Intrinsically photosensitive retinal ganglion cells are the primary but not exclusive circuit for light aversion
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.
- SourceAvailable from: Carly M. Moody
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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. "
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
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ABSTRACT: It is now a decade since the first published reports that a small proportion of mammalian retinal ganglion cells are directly photoresponsive. These cells have been termed intrinsically photosensitive retinal ganglion cells (ipRGCs) and comprise a small proportion of the total population of retinal ganglion cells. The demonstration that these ganglion cells respond to light even when isolated from the rest of the retina established them as potentially autonomous photoreceptors, overturning the dogma that all visual information originates with rods and cones. It also provided a focus for what has developed into a new branch of visual science. Here we place the discovery of ipRGCs into context and review the development of this field over the last decade, with particular emphasis on prospects for practical application.Current biology: CB 02/2013; 23(3):R125-33. DOI:10.1016/j.cub.2012.12.029
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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