Intrinsically photosensitive retinal ganglion cells are the primary but not exclusive circuit for light aversion

ArticleinExperimental Eye Research 105 · October 2012with11 Reads
DOI: 10.1016/j.exer.2012.09.012 · Source: PubMed
Abstract
Photoallodynia (photophobia) occurs when normal levels of light cause pain ranging from uncomfortable to debilitating. The only current treatment for photoallodynia is light avoidance. The first step to understanding the mechanisms of photoallodynia is to develop reliable animal behavioral tests of light aversion and identify the photoreceptors required to initiate this response. A reliable light/dark box behavioral assay was developed that measures light aversion independently from anxiety, allowing direct testing of one endophenotype of photoallodynia in mice. Mice lacking intrinsically photosensitive retinal ganglion cells (ipRGCs) exhibit reduced aversion to bright light, suggesting these cells are the primary circuit for light aversion. Mice treated with exogenous μ opiate receptor agonists exhibited dramatically enhanced light aversion, which was not dependent on ipRGCs, suggesting an alternative pathway for light is engaged. Morphine enhances retinal electrophysiological responses to light but only at low levels. This suggests that for the dramatic light aversion observed, opiates also sensitize central brain regions of photoallodynia. Taken together, our results suggest that light aversion has at least two dissociable mechanisms by which light causes specific allodynia behaviors: a primary ipRGC-based circuit, and a secondary ipRGC-independent circuit that is unmasked by morphine sensitization. These models will be useful in delineating upstream light sensory pathways and downstream avoidance pathways that apply to photoallodynia.
    • "In this study, NTG induced light aversion at non-aversive, moderate illumination levels at a dose and time that is known to activate TG neurons, increase pain responses, and trigger migraine in susceptible individuals and migraine-and painrelated symptoms in mice (Olesen et al., 1994; Tassorelli et al., 2005; Pradhan, 2012). The difference in light aversion between pre-and post-NTG is comparable to the difference in light aversion between 0 and 1000 lux in mice with dilated pupils (Matynia et al., 2012). While there is not a linear relationship between light aversion and light levels, this is nonetheless indicative of a high degree of sensitization. "
    [Show abstract] [Hide abstract] ABSTRACT: The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve. Here, we show that melanopsin is expressed in both human and mouse TG neurons. In mice, they represent 3% of small TG neurons that are preferentially localized in the ophthalmic branch of the trigeminal nerve and are likely nociceptive C fibers and high-threshold mechanoreceptor Aδ fibers based on a strong size-function association. These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. Mice with severe bilateral optic nerve crush exhibit no light-induced responses including behavioral light aversion until treated with nitroglycerin, an inducer of migraine in people and migraine-like symptoms in mice. With nitroglycerin, these same mice with optic nerve crush exhibit significant light aversion. Furthermore, this retained light aversion remains dependent on melanopsin-expressing neurons. Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior.
    Full-text · Article · Aug 2016
    • "At the start of each trial, a lux meter (Traceable Dual-Range light meter, VWR International , Radnor, PA, USA) was used to measure light intensity in the light and dark compartments; measurements in the dark compartment did not exceed 3 lx and the darkest corner of the light compartment exceeded 700 lx. Past studies using the light–dark paradigm have shown that mice find 500 lx aversive (Costall et al., 1989; Matynia et al., 2012). A Plexiglas lid with two holes (1.6 cm diameter), each centrally placed above the light and dark compartments, was custom made to fit the testing apparatus. "
    [Show abstract] [Hide abstract] ABSTRACT: Isoflurane and carbon dioxide (CO2) gas are used for rodent euthanasia. This study compared mouse aversion to isoflurane versus gradual-fill CO2 gas, and compared two methods of isoflurane delivery: vaporiser and drop. Mouse acclimation to a light–dark apparatus was used to create a light aversion test based on an unconditioned preference for dark versus light areas. Mice chose between remaining in a dark compartment with rising concentration of one of three treatments (20% gradual-fill chamber vol/min of CO2, n = 8; 5% isoflurane administered using a vaporiser set at 4 L/min oxygen flow, n = 9; or 5% liquid isoflurane dropped on gauze, n = 9), or escaping to a brightly lit compartment. On average (±S.E.) mice left the dark compartment after 29.2 ± 6.1 s in the isoflurane vaporiser treatment. Initial withdrawal time was lower for the CO2 treatment (P = 0.04), averaging 16.6 ± 2.8 s, and lower still for the isoflurane drop treatment (P < 0.001), averaging 2.9 ± 0.79 s. Five of nine mice became recumbent in the dark compartment when exposed to the isoflurane vaporiser treatment compared to only two of nine mice during the drop treatment (P = 0.3) and zero of eight mice during the CO2 method (P = 0.03). The isoflurane concentrations rose more quickly using the drop versus the vaporiser method, likely explaining the increased willingness of mice to be exposed to isoflurane administered via a vaporiser machine. Re-exposure to isoflurane with the vaporiser was more aversive than initial exposure; only two of nine mice stayed in the dark compartment until recumbency. These results support the recommendation that mice with no previous exposure to isoflurane should be euthanised using isoflurane administered by a vaporiser rather than CO2 gas, and suggest that the drop method (as applied in the current study) is not a suitable alternative.
    Full-text · Article · Sep 2014
    • "Open and brightly lit spaces are typically characterized as dangerous environments, making a light/dark box exploration assay a good measure for anxiety and anxiolytic drugs.106,107 Avoidance of light in a light/dark box is melanopsin-108,109 and ipRGC-dependent98 however anxiety from novel environments increases the level of light aversion,98,110 indicating that ipRGCs mediate both innate and anxiety-induced light aversion. The aversive capacity of light is also observed in mice in pavlovian, associative conditioning to a noxious stimulus.111,112 "
    [Show abstract] [Hide abstract] ABSTRACT: Mammalian vision consists of the classic image-forming pathway involving rod and cone photoreceptors interacting through a neural network within the retina before sending signals to the brain, and a non image-forming pathway that uses a photosensitive cell employing an alternative and evolutionary ancient phototransduction system and a direct connection to various centers in the brain. Intrinsically photosensitive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin, which is independently capable of photon detection while also receiving synaptic input from rod and cone photoreceptors via bipolar cells. These cells are the retinal sentry for subconscious visual processing that controls circadian photoentrainment and the pupillary light reflex. Classified as irradiance detectors, recent investigations have led to expanding roles for this specific cell type and its own neural pathways, some of which are blurring the boundaries between image-forming and non image-forming visual processes.
    Full-text · Article · Sep 2013
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