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

Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Experimental Eye Research (Impact Factor: 2.71). 10/2012; 105. DOI: 10.1016/j.exer.2012.09.012
Source: PubMed


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.

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    • "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. "
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    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.
    Applied Animal Behaviour Science 09/2014; 158. DOI:10.1016/j.applanim.2014.04.011 · 1.69 Impact Factor
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    • "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 "
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    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.
    Journal of Experimental Neuroscience 09/2013; 7:43-50. DOI:10.4137/JEN.S11267
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    • "A limitation of the DC preference test is that although it can reveal visual deficiencies, it does not distinguish whether such deficiencies may be in image-forming vs. non-image-forming photoreception. The DC test depends on behavioral aversion to light, and this response depends more on melanopsin-positive intrinsically photosensitive retinoganglion cells than on the retinal rod and cone photoreceptors that mediate image-forming vision [25-27]. Never the less, it has been reported that mice with deficiencies in either image-forming or non-image-forming vision will fail the DC test [28], revealing at least one type of deficiency, and thus we considered the DC test to be adequate as a validation assessment for SLAG data. "
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    ABSTRACT: There is significant interest in the generation of improved assays to clearly identify experimental mice possessing functional vision, a property that could qualify mice for inclusion in behavioral and neuroscience studies. Widely employed current methods rely on mouse responses to visual cues in assays of reflexes, depth perception, or cognitive memory. However, commonly assessed mouse reflexes can sometimes be ambiguous in their expression, while depth perception assays are sometimes confounded by variation in anxiety responses and exploratory conduct. Furthermore, in situations where experimental groups vary in their cognitive memory capacity, memory assays may not be ideal for assessing differences in vision. We have optimized a non-invasive behavioral assay that relies on an untrained, innate response to identify individual experimental mice possessing functional vision: slow angled-descent forepaw grasping (SLAG). First, we verified that SLAG performance depends on vision and not olfaction. Next, all members of an age-ranged cohort of 158 C57BL/6 mice (57 wild-type, 101 knockout, age range 44--241 days) were assessed for functional vision using the SLAG test without training or conditioning. Subjecting the population to a second innate behavioral test, Dark Chamber preference, corroborated that the functional vision assessment of SLAG was valid. We propose that the SLAG assay is immediately useful to quickly and clearly identify experimental mice possessing functional vision. SLAG is based on a behavioral readout with a significant innate component with no requirement for training. This will facilitate the selection of mice of known sighted status in vision-dependent experiments that focus on other types of behavior, neuroscience, and/or cognitive memory.
    Behavioral and Brain Functions 08/2013; 9(1):35. DOI:10.1186/1744-9081-9-35 · 1.97 Impact Factor
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