scholarly journals Regulation of light's action in the mammalian circadian clock: role of the extrasynaptic GABAA receptor

2009 ◽  
Vol 296 (5) ◽  
pp. R1606-R1612 ◽  
Author(s):  
J. Christopher Ehlen ◽  
Ketema N. Paul
Keyword(s):  
Wheel Running ◽  
Phase Shifts ◽  
Constant Darkness ◽  
Receptor Subtypes ◽  
Mrna Levels ◽  
Subjective Night ◽  
Behavioral Phase ◽  
Free Running ◽  
Light Input

GABAA receptor agonists act in the suprachiasmatic nucleus (SCN) to reset circadian rhythms during the day but inhibit the ability of light to reset rhythms during the night. In the present study, we examined whether these paradoxical differences in the effect of GABAA receptor stimulation on the circadian system are mediated by separate GABAA receptor subtypes. 4,5,6,7-Tetrahydroisoxazolo[5,4- c]pyridin-3-ol (THIP), a GABAA receptor agonist, preferentially activates GABAA receptors in extrasynaptic locations. THIP, muscimol (a GABAA agonist), or vehicle were microinjected into the SCN region of Syrian hamsters free-running in constant darkness during the mid-subjective day, early subjective night, or late subjective night. The subjective night injections were followed by a light pulse or sham control. Behavioral phase shifts of wheel running rhythms and both Period1 ( Per1) and Per2 mRNA levels in the SCN were assessed. Animals that received THIP during the subjective day did not exhibit significant phase alterations. During the early and late subjective night, however, THIP abolished the phase-shifting effects of light and the ability of light to increase Per1 and Per2 mRNA levels. The ability of N-methyl-d-aspartic acid to phase-shift wheel running rhythms was also attenuated by THIP. Together these data demonstrate that THIP does not produce phase shifts during the subjective day, but does inhibit the ability of light to produce phase shifts. Thus, extrasynaptic GABAA receptors appear to play a role in regulating light input to the SCN, while a different population of GABAA receptors appears to be responsible for daytime effects of GABA.

scholarly journals Functional Significance of the Excitatory Effects of GABA in the Suprachiasmatic Nucleus

2018 ◽  
Vol 33 (4) ◽  
pp. 376-387 ◽  
Author(s):  
John K. McNeill ◽  
James C. Walton ◽  
H. Elliott Albers
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Constant Darkness ◽  
Circadian Pacemaker ◽  
Inhibitory Neurotransmitter ◽  
Subjective Night ◽  
Free Running ◽  
Excitatory Responses ◽  
Reduced Light

Over 90% of neurons within the suprachiasmatic nucleus (SCN) express γ-aminobutyric acid (GABA). Although GABA is primarily an inhibitory neurotransmitter, in vitro studies suggest that the activation of GABAA receptors (GABAAR) elicits excitation in the adult SCN. The ratio of excitatory to inhibitory responses to GABA depends on the balance of chloride influx by Na+-K+-Cl– cotransporter 1 (NKCC1) and chloride efflux by K+-Cl– cotransporters (KCCs). Excitatory responses to GABA can be blocked by inhibition of the inward chloride cotransporter, NKCC1, with the loop diuretic bumetanide. Here we investigated the role of NKCC1 activity in phase shifting the circadian pacemaker in response to photic and nonphotic signals in male Syrian hamsters housed in constant darkness. In the early subjective night (CT 13.5), injection of bumetanide into the SCN reduced light-induced phase delays. However, during the late subjective night (CT 19), bumetanide administration did not alter light-induced phase advances. Injection of bumetanide during the subjective day (CT 6) did not alter the phase of free-running circadian rhythms but attenuated phase advances induced by injection of the GABAAR agonist muscimol into the SCN. These data support the hypothesis that the excitatory effects of endogenously released GABA contribute to the ability of light to induce phase delays, thereby contributing to the most important function of the circadian system, its entrainment with the day-night cycle. Further, the finding that bumetanide inhibits the phase-advancing effects of muscimol during the subjective day supports the hypothesis that the excitatory responses to GABA also contribute to the ability of nonphotic stimuli to phase shift the circadian pacemaker.

Gonadal hormones organize and modulate the circadian system of the rat

1981 ◽  
Vol 241 (1) ◽  
pp. R62-R66 ◽  
Author(s):  
H. E. Albers
Keyword(s):  
Testosterone Propionate ◽  
Wheel Running ◽  
Activity Rhythm ◽  
Gonadal Hormones ◽  
Circadian System ◽  
Female Rats ◽  
Constant Darkness ◽  
Before And After ◽  
Free Running ◽  
Free Running Period

The circadian wheel-running rhythms of gonadectomized adult male, female, and perinatally androgenized female rats, maintained in constant darkness, were examined before and after implantation of Silastic capsules containing cholesterol (C) or estradiol-17 beta (E). The free-running period of the activity rhythm (tau) before capsule implantation tended to be shorter in animals exposed to perinatal androgen. Administration of C did not reliably alter tau in any group. E significantly shortened tau in 100% of females injected with oil on day 3 of life. In females, injected with 3.5 micrograms testosterone propionate on day 3, and males, E shortened or lengthened tau, with the direction and magnitude of this change in tau inversely related to the length of the individual's pretreatment tau. These data indicate that the presence of perinatal androgen does not eliminate the sensitivity of the circadian system of the rat to estrogen, since estrogen alters tau in a manner that depends on its pretreatment length.

Reduced glucose availability attenuates circadian responses to light in mice

1999 ◽  
Vol 276 (4) ◽  
pp. R1063-R1070 ◽  
Author(s):  
Etienne Challet ◽  
Susan Losee-Olson ◽  
Fred W. Turek
Keyword(s):  
Locomotor Activity ◽  
Glucose Utilization ◽  
Insulin Treatment ◽  
Phase Shifts ◽  
Constant Darkness ◽  
Phase Resetting ◽  
Light Pulses ◽  
Subjective Night ◽  
Saline Administration ◽  
Glucose Availability

To test whether circadian responses to light are modulated by decreased glucose availability, we analyzed photic phase resetting of the circadian rhythm of locomotor activity in mice exposed to four metabolic challenges: 1) blockade of glucose utilization induced by 2-deoxy-d-glucose (2-DG), 2) fasting (food was removed for 30 h), 3) insulin administration, and 4) insulin treatment after fasting. In mice housed in constant darkness, light pulses applied during early subjective night induced phase delays of the rhythm of locomotor activity, whereas light pulses applied during late subjective night caused phase advances. There was an overall reduction of light-induced phase shifts, with a more pronounced effect for delays, in mice pretreated with 500 mg/kg ip 2-DG compared with mice injected with saline. Administration of glucose with 2-DG prevented the reduction of light-induced phase delays. Furthermore, phase delays were reduced in fed mice pretreated with 5 IU/kg sc insulin and in fasted mice injected with saline or insulin compared with control fed mice. These results show that circadian responses to light are reduced when brain glucose availability is decreased, suggesting a metabolic modulation of light-induced phase shifts.

scholarly journals Reduced VIP Expression Affects Circadian Clock Function in VIP-IRES-CRE Mice (JAX 010908)

2020 ◽  
Vol 35 (4) ◽  
pp. 340-352 ◽  
Author(s):  
Deborah A. M. Joye ◽  
Kayla E. Rohr ◽  
Danielle Keller ◽  
Thomas Inda ◽  
Adam Telega ◽  
...  
Keyword(s):  
Constant Darkness ◽  
Wild Type ◽  
Free Running ◽  
Dna Editing ◽  
Editing Enzyme ◽  
Free Running Period ◽  
Precise Role ◽  
Insight Into ◽  
Master Clock

Circadian rhythms are programmed by the suprachiasmatic nucleus (SCN), which relies on neuropeptide signaling to maintain daily timekeeping. Vasoactive intestinal polypeptide (VIP) is critical for SCN function, but the precise role of VIP neurons in SCN circuits is not fully established. To interrogate their contribution to SCN circuits, VIP neurons can be manipulated specifically using the DNA-editing enzyme Cre recombinase. Although the Cre transgene is assumed to be inert by itself, we find that VIP expression is reduced in both heterozygous and homozygous adult VIP-IRES-Cre mice (JAX 010908). Compared with wild-type mice, homozygous VIP-Cre mice display faster reentrainment and shorter free-running period but do not become arrhythmic in constant darkness. Consistent with this phenotype, homozygous VIP-Cre mice display intact SCN PER2::LUC rhythms, albeit with altered period and network organization. We present evidence that the ability to sustain molecular rhythms in the VIP-Cre SCN is not due to residual VIP signaling; rather, arginine vasopressin signaling helps to sustain SCN function at both intracellular and intercellular levels in this model. This work establishes that the VIP-IRES-Cre transgene interferes with VIP expression but that loss of VIP can be mitigated by other neuropeptide signals to help sustain SCN function. Our findings have implications for studies employing this transgenic model and provide novel insight into neuropeptide signals that sustain daily timekeeping in the master clock.

LXRβ is the dominant LXR subtype in skeletal muscle regulating lipogenesis and cholesterol efflux

2010 ◽  
Vol 298 (3) ◽  
pp. E602-E613 ◽  
Author(s):  
N. P. Hessvik ◽  
M. V. Boekschoten ◽  
M. A. Baltzersen ◽  
S. Kersten ◽  
X. Xu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Cholesterol Efflux ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Receptor Subtypes ◽  
Mrna Levels ◽  
Functional Studies ◽  
X Receptors

Liver X receptors (LXRs) are important regulators of cholesterol, lipid, and glucose metabolism and have been extensively studied in liver, macrophages, and adipose tissue. However, their role in skeletal muscle is poorly studied and the functional role of each of the LXRα and LXRβ subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild-type (WT) and LXRα and LXRβ knockout (KO) mice were established. The present study showed that treatment with the LXR agonist T0901317 increased lipogenesis and apoA1-dependent cholesterol efflux in LXRα KO and WT myotubes but not in LXRβ KO cells. The functional studies were confirmed by T0901317-induced increase in mRNA levels of LXR target genes involved in lipid and cholesterol metabolism in myotubes established from WT and LXRα KO mice, whereas only minor changes were observed for these genes in myotubes from LXRβ KO mice. Gene expression analysis using microarrays showed that very few genes other than the classical, well-known LXR target genes were regulated by LXR in skeletal muscle. The present study also showed that basal glucose uptake was increased in LXRβ KO myotubes compared with WT myotubes, suggesting a role for LXRβ in glucose metabolism in skeletal muscle. In conclusion, LXRβ seems to be the main LXR subtype regulating lipogenesis and cholesterol efflux in skeletal muscle.

Two Coupled Circadian Oscillators Are Involved in Nonphotic Acceleration of Reentrainment to Shifted Light Cycles in Mice

2018 ◽  
Vol 33 (6) ◽  
pp. 614-625 ◽  
Author(s):  
Yujiro Yamanaka ◽  
Sato Honma ◽  
Ken-ichi Honma
Keyword(s):  
Behavioral Interventions ◽  
Wheel Running ◽  
Dark Period ◽  
Phase Shifts ◽  
Constant Darkness ◽  
Circadian Oscillators ◽  
Behavioral Rhythm ◽  
Activity Onset ◽  
Activity Band ◽  
The Relationship

The onset and offset of an activity band in the circadian behavioral rhythm are known to differentially reentrain to shifted light-dark cycles (LD). Differential reentrainment could be explained by different light responsivities of circadian oscillators underlying these phase-markers. In contrast, reentrainment is accelerated by exposure to nonphotic time cues such as timed wheel-running. However, the relationship between the 2 oscillators and nonphotic acceleration of reentrainment is largely unknown. We examined phase-shifts of the mouse behavioral rhythm in response to an 8-h phase-advanced shift of LD and effects of behavioral interventions: maintained in a home cage (HC), exposed to a running wheel (RW) in HC (HC+RW), transferred to a new cage (NC), and exposed to RW in NC (NC+RW). Each intervention was given for 3h from the beginning of the shifted dark period and repeated for 4 days. Following the last dark period, the mice were released into constant darkness (DD). As a result, activity onset and offset were differentially phase-shifted. The activity onset on the first day of DD (DD1) was phase-advanced from the baseline slightly in HC and HC+RW, substantially in NC+RW, but not significantly in NC. The amount of phase-shift was significantly larger in the NC+RW than in the other groups. In contrast, the activity offset was significantly advanced in all groups by 6 to 8 h. The differential phase-shifts resulted in shortening of the activity band (α compression). The α compression was gradually relieved upon exposure to DD (α decompression), and the activity band finally became stable. Interestingly, the magnitude of phase-shifts of activity offset, but not of activity onset, in the following DD was negatively correlated with the extent of α compression in DD1. These findings indicate that the 2 circadian oscillators underlying activity onset and offset are involved in asymmetric phase-shifts and nonphotic acceleration of reentrainment.

Light Has Diverse Spatiotemporal Molecular Changes in the Mouse Suprachiasmatic Nucleus

2020 ◽  
Vol 35 (6) ◽  
pp. 576-587
Author(s):  
Phan Q. Duy ◽  
Ruchi Komal ◽  
Melissa E. S. Richardson ◽  
Katie S. Hahm ◽  
Diego C. Fernandez ◽  
...  
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Phase Shifts ◽  
Molecular Changes ◽  
Circadian Expression ◽  
Subjective Night ◽  
Small Phase ◽  
Behavioral Phase ◽  
Large Phase ◽  
Light Effects ◽  
Activity Dependent

To be physiologically relevant, the period of the central circadian pacemaker, located in the suprachiasmatic nucleus (SCN), has to match the solar day in a process known as circadian photoentrainment. However, little is known about the spatiotemporal molecular changes that occur in the SCN in response to light. In this study, we sought to systematically characterize the circadian and light effects on activity-dependent markers of transcriptional (cFos), translational (pS6), and epigenetic (pH3) activities in the mouse SCN. To investigate circadian versus light influences on these molecular responses, we harvested brains from adult wild-type mice in darkness at different circadian times (CT) or from mice exposed to a 15-min light pulse at the middle of the subjective day (CT6, no phase shifts), early subjective night (CT14, large phase delays), or late subjective night (CT22, small phase advances). We found that cFos and pS6 exhibited rhythmic circadian expression in the SCN with distinct spatial rhythms, whereas pH3 expression was undetectable at all circadian phases. cFos rhythms were largely limited to the SCN shell, whereas pS6 rhythms encompassed the entire SCN. pH3, pS6, and cFos showed gating in response to light; however, we were surprised to find that the expression levels of these markers were not higher at phases when larger phase shifts are observed behaviorally (CT14 versus CT22). We then used animals lacking melanopsin (melanopsin knockout [MKO]), which show deficits in phase delays, to further investigate whether changes in these molecular markers correspond to behavioral phase shifts. Surprisingly, only pS6 showed deficits in MKOs at CT14. Therefore, our previous understanding of the molecular pathways that lead to circadian photoentrainment needs to be revised.

Administering triazolam on a circadian basis entrains the activity rhythm of hamsters

1989 ◽  
Vol 256 (3) ◽  
pp. R639-R645
Author(s):  
O. Van Reeth ◽  
F. W. Turek
Keyword(s):  
Response Curve ◽  
Wheel Running ◽  
Phase Response Curve ◽  
Activity Rhythm ◽  
Phase Relationship ◽  
Phase Shifts ◽  
Phase Response ◽  
Light Pulses ◽  
Circadian Time ◽  
Free Running

A single injection of the short-acting benzodiazepine, triazolam, can induce permanent phase shifts in the circadian rhythm of locomotor activity in free-running hamsters, with the direction and magnitude of the phase shifts being dependent on the circadian time of treatment. The shape of the "phase-response curve" to triazolam injections is totally different from that for light pulses. These findings raise the possibility that repeated injections of triazolam on a circadian basis might be capable of entraining the circadian pacemaker underlying the activity rhythm of hamsters and that the entrainment pattern might differ from that observed in animals entrained to light pulses. To test this hypothesis, blind hamsters received intraperitoneal injections of triazolam (or vehicle) every 23.34, 23.72, 24.00 or 24.66 h for 19-20 days, and the effect of these injections on the period of the rhythm of wheel-running behavior was determined during and after treatment. Repeated injections of 0.1 mg triazolam at these time intervals resulted in the entrainment of the activity rhythm in 36 of 40 animals, whereas 0 of 40 animals entrained to vehicle injections. Importantly, the phase relationship between triazolam injections and the circadian activity rhythm was dependent on the period of drug treatment and could be predicted from the phase-response curve to single injections of triazolam. These phase relationships are dramatically different from those observed between the activity rhythm and 1-h light pulses presented at similar circadian intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Injury-elicited differential transcriptional regulation of phospholipid growth factor receptors in the cornea

2002 ◽  
Vol 283 (6) ◽  
pp. C1646-C1654 ◽  
Author(s):  
De-An Wang ◽  
Haiming Du ◽  
Jonathan H. Jaggar ◽  
David N. Brindley ◽  
Gabor J. Tigyi ◽  
...  
Keyword(s):  
Wound Healing ◽  
Specific Activity ◽  
Receptor Subtypes ◽  
Mrna Levels ◽  
Rabbit Cornea ◽  
Corneal Injury ◽  
Corneal Wound ◽  
Changing Role ◽  
First Time

The phospholipid growth factors (PLGFs), including lysophosphatidic acid (LPA), have been implicated in corneal wound healing. PLGF concentrations and activities are elevated after corneal injury. Using real-time PCR, we quantified receptor mRNA levels in the healing rabbit cornea. In intact corneas, transcripts for S1P1, LPA1, and LPA3 receptor subtypes were detected, as was lipid phosphate phosphatase 1 (LPP1). After wounding, the trend for endothelium and keratocytes was for significant decreases in transcript numbers for the three receptor subtypes, whereas epithelial cells showed increased transcript numbers, except for an S1P1 decrease in healing cells. LPP1 transcript numbers were decreased in keratocytes and endothelium, although LPP-specific activity was unchanged. LPA-elicited Ca2+ transients were significantly reduced in the healing endothelium. Consistent with reduced LPA3 receptor numbers, dioctylglycerol pyrophosphate, a selective antagonist, reduced LPA-induced Ca2+ transients 2.7-fold in nonwounded epithelium but only 1.5-fold in wound-healing endothelium. These data for the first time establish physiologically relevant differential changes in the expression of PLGF receptor subtypes and provide evidence for the changing role of LPA3 receptors in endothelial cells.

scholarly journals Synaptic Protein Phosphorylation Networks Are Associated With Electroacupuncture-Induced Circadian Control in the Suprachiasmatic Nucleus

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxiao Lu ◽  
Minjie Zhou ◽  
Nannan Liu ◽  
Chengshun Zhang ◽  
Zhengyu Zhao ◽  
...  
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Posttranslational Modifications ◽  
Current Data ◽  
Molecular Characteristics ◽  
Constant Darkness ◽  
Protein Protein Interaction ◽  
Circadian Control ◽  
Long Time ◽  
Free Running

Phosphorylation is one of the most important posttranslational modifications and regulates the physiological process. While recent studies highlight a major role of phosphorylation in the regulation of sleep–wake cycles to a lesser extent, the phosphoproteome in the suprachiasmatic nucleus (SCN) is not well-understood. Herein, we reported that the EA treatment elicits partial reparation of circadian rhythmicity when mice were exposure to constant darkness for long time. We investigated the effects of EA on circadian rhythms in constant darkness between EA stimulation and free-running control. Next, mass spectrometry–based phosphoproteome was utilized to explore the molecular characteristics of EA-induced phosphorylation modification in the SCN. A total of 6,192 distinct phosphosites on 2,488 proteins were quantified. Functional annotation analysis and protein–protein interaction networks demonstrated the most significant enriched phosphor-proteins and phosphosites involved in postsynapse and glutamatergic synapse. The current data indicated that most of the altered molecules are structural proteins. The target proteins, NMDAR and CAMK2, were selected for verification, consistent with the results of LC–MS/MS. These findings revealed a complete profile of phosphorylation modification in response to EA.

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