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Photopotentiation of Ganglion Cell Photoreceptors and Pupillary Light Responses

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Photopotentiation of Ganglion Cell Photoreceptors and Pupillary Light Responses Photopotentiation of Ganglion Cell Photoreceptors and Pupillary Light Responses Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Phillip Thomas Yuhas, O.D. M.S. Graduate Program in Vision Science The Ohio State University 2019 Dissertation Committee: Dr. Andrew Hartwick, Advisor Dr. Angela Brown Dr. Dean VanNasdale Dr. Jordan Renna Copyright by Phillip Thomas Yuhas 2019 i Abstract A rare subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin that enables them to capture light and signal downstream targets independently from rods and cones. These blue-light sensitive, sluggish neurons act as irradiance detectors, signaling environmental light levels to brain centers that control aspects of non-image-forming vision, including the pupillary light response. Under physiological conditions, these cells are not isolated from external modulators. The overall objective of this dissertation was to quantify how ipRGC function can be influenced by retinal neuromodulators and then explore conditions in vivo in which ipRGC modulation may occur or be altered. First, multielectrode array recordings were obtained from rat retinas in vitro to determine whether dopamine D1 receptor agonists and antagonists affect light-evoked spiking in RGCs, including ipRGCs. The D1 receptor agonist, SKF 38393, significantly increased the spiking of synaptically intact ipRGCs and ON RGCs in response to a bright, flickering blue light, compared to baseline. A delayed SKF 38393-mediated enhancement was observed for ipRGCs that were pharmacologically isolated from glutamatergic input. Exposure to a D1 receptor antagonist, SCH 23390, did not significantly alter light-evoked spiking in pharmacologically isolated ipRGCs. Second, I analyzed human pupillary light responses to different flickering light stimuli in order to determine whether prior light exposure influences the contribution of ipRGCs to the pupillary light reflex. I found that a bright stimulus that flickered between ii darkness and red and blue lights was able to progressively increase the amount of sustained pupil constriction that occurred after the offset of each light. This aspect of the pupillary light response is primarily driven by intrinsic melanopsin-related photoresponses of ipRGCs. More gradual photopotentiation was observed in the pupillary light responses to a bright, red flickering stimulus and to three dim flickering stimuli of various spectral compositions (red, blue, and red-blue alternating). Initial pulses of all these stimuli appeared to be below threshold necessary for melanopsin activation in dark adapted ipRGCs. However, these results support the premise that these relatively dim stimuli can activate melanopsin with repeated light exposures, indicating that ipRGCs have a larger dynamic range of light sensitivity than previously thought. Third, I investigated the pupillary light responses to red and blue flickering lights in human subjects suffering from post-traumatic brain injury (TBI) photophobia and compared the results to matched controls. The mean pupil responses did not differ between these two groups, but there was significantly more variability in the TBI group. This finding suggests that, although ipRGC light sensitivity does not uniformly change after a TBI, there may be heterogeneous effects of the injury on ipRGC function. In addition, I found that clinical observers cannot identify light-aversion behavior elicited by flickering red and blue lights in photophobic TBI subjects. The need remains for an objective test for detecting photophobia and monitoring its progression in individuals with TBI. iii Dedication To my wife, children, and parents iv Acknowledgements I am deeply appreciative to my PhD advisor, Dr. Andrew Hartwick, for his mentorship during the last eight years. His thoughtful guidance during my graduate school training and constructive feedback on all my various projects have made my time with him not only productive but also enjoyable. I aim to model my academic career after his example. In addition, I am thankful to Dr. Hartwick’s former and current doctoral students, including Puneet Sodhi, Patrick Shorter, and Elizabeth Galko, for their contributions to this dissertation and their continued companionship. Finally, I am grateful to Jacsen Luthy, a bright and industrious high school student. His immunohistochemistry experiments enhanced chapter two of this dissertation. v Vita 2006 ..................................... Saint Ignatius High School 2010 ..................................... B.A. Theology & Pre-medicine, University of Notre Dame 2014 ..................................... M.S. Vision Science, The Ohio State University 2014 ..................................... O.D. Optometry, The Ohio State University 2014 to present .................... Clinical Instructor, The Ohio State University Publications Yuhas, P. T., Shorter, P. D., McDaniel, C. E., Earley, M. J., & Hartwick, A. T. (2017). Blue and Red Light-Evoked Pupil Responses in Photophobic Subjects with TBI. Optom Vis Sci, 94(1), 108-117. Yuhas, P. T., Shorter, P. D., McDaniel, C. E., Earley, M. J., & Hartwick, A. T. (2019). Observer-perceived light aversion behaviour in photophobic subjects with traumatic brain injury. Clin Exp Optom. Epub ahead of print. Fields of Study Major Field: Vision Science vi Table of Contents Abstract ................................................................................................................. ii Dedication ............................................................................................................. iv Acknowledgements ............................................................................................... v Vita ........................................................................................................................ vi List of Tables ......................................................................................................... viii List of Figures ........................................................................................................ ix Chapter 1: Introduction .......................................................................................... 1 Chapter 2: Dopamine D1 receptor-mediated enhancement of ipRGC photoresponses ..................................................................................................... 13 Chapter 3: Photopotentiation of the human pupillary light response after stimulation with red and blue flickering lights ......................................................... 71 Chapter 4: Observer-perceived light aversion behavior and light-evoked pupil responses in photophobic subjects with TBI .................................................. 139 Chapter 5: Conclusions ......................................................................................... 201 References ............................................................................................................ 214 Appendix: Automated processing of pupil recordings ............................................ 253 vii List of Tables 3.1 Retinal illumination caused by the red and blue light stimuli utilized on healthy human subjects .................................................................................... 95 4.1 Head injury history of TBI subjects .................................................................. 160 4.2 Retinal illumination caused by the red and blue light stimuli utilized on the TBI, control, and student subjects ............................................................... 161 4.3 Demographics of TBI and control subjects ...................................................... 172 4.4 Medications prescribed to the TBI and control subjects during the study ........ 173 4.5 Demographics of student study group ............................................................ 173 4.6 Standard video grading scale ......................................................................... 182 viii List of Figures 2.1 Schematic representation of in vitro retinal recordings .................................... 31 2.2 Comparison of ipRGC density in rat retina to density of electrodes on MEA array ........................................................................................................ 42 2.3 Group data showing effect of D1 dopamine receptor agonist on ON RGCs ..... 43 2.4 Representative spike rasters showing the effects of D1 dopamine receptor agonist on an ipRGC ............................................................................... 44 2.5 Group data showing effect of D1 dopamine receptor agonist on ipRGCs ........ 45 2.6 Pulse-by-pulse effect of a D1 dopamine receptor agonist on ipRGCs ............. 47 2.7 Effect of D1 dopamine receptor agonist on pharmacologically isolated ipRGCs ................................................................................................... 48 2.8 Effect of D1 dopamine receptor antagonism on ON RGCs .............................. 50 2.9 Effect of D1 dopamine receptor antagonism on ipRGCs.................................. 51 2.10 Effects of D1 dopamine receptor antagonism on pharmacologically-isolated ipRGCs ....................................................................... 53 2.11 Representative spike rasters showing the effects of D1 dopamine receptor agonist on an OFF RGC .........................................................................
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