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Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.

Perganta G, Barnard AR, Katti C, Vachtsevanos A, Douglas RH, MacLaren RE, Votruba M, Sekaran S - PLoS ONE (2013)

Bottom Line: There were no significant differences in any parameter tested relative to wildtype littermate controls.Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes.The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Neurosciences, Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP) mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

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Induction of sleep by acute light in Opa1+/+ and Opa1+/− mice.(A) The average immobility-defined sleep is plotted against zeitgeber time in a normal 12∶12 h LD cycle (1 h resolution) for Opa1+/+ (n = 5) and Opa1+/− (n = 6) mice. Animals were largely immobile in the day phase of the LD cycle. White background indicates the day portion and grey background the night portion of the 24 h LD cycle. (B) The effect of the administration of the 1-h light pulse (white background) at ZT 14 during the night phase is shown. Both genotypes demonstrated an increase in immobility during the light pulse (10 min resolution). Quantification of (C) sleep latency and (D) total sleep during light exposure found no significant differences between genotypes (unpaired student's t-test). All data are presented as mean ± SEM.
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pone-0056350-g004: Induction of sleep by acute light in Opa1+/+ and Opa1+/− mice.(A) The average immobility-defined sleep is plotted against zeitgeber time in a normal 12∶12 h LD cycle (1 h resolution) for Opa1+/+ (n = 5) and Opa1+/− (n = 6) mice. Animals were largely immobile in the day phase of the LD cycle. White background indicates the day portion and grey background the night portion of the 24 h LD cycle. (B) The effect of the administration of the 1-h light pulse (white background) at ZT 14 during the night phase is shown. Both genotypes demonstrated an increase in immobility during the light pulse (10 min resolution). Quantification of (C) sleep latency and (D) total sleep during light exposure found no significant differences between genotypes (unpaired student's t-test). All data are presented as mean ± SEM.

Mentions: Previous studies have shown that acute light exposure at night induces sleep in nocturnal species[19], [31], [32], [33] and that this process is distinct from the process of negative masking[19], [31]. At 200 lux, light induces sleep in wildtype mice and in rodless/coneless mice but sleep induction is impaired in melanopsin knockout mice[31]. We examined the acute effects of 200 lux light on sleep in Opa1 mutant mice and wild-type controls by administering a 1 h light pulse 2 h after the onset of dark (ZT 14) when the homeostatic and circadian drives for wakefulness are high. We used videotracking assessment of immobility as a measure of sleep which has been found to highly correlate with EEG/EMG recordings of sleep[23]. Opa1+/+ and Opa1+/− mice exhibited low immobility-defined sleep (i.e. high activity) during the dark period of a normal 12∶12 LD cycle as would be expected for a nocturnal species (Figure 4A). In response to the light pulse, a sharp increase in immobility-defined sleep was observed in both genotypes within 30 min of lights on (Figure 4B). Immobility levels subsequently declined to ∼50% of baseline by the end of the light pulse. The sleep induction response differed from negative masking where the suppression in activity levels was maintained during the entire first hour of the light pulse. This adds further support to acute light induced sleep and negative masking being distinct processes. The latency to the first 2 min of continuous immobility (sleep latency) was not significantly different between genotypes (Figure 4C). During acute light exposure, the total time spent asleep was also not significantly different between wildtype and mutant mice (Figure 4D) suggesting that both genotypes sustained the inhibitory response to light.


Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.

Perganta G, Barnard AR, Katti C, Vachtsevanos A, Douglas RH, MacLaren RE, Votruba M, Sekaran S - PLoS ONE (2013)

Induction of sleep by acute light in Opa1+/+ and Opa1+/− mice.(A) The average immobility-defined sleep is plotted against zeitgeber time in a normal 12∶12 h LD cycle (1 h resolution) for Opa1+/+ (n = 5) and Opa1+/− (n = 6) mice. Animals were largely immobile in the day phase of the LD cycle. White background indicates the day portion and grey background the night portion of the 24 h LD cycle. (B) The effect of the administration of the 1-h light pulse (white background) at ZT 14 during the night phase is shown. Both genotypes demonstrated an increase in immobility during the light pulse (10 min resolution). Quantification of (C) sleep latency and (D) total sleep during light exposure found no significant differences between genotypes (unpaired student's t-test). All data are presented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569441&req=5

pone-0056350-g004: Induction of sleep by acute light in Opa1+/+ and Opa1+/− mice.(A) The average immobility-defined sleep is plotted against zeitgeber time in a normal 12∶12 h LD cycle (1 h resolution) for Opa1+/+ (n = 5) and Opa1+/− (n = 6) mice. Animals were largely immobile in the day phase of the LD cycle. White background indicates the day portion and grey background the night portion of the 24 h LD cycle. (B) The effect of the administration of the 1-h light pulse (white background) at ZT 14 during the night phase is shown. Both genotypes demonstrated an increase in immobility during the light pulse (10 min resolution). Quantification of (C) sleep latency and (D) total sleep during light exposure found no significant differences between genotypes (unpaired student's t-test). All data are presented as mean ± SEM.
Mentions: Previous studies have shown that acute light exposure at night induces sleep in nocturnal species[19], [31], [32], [33] and that this process is distinct from the process of negative masking[19], [31]. At 200 lux, light induces sleep in wildtype mice and in rodless/coneless mice but sleep induction is impaired in melanopsin knockout mice[31]. We examined the acute effects of 200 lux light on sleep in Opa1 mutant mice and wild-type controls by administering a 1 h light pulse 2 h after the onset of dark (ZT 14) when the homeostatic and circadian drives for wakefulness are high. We used videotracking assessment of immobility as a measure of sleep which has been found to highly correlate with EEG/EMG recordings of sleep[23]. Opa1+/+ and Opa1+/− mice exhibited low immobility-defined sleep (i.e. high activity) during the dark period of a normal 12∶12 LD cycle as would be expected for a nocturnal species (Figure 4A). In response to the light pulse, a sharp increase in immobility-defined sleep was observed in both genotypes within 30 min of lights on (Figure 4B). Immobility levels subsequently declined to ∼50% of baseline by the end of the light pulse. The sleep induction response differed from negative masking where the suppression in activity levels was maintained during the entire first hour of the light pulse. This adds further support to acute light induced sleep and negative masking being distinct processes. The latency to the first 2 min of continuous immobility (sleep latency) was not significantly different between genotypes (Figure 4C). During acute light exposure, the total time spent asleep was also not significantly different between wildtype and mutant mice (Figure 4D) suggesting that both genotypes sustained the inhibitory response to light.

Bottom Line: There were no significant differences in any parameter tested relative to wildtype littermate controls.Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes.The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Neurosciences, Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP) mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

Show MeSH
Related in: MedlinePlus