Signal Integration and Diversification by Melanopsin-Expressing Retinal Ganglion Cells

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Signal Integration and Diversification by Melanopsin-Expressing Retinal Ganglion Cells

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Title: Signal Integration and Diversification by Melanopsin-Expressing Retinal Ganglion Cells
Author: Emanuel, Alan ORCID  0000-0002-6479-4263
Citation: Emanuel, Alan. 2016. Signal Integration and Diversification by Melanopsin-Expressing Retinal Ganglion Cells. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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Abstract: There are three classes of light-sensing cells in the mammalian retina: rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). This dissertation focuses on the signals generated by the ipRGCs, which are important for the regulation of many non-image-forming visual functions such as regulation of the circadian clock, pupillary light reflex, sleep, locomotor activity, and hormone levels. Dysregulation of these functions can have profound effects on health. How ipRGCs regulate these functions remains incompletely understood because many of their basic properties have not yet been established. To better understand ipRGCs, I conducted a quantitative electrophysiological examination of their light responses within the in vitro mouse retina.

Chapter 2 presents evidence that melanopsin, the light-sensing pigment that initiates phototransduction within ipRGCs, has three stable states that are interconverted by light. Two of these states are silent and have distinct spectral sensitivities, which allows ipRGCs to integrate over a relatively broad range of wavelengths. The stability of the active state results in the production of a persistent response that long outlasts the offset of the stimulus and allows ipRGCs to integrate light over time. Most light stimuli, including short-wavelength and white light produce a large fraction of the active state and its associated persistent response. In contrast, long-wavelength light produces a much smaller fraction of the active state and can be used to decrease the persistent response. The effects of melanopsin tristability appear to be particularly suited for the functions regulated by ipRGCs. These effects are absent in other known photoreceptors, which have pigments with only one or two stable states.

IpRGC phototransduction persists for minutes even after illumination has ceased because the signaling state of melanopsin is thermally stable. In Chapter 3, I describe experiments that examine how this persistence influences two fundamental aspects of ipRGC function: activation and adaptation. I found that increased persistence is associated with ipRGC activation that encodes a narrower band of light intensities. Thus, although persistence endows ipRGCs with temporal integration, it does so at the cost of dynamic range. In addition, persistence drives adaptation to desensitize the cell. Accordingly, acutely decreasing the persistent response with long-wavelength light can result in a subsequent recovery of sensitivity. However, this effect is highly variable across the population; some cells show greater desensitization from the long-wavelength light than resensitization from its reduction of the persistent response. Therefore, the balance of activation and adaptation differs among ipRGCs, such that light history may diversify the signals generated by the population.

There are multiple subtypes of ipRGCs, but even a single subtype regulates many distinct functions. In Chapter 4, I describe a systematic approach for examination of the diversity in the biophysical parameters governing ipRGC signaling, including phototransduction, synaptic input, passive membrane properties, and spike generation. Comparison of these parameters across cells revealed a large degree of heterogeneity both between and within two morphologically-defined ipRGC subtypes. The diversity in ipRGC signal generation does not appear to divide among ipRGCs that project to different brain regions that control distinct functions; ipRGCs that project to the hypothalamus have diverse physiological properties that are highly overlapping with the ipRGCs that project to the pretectum. This suggests that functions driven by both areas have access to information from ipRGCs with a similar, broad range of characteristics.

In summary, the research described within this dissertation has revealed that visual pigments can be tristable in physiological conditions and this tristability has unique consequences for signal generation. Furthermore, it has provided insight into the high degree of biophysical diversity that can be present even within a single, molecularly-defined type of neuron. These findings contribute to the emerging understanding of ipRGCs and their distinctions from the classical rod and cone photoreceptors.
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