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Mice deficient of glutamatergic signaling from intrinsically photosensitive retinal ganglion cells exhibit abnormal circadian photoentrainment.

Purrier N, Engeland WC, Kofuji P - PLoS ONE (2014)

Bottom Line: The relative contribution of each neurotransmitter system for the circadian photoentrainment and other NIF visual responses is still unresolved.Other NIF responses such as the PLR and negative masking responses to light were also partially attenuated.Overall, these results suggest that glutamate from ipRGCs drives circadian photoentrainment and negative masking responses to light.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States of America.

ABSTRACT
Several aspects of behavior and physiology, such as sleep and wakefulness, blood pressure, body temperature, and hormone secretion exhibit daily oscillations known as circadian rhythms. These circadian rhythms are orchestrated by an intrinsic biological clock in the suprachiasmatic nuclei (SCN) of the hypothalamus which is adjusted to the daily environmental cycles of day and night by the process of photoentrainment. In mammals, the neuronal signal for photoentrainment arises from a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) that send a direct projection to the SCN. ipRGCs also mediate other non-image-forming (NIF) visual responses such as negative masking of locomotor activity by light, and the pupillary light reflex (PLR) via co-release of neurotransmitters glutamate and pituitary adenylate cyclase-activating peptide (PACAP) from their synaptic terminals. The relative contribution of each neurotransmitter system for the circadian photoentrainment and other NIF visual responses is still unresolved. We investigated the role of glutamatergic neurotransmission for circadian photoentrainment and NIF behaviors by selective ablation of ipRGC glutamatergic synaptic transmission in mice. Mutant mice displayed delayed re-entrainment to a 6 h phase shift (advance or delay) in the light cycle and incomplete photoentrainment in a symmetrical skeleton photoperiod regimen (1 h light pulses between 11 h dark periods). Circadian rhythmicity in constant darkness also was reduced in some mutant mice. Other NIF responses such as the PLR and negative masking responses to light were also partially attenuated. Overall, these results suggest that glutamate from ipRGCs drives circadian photoentrainment and negative masking responses to light.

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Negative masking responses to light are impaired in the Vglut2-cKO mice.Control and Vglut2-cKO mice were subjected to 3.5 h light: 3.5 h dark cycles for 14 days. (A) Control mice show robust activity during dark period reflecting strong aversion to locomotor activity under bright light conditions. The Vglut2-cKO mice, on the other hand, exhibited activity in both dark and light periods indicative of less pronounced negative masking responses to light. Shaded regions indicate periods of darkness. (B) Activity in the dark normalized to the total activity is higher in the control (n = 7) than the Vglut2-cKO (n = 8) mice (** p<0.05). (C) Analysis of the individual mice shows more variable masking responses among the Vglut2-cKO mice (n = 9) than control littermates (n = 7).
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pone-0111449-g006: Negative masking responses to light are impaired in the Vglut2-cKO mice.Control and Vglut2-cKO mice were subjected to 3.5 h light: 3.5 h dark cycles for 14 days. (A) Control mice show robust activity during dark period reflecting strong aversion to locomotor activity under bright light conditions. The Vglut2-cKO mice, on the other hand, exhibited activity in both dark and light periods indicative of less pronounced negative masking responses to light. Shaded regions indicate periods of darkness. (B) Activity in the dark normalized to the total activity is higher in the control (n = 7) than the Vglut2-cKO (n = 8) mice (** p<0.05). (C) Analysis of the individual mice shows more variable masking responses among the Vglut2-cKO mice (n = 9) than control littermates (n = 7).

Mentions: In line with the PLR results, we also observed major deficiencies in negative masking responses to light. Bright light suppresses locomotor activity in nocturnal animals including mice [31]. Running wheel activity was recorded for two weeks in mice kept on 3.5:3.5 light/dark (LD) cycles to measure effects of light independent of circadian rhythms [23]. This light cycle assesses negative masking, because it is difficult for the mice to entrain to light cycles that move across the circadian cycle [23]. By plotting running activity for a period of 7 h for the control and Vglut2-CKO mice, it is apparent that their locomotor activity in the dark and light periods differ (Figure 6A). While the control mice restricted their activity to the dark periods of the ultradian cycle (activity in the dark period/total activity  = 0.95±0.01, n = 7), the Vglut2-cKO mice show activities across the light-dark cycles (activity in the dark period/total activity  = 0.77±0.04, n = 9) demonstrating significant impaired negative masking responses to light (Figure 6B). Heterogeneity of responses to light was prominent among the Vglut2-cKO mice (Figure 6C). While some mutant mice showed almost no preference for locomotor activity in the dark, other mice showed locomotor activity restricted to the dark periods (Figure 6C).


Mice deficient of glutamatergic signaling from intrinsically photosensitive retinal ganglion cells exhibit abnormal circadian photoentrainment.

Purrier N, Engeland WC, Kofuji P - PLoS ONE (2014)

Negative masking responses to light are impaired in the Vglut2-cKO mice.Control and Vglut2-cKO mice were subjected to 3.5 h light: 3.5 h dark cycles for 14 days. (A) Control mice show robust activity during dark period reflecting strong aversion to locomotor activity under bright light conditions. The Vglut2-cKO mice, on the other hand, exhibited activity in both dark and light periods indicative of less pronounced negative masking responses to light. Shaded regions indicate periods of darkness. (B) Activity in the dark normalized to the total activity is higher in the control (n = 7) than the Vglut2-cKO (n = 8) mice (** p<0.05). (C) Analysis of the individual mice shows more variable masking responses among the Vglut2-cKO mice (n = 9) than control littermates (n = 7).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214747&req=5

pone-0111449-g006: Negative masking responses to light are impaired in the Vglut2-cKO mice.Control and Vglut2-cKO mice were subjected to 3.5 h light: 3.5 h dark cycles for 14 days. (A) Control mice show robust activity during dark period reflecting strong aversion to locomotor activity under bright light conditions. The Vglut2-cKO mice, on the other hand, exhibited activity in both dark and light periods indicative of less pronounced negative masking responses to light. Shaded regions indicate periods of darkness. (B) Activity in the dark normalized to the total activity is higher in the control (n = 7) than the Vglut2-cKO (n = 8) mice (** p<0.05). (C) Analysis of the individual mice shows more variable masking responses among the Vglut2-cKO mice (n = 9) than control littermates (n = 7).
Mentions: In line with the PLR results, we also observed major deficiencies in negative masking responses to light. Bright light suppresses locomotor activity in nocturnal animals including mice [31]. Running wheel activity was recorded for two weeks in mice kept on 3.5:3.5 light/dark (LD) cycles to measure effects of light independent of circadian rhythms [23]. This light cycle assesses negative masking, because it is difficult for the mice to entrain to light cycles that move across the circadian cycle [23]. By plotting running activity for a period of 7 h for the control and Vglut2-CKO mice, it is apparent that their locomotor activity in the dark and light periods differ (Figure 6A). While the control mice restricted their activity to the dark periods of the ultradian cycle (activity in the dark period/total activity  = 0.95±0.01, n = 7), the Vglut2-cKO mice show activities across the light-dark cycles (activity in the dark period/total activity  = 0.77±0.04, n = 9) demonstrating significant impaired negative masking responses to light (Figure 6B). Heterogeneity of responses to light was prominent among the Vglut2-cKO mice (Figure 6C). While some mutant mice showed almost no preference for locomotor activity in the dark, other mice showed locomotor activity restricted to the dark periods (Figure 6C).

Bottom Line: The relative contribution of each neurotransmitter system for the circadian photoentrainment and other NIF visual responses is still unresolved.Other NIF responses such as the PLR and negative masking responses to light were also partially attenuated.Overall, these results suggest that glutamate from ipRGCs drives circadian photoentrainment and negative masking responses to light.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States of America.

ABSTRACT
Several aspects of behavior and physiology, such as sleep and wakefulness, blood pressure, body temperature, and hormone secretion exhibit daily oscillations known as circadian rhythms. These circadian rhythms are orchestrated by an intrinsic biological clock in the suprachiasmatic nuclei (SCN) of the hypothalamus which is adjusted to the daily environmental cycles of day and night by the process of photoentrainment. In mammals, the neuronal signal for photoentrainment arises from a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) that send a direct projection to the SCN. ipRGCs also mediate other non-image-forming (NIF) visual responses such as negative masking of locomotor activity by light, and the pupillary light reflex (PLR) via co-release of neurotransmitters glutamate and pituitary adenylate cyclase-activating peptide (PACAP) from their synaptic terminals. The relative contribution of each neurotransmitter system for the circadian photoentrainment and other NIF visual responses is still unresolved. We investigated the role of glutamatergic neurotransmission for circadian photoentrainment and NIF behaviors by selective ablation of ipRGC glutamatergic synaptic transmission in mice. Mutant mice displayed delayed re-entrainment to a 6 h phase shift (advance or delay) in the light cycle and incomplete photoentrainment in a symmetrical skeleton photoperiod regimen (1 h light pulses between 11 h dark periods). Circadian rhythmicity in constant darkness also was reduced in some mutant mice. Other NIF responses such as the PLR and negative masking responses to light were also partially attenuated. Overall, these results suggest that glutamate from ipRGCs drives circadian photoentrainment and negative masking responses to light.

Show MeSH
Related in: MedlinePlus