes that has highly specific molecular marker, which allows for the production of many genetic tools. Additionally, ipRGCs have defined projections that are distinct from other RGC subtypes, and ipRGCs have a well-established role in several testable behaviors, which provide a reliable output of their function. While ipRGC have a well-established role in mediating non-image light responses such as circadian photoentrainment, these cells are functional at early postnatal stages. Using genetic tools, labeling methods, and a variety of light cycles and conditions, I investigated how ipRGCs become integrated into retinal circuitry and whether they can influence the development of non-image or image forming visual systems. I found that ipRGCs undergo proximity-dependent Bax-mediated apoptosis to become evenly distributed across the retina and that disrupting this retinal mosaic impairs integration of ipRGCs into retinal circuitry. Additionally, I found ipRGCs are necessary during development to set the period of the circadian clock, a process that I further showed to be light-dependent. ipRGCs also have a light-independent developmental role in regulating the spatiotemporal properties of spontaneous activity in the retina, and without this regulation, retinotopic circuitry in the brain abnormal, which in turn results in reduced visual acuity. Lastly, since ipRGCs have a critical light-dependent role in circadian regulation, I investigated the phototransduction cascade of ipRGCs, and revealed that it is more complicated than previously appreciated. My graduate work has extended our understanding of how ipRGCs develop and revealed their critical role in the development of both the circadian and image forming visual systems.