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.

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.

scholarly journals Free-running circadian breathing rhythms are eliminated by suprachiasmatic nucleus lesion

2020 ◽  
Vol 129 (1) ◽  
pp. 49-57
Author(s):  
Benton S. Purnell ◽  
Gordon F. Buchanan
Keyword(s):  
Sleep Apnea ◽  
Circadian Rhythms ◽  
Suprachiasmatic Nucleus ◽  
Time Of Day ◽  
Sudden Unexpected Death ◽  
Constant Darkness ◽  
Unexpected Death ◽  
Treatment And Prevention ◽  
Free Running

It has long been appreciated that breathing is altered by time of day. This study demonstrates that rhythmicity in breathing persists in constant darkness but is dependent on the suprachiasmatic nucleus in the hypothalamus. Understanding circadian rhythms in breathing may be important for the treatment and prevention of diseases such as sleep apnea and sudden unexpected death in epilepsy.

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 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.

scholarly journals Specialized dietary food products in oncological practice

2020 ◽  
pp. 111-117
Author(s):  
T. L. Pilat
Keyword(s):  
Cancer Patients ◽  
Food Products ◽  
Current Data ◽  
The Body ◽  
Malignant Neoplasms ◽  
Energy Deficiency ◽  
Protein Energy ◽  
Long Time ◽  
Dietary Food

This review presents current data on the role of nutritional support in patients with cancer. The main reasons for the decrease in body weight, protein-energy deficiency in the development of malignant neoplasms are described. The data substantiating the appointment of dietary food products in various phases of the disease to patients receiving systemic anticancer therapy (chemotherapy, targeted therapy, immunotherapy) for a long time, and to cancer patients who underwent volumetric abdominal surgery are presented. The mechanisms of intoxication arising as a result of the disease itself, as well as a result of prolonged polychemoor irradiation therapy, are described in detail. The concept and mechanisms of endogenous intoxication syndrome are given. Special attention is paid to the role of the cytochrome system of the liver in detoxification processes. It has been shown that the accumulation of toxic metabolites in cancer disrupts the activity of the organs of detoxification and excretion, metabolites accumulate in tissues, which leads to difficulty in regulating the functions of the body and its protection from intoxication factors. The results of clinical studies of the data are presented and their effectiveness of the use of specialized dietary products of domestic production for cancer patients is presented. Detoxification protein cocktail for cancer patients (based on animal protein), Lactose-free detoxification protein cocktail for cancer patients (based on plant protein) and Drink detoxification for cancer patients (fruit-based). These specialized products have promote tonic, antioxidant, anti-inflammatory, analgesic, anti-toxic, detoxifying properties. It has been shown that dietary products contribute to the restoration of the concentration in the blood of the most important enzymes of antitoxic liver defense – ALT and AST, gamma-HT, total and direct bilirubin, and urea.

scholarly journals The role of neurotrophins in post-stroke rehabilitation

2021 ◽  
Vol 25 (4) ◽  
pp. 651-656
Author(s):  
D. S. Sukhan ◽  
H. P. Liudkevych ◽  
І. V. Olkhova ◽  
Y. O. Botanevych ◽  
V. S. Orlenko ◽  
...  
Keyword(s):  
Stroke Rehabilitation ◽  
Web Of Science ◽  
Structure And Function ◽  
Current Data ◽  
Long Time ◽  
New Treatments ◽  
And Function ◽  
Further Development ◽  
The Brain

Annotation. Acute disorder of cerebral circulation (ADCC) occupies leading positions in mortality and disability in Ukraine, despite new treatments and modern medical care. Current data suggest that the problem of treatment and rehabilitation of patients after ADCC can be solved with the help of neurotrophins – a family of proteins that regulate the processes of plasticity in the brain. Due to the similarity of their structure, they are able to act as a holistic system, helping to repair damaged areas of the brain. Therefore, the purpose of this review was to collect information on the structure and function of neurotrophins BDNF, NGF, NT-3 and NT-4, their role in neuroplasticity after stroke in order to develop modern methods of influencing them for further implementation in practice. For this purpose, 50 sources from the main databases (Elsevier, Pubmed, Web of Science, Google Scholar) were used. The systematic review describes the structure of neurotrophins and their function, mechanisms of neuroplasticity and methods of influencing it, in particular exercise and diet. Since these methods have a general therapeutic effect and require a long time for its onset, the prospects for further development are the creation of drugs targeted to the neurotrophin system for effective rehabilitation of patients after stroke.

scholarly journals The Phosphorylation of CREB at Serine 133 Is a Key Event for Circadian Clock Timing and Entrainment in the Suprachiasmatic Nucleus

2018 ◽  
Vol 33 (5) ◽  
pp. 497-514 ◽  
Author(s):  
Kelin L. Wheaton ◽  
Katelin F. Hansen ◽  
Sydney Aten ◽  
Kyle A. Sullivan ◽  
Hyojung Yoon ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Suprachiasmatic Nucleus ◽  
Wheel Running ◽  
Slice Culture ◽  
Creb Phosphorylation ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Free Running

Within the suprachiasmatic nucleus (SCN)—the locus of the master circadian clock— transcriptional regulation via the CREB/CRE pathway is implicated in the functioning of the molecular clock timing process, and is a key conduit through which photic input entrains the oscillator. One event driving CRE-mediated transcription is the phosphorylation of CREB at serine 133 (Ser133). Indeed, numerous reporter gene assays have shown that an alanine point mutation in Ser133 reduces CREB-mediated transcription. Here, we sought to examine the contribution of Ser133 phosphorylation to the functional role of CREB in SCN clock physiology in vivo. To this end, we used a CREB knock-in mouse strain, in which Ser133 was mutated to alanine (S/A CREB). Under a standard 12 h light-dark cycle, S/A CREB mice exhibited a marked alteration in clock-regulated wheel running activity. Relative to WT mice, S/A CREB mice had highly fragmented bouts of locomotor activity during the night phase, elevated daytime activity, and a delayed phase angle of entrainment. Further, under free-running conditions, S/A CREB mice had a significantly longer tau than WT mice and reduced activity amplitude. In S/A CREB mice, light-evoked clock entrainment, using both Aschoff type 1 and 6 h “jet lag” paradigms, was markedly reduced relative to WT mice. S/A CREB mice exhibited attenuated transcriptional drive, as assessed by examining both clock-gated and light-evoked gene expression. Finally, SCN slice culture imaging detected a marked disruption in cellular clock phase synchrony following a phase-resetting stimulus in S/A CREB mice. Together, these data indicate that signaling through CREB phosphorylation at Ser133 is critical for the functional fidelity of both SCN timing and entrainment.

Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes

2004 ◽  
Vol 287 (1) ◽  
pp. R47-R57 ◽  
Author(s):  
Priyattam J. Shiromani ◽  
Man Xu ◽  
Elizabeth M. Winston ◽  
Samara N. Shiromani ◽  
Dmitry Gerashchenko ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Slow Wave Sleep ◽  
Genetic Model ◽  
Constant Darkness ◽  
Homeostatic Regulation ◽  
Targeted Disruption ◽  
Free Running ◽  
Sleep Drive ◽  
Sleep Amount

In mammals, sleep is regulated by circadian and homeostatic mechanisms. The circadian component, residing in the suprachiasmatic nucleus (SCN), regulates the timing of sleep, whereas homeostatic factors determine the amount of sleep. It is believed that these two processes regulating sleep are independent because sleep amount is unchanged after SCN lesions. However, because such lesions necessarily damage neuronal connectivity, it is preferable to investigate this question in a genetic model that overcomes the confounding influence of circadian rhythmicity. Mice with disruption of both mouse Period genes ( mPer) 1 and mPer2 have a robust diurnal sleep-wake rhythm in an entrained light-dark cycle but lose rhythmicity in a free-run condition. Here, we examine the role of the mPer genes on the rhythmic and homeostatic regulation of sleep. In entrained conditions, when averaged over the 24-h period, there were no significant differences in waking, slow-wave sleep (SWS), or rapid eye movement (REM) sleep between mPer1, mPer2, mPer3, mPer1-mPer2 double-mutant, and wild-type mice. The mice were then kept awake for 6 h (light period 6–12), and the mPer mutants exhibited increased sleep drive, indicating an intact sleep homeostatic response in the absence of the mPer genes. In free-run conditions (constant darkness), the mPer1-mPer2 double mutants became arrhythmic, but they continued to maintain their sleep levels even after 36 days in free-running conditions. Although mPer1 and mPer2 represent key elements of the molecular clock in the SCN, they are not required for homeostatic regulation of the daily amounts of waking, SWS, or REM sleep.

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