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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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Circadian locomotor activity for the Vglut2-cKO and control mice under LD and DD conditions.(A–C) Representative activity records from animals initially held in a 12:12 LD cycle then transferred to DD. Control (Ctrl)(A) and mutant (Vglut2-cKO)(B–C) animals demonstrate entrainment in LD as indicated by enhanced activity in the dark period. In DD the animals show a free running activity rhythm with some Vglut2-cKO mice exhibiting low-amplitude rhythms (B). In these animals, although the majority of activity was confined to the dark phase under LD, activity onset in DD was variable. Shaded regions indicate periods of darkness mirrored in LD bars above the actograms. (D–E) Amplitude of locomotor activity in DD was more variable among Vglut2-cKO (n = 17) than control (n = 9) mice. (F) Period of locomotor activity was comparable between control (n = 9) and Vglut2-cKO (n = 17) mice.
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pone-0111449-g002: Circadian locomotor activity for the Vglut2-cKO and control mice under LD and DD conditions.(A–C) Representative activity records from animals initially held in a 12:12 LD cycle then transferred to DD. Control (Ctrl)(A) and mutant (Vglut2-cKO)(B–C) animals demonstrate entrainment in LD as indicated by enhanced activity in the dark period. In DD the animals show a free running activity rhythm with some Vglut2-cKO mice exhibiting low-amplitude rhythms (B). In these animals, although the majority of activity was confined to the dark phase under LD, activity onset in DD was variable. Shaded regions indicate periods of darkness mirrored in LD bars above the actograms. (D–E) Amplitude of locomotor activity in DD was more variable among Vglut2-cKO (n = 17) than control (n = 9) mice. (F) Period of locomotor activity was comparable between control (n = 9) and Vglut2-cKO (n = 17) mice.

Mentions: We first analyzed the characteristics of the circadian activity pattern of Vglut2-cKO mice and their respective control littermates. The general pattern of activity in a light regimen of 12 h lights on and 12 h lights off (LD) condition was similar in both genotypes, with bouts of activity occurring after lights off, which lasted for several hours (Figures 2 A–C). However, some Vglut2-cKO mice showed a more irregular pattern of circadian locomotor activity with some running even with lights on (Figure 2B). To reveal the endogenous circadian locomotor activity, we transferred the mice to constant dark conditions (DD). The general pattern of activity in DD condition was also equivalent in both mice genotypes with most mice demonstrating a free-running rhythm. However, as under LD conditions, some mutant mice showed irregular bouts of running activity during all phases of circadian time (Figure 2B). Control mice used in this experiment had an average free-running period of 23.40±0.12 h (n = 9), whereas the Vglut2-cKO group averaged 23.63±0.09 h (n = 17). Collectively, the Vglut2-cKO mice group displayed a trend for more variable circadian rhythmicity than the control group in DD conditions although differences in amplitude variance of the wheel-running rhythm did not reach statistical significance (Figures 2D–E).


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

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

Circadian locomotor activity for the Vglut2-cKO and control mice under LD and DD conditions.(A–C) Representative activity records from animals initially held in a 12:12 LD cycle then transferred to DD. Control (Ctrl)(A) and mutant (Vglut2-cKO)(B–C) animals demonstrate entrainment in LD as indicated by enhanced activity in the dark period. In DD the animals show a free running activity rhythm with some Vglut2-cKO mice exhibiting low-amplitude rhythms (B). In these animals, although the majority of activity was confined to the dark phase under LD, activity onset in DD was variable. Shaded regions indicate periods of darkness mirrored in LD bars above the actograms. (D–E) Amplitude of locomotor activity in DD was more variable among Vglut2-cKO (n = 17) than control (n = 9) mice. (F) Period of locomotor activity was comparable between control (n = 9) and Vglut2-cKO (n = 17) mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111449-g002: Circadian locomotor activity for the Vglut2-cKO and control mice under LD and DD conditions.(A–C) Representative activity records from animals initially held in a 12:12 LD cycle then transferred to DD. Control (Ctrl)(A) and mutant (Vglut2-cKO)(B–C) animals demonstrate entrainment in LD as indicated by enhanced activity in the dark period. In DD the animals show a free running activity rhythm with some Vglut2-cKO mice exhibiting low-amplitude rhythms (B). In these animals, although the majority of activity was confined to the dark phase under LD, activity onset in DD was variable. Shaded regions indicate periods of darkness mirrored in LD bars above the actograms. (D–E) Amplitude of locomotor activity in DD was more variable among Vglut2-cKO (n = 17) than control (n = 9) mice. (F) Period of locomotor activity was comparable between control (n = 9) and Vglut2-cKO (n = 17) mice.
Mentions: We first analyzed the characteristics of the circadian activity pattern of Vglut2-cKO mice and their respective control littermates. The general pattern of activity in a light regimen of 12 h lights on and 12 h lights off (LD) condition was similar in both genotypes, with bouts of activity occurring after lights off, which lasted for several hours (Figures 2 A–C). However, some Vglut2-cKO mice showed a more irregular pattern of circadian locomotor activity with some running even with lights on (Figure 2B). To reveal the endogenous circadian locomotor activity, we transferred the mice to constant dark conditions (DD). The general pattern of activity in DD condition was also equivalent in both mice genotypes with most mice demonstrating a free-running rhythm. However, as under LD conditions, some mutant mice showed irregular bouts of running activity during all phases of circadian time (Figure 2B). Control mice used in this experiment had an average free-running period of 23.40±0.12 h (n = 9), whereas the Vglut2-cKO group averaged 23.63±0.09 h (n = 17). Collectively, the Vglut2-cKO mice group displayed a trend for more variable circadian rhythmicity than the control group in DD conditions although differences in amplitude variance of the wheel-running rhythm did not reach statistical significance (Figures 2D–E).

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