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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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Attenuated PLRs in Vglut2-cKO mice.(A) Images of control and Vglut2-CKO mice pupils before and during exposure to high intensity (3.8 mW/cm2) white light stimuli. (B) Summary of PLRs measured in control mice. Consensual PLRs were measured in control (n = 8) and Vglut2-cKO (n = 10) mice. Vglut2-cKO mice show severe deficits in PLRs under low (4 µW/cm2) and high (3.8 mW/cm2) intensity white light stimuli (** p<0.05). Light stimuli were delivered for 20 s and maximum pupil area was measured before and during the light stimulus. Percent of pupil area following the light stimulus is shown normalized to the pupil area during dark conditions.
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pone-0111449-g005: Attenuated PLRs in Vglut2-cKO mice.(A) Images of control and Vglut2-CKO mice pupils before and during exposure to high intensity (3.8 mW/cm2) white light stimuli. (B) Summary of PLRs measured in control mice. Consensual PLRs were measured in control (n = 8) and Vglut2-cKO (n = 10) mice. Vglut2-cKO mice show severe deficits in PLRs under low (4 µW/cm2) and high (3.8 mW/cm2) intensity white light stimuli (** p<0.05). Light stimuli were delivered for 20 s and maximum pupil area was measured before and during the light stimulus. Percent of pupil area following the light stimulus is shown normalized to the pupil area during dark conditions.

Mentions: Lack of fast glutamatergic signaling from ipRGCs would be expected to impair NIF visual functions attributed to these cells such as the pupillary light reflex (PLR) and negative masking responses to light [29], [30]. We first measured the consensual PLR in these mice at two light intensities (high light intensity  = 3.8 mW/cm2 and low light intensity  = 4 µW/cm2). PLR was evoked by a white light stimulus of 20 seconds duration. In control littermate mice, the pupillary area constricted to ∼8% under high light intensity (n = 8) and ∼46% under low light intensity (n = 8) in comparison to prestimulus conditions (Figure 5A–B). In contrast, the Vglut2-cKO mice showed a much attenuated PLR. The pupillary area constricted to only 78% under high light intensity (n = 10) and 86% under low light intensity (n = 10). Application of 100 mM carbachol in the mutant mouse eye (n = 3) was able to elicit full pupillary constriction (data not shown), indicating that lack of light-evoked responses was not due to malformation of the pupillary constriction apparatus.


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

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

Attenuated PLRs in Vglut2-cKO mice.(A) Images of control and Vglut2-CKO mice pupils before and during exposure to high intensity (3.8 mW/cm2) white light stimuli. (B) Summary of PLRs measured in control mice. Consensual PLRs were measured in control (n = 8) and Vglut2-cKO (n = 10) mice. Vglut2-cKO mice show severe deficits in PLRs under low (4 µW/cm2) and high (3.8 mW/cm2) intensity white light stimuli (** p<0.05). Light stimuli were delivered for 20 s and maximum pupil area was measured before and during the light stimulus. Percent of pupil area following the light stimulus is shown normalized to the pupil area during dark conditions.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111449-g005: Attenuated PLRs in Vglut2-cKO mice.(A) Images of control and Vglut2-CKO mice pupils before and during exposure to high intensity (3.8 mW/cm2) white light stimuli. (B) Summary of PLRs measured in control mice. Consensual PLRs were measured in control (n = 8) and Vglut2-cKO (n = 10) mice. Vglut2-cKO mice show severe deficits in PLRs under low (4 µW/cm2) and high (3.8 mW/cm2) intensity white light stimuli (** p<0.05). Light stimuli were delivered for 20 s and maximum pupil area was measured before and during the light stimulus. Percent of pupil area following the light stimulus is shown normalized to the pupil area during dark conditions.
Mentions: Lack of fast glutamatergic signaling from ipRGCs would be expected to impair NIF visual functions attributed to these cells such as the pupillary light reflex (PLR) and negative masking responses to light [29], [30]. We first measured the consensual PLR in these mice at two light intensities (high light intensity  = 3.8 mW/cm2 and low light intensity  = 4 µW/cm2). PLR was evoked by a white light stimulus of 20 seconds duration. In control littermate mice, the pupillary area constricted to ∼8% under high light intensity (n = 8) and ∼46% under low light intensity (n = 8) in comparison to prestimulus conditions (Figure 5A–B). In contrast, the Vglut2-cKO mice showed a much attenuated PLR. The pupillary area constricted to only 78% under high light intensity (n = 10) and 86% under low light intensity (n = 10). Application of 100 mM carbachol in the mutant mouse eye (n = 3) was able to elicit full pupillary constriction (data not shown), indicating that lack of light-evoked responses was not due to malformation of the pupillary constriction apparatus.

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