Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice

2007 ◽  
Vol 102 (1) ◽  
pp. 241-248 ◽  
Author(s):  
Akira Nakamura ◽  
Wei Zhang ◽  
Masashi Yanagisawa ◽  
Yasuichiro Fukuda ◽  
Tomoyuki Kuwaki
Keyword(s):  
Rem Sleep ◽  
Knockout Mice ◽  
Slow Wave Sleep ◽  
Ventilatory Response ◽  
Control Of Breathing ◽  
Dependent Manner ◽  
Wild Type ◽  
Vigilance State ◽  
State Dependent ◽  
Respiratory Parameters

Exogenous administration of orexin can promote wakefulness and respiration. Here we examined whether intrinsic orexin participates in the control of breathing in a vigilance state-dependent manner. Ventilation was recorded together with electroencephalography and electromyography for 6 h during the daytime in prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates. Respiratory parameters were separately determined during quiet wakefulness (QW), slow-wave sleep (SWS), or rapid eye movement (REM) sleep. Basal ventilation was normal in ORX-KO, irrespective of vigilance states. The hypercapnic ventilatory response during QW in ORX-KO (0.19 ± 0.01 ml·min−1·g−1·%CO2−1) was significantly smaller than that in WT mice (0.38 ± 0.04 ml·min−1·g−1·%CO2−1), whereas the responses during SWS and REM in ORX-KO were comparable to those in WT mice. Hypoxic responses during wake and sleep periods were not different between the genotypes. Spontaneous but not postsigh sleep apneas were more frequent in ORX-KO than in WT littermates during both SWS and REM sleep. Our findings suggest that orexin plays a crucial role both in CO2 sensitivity during wakefulness and in preserving ventilation stability during sleep.

Negative pressure effects on mechanically opposing pharyngeal muscles in awake and sleeping goats

2001 ◽  
Vol 91 (5) ◽  
pp. 2289-2297 ◽  
Author(s):  
Thom R. Feroah ◽  
H. V. Forster ◽  
L. Pan ◽  
N. E. Schlick ◽  
Paul Martino ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Negative Pressure ◽  
Slow Wave Sleep ◽  
Pressure Response ◽  
Pressure Effects ◽  
Upper Airways ◽  
Tp 31 ◽  
State Dependent ◽  
Pharyngeal Muscles ◽  
Pressure Tests

Our aim was to investigate the effects of the negative pressure reflex on mechanically opposing pharyngeal muscles during wakefulness, slow-wave sleep (SWS), and rapid eye movement (REM) sleep. In four goats with isolated upper airways, we measured tracheal airflow and electrical activity of the thyropharyngeus (TP; constricting), the stylopharyngeus (SP; dilating), and the diaphragm (Dia). In the wakefulness state in response to negative pressure tests, TP decreased (65%), SP increased (198%), and tidal volume (Vt) (66%) and rate of rise of Dia (Diaslope, 69%) decreased ( P < 0.02). Similarly, during SWS, the negative pressure response of TP (31%), Vt (61%), and Diaslope (60%) decreased, whereas SP (113%) increased, relative to SWS control ( P < 0.02). In REM sleep, the negative pressure response by TP and SP were small, whereas both Vt (38%) and Diaslope (24%) were greatly decreased ( P < 0.02) compared with REM control. Inspiratory duration remained unchanged in response to negative pressure tests in all states. These data provide evidence that mechanically opposing inspiratory and expiratory pharyngeal muscles are reciprocally controlled and their response to negative pressure are state dependent.

scholarly journals Electroacupuncture Stimulation at CV12 Inhibits Gastric Motility via TRPV1 Receptor

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Zhi Yu ◽  
Xin Cao ◽  
Youbing Xia ◽  
Binbin Ren ◽  
Hong Feng ◽  
...  
Keyword(s):  
Gastric Motility ◽  
Knockout Mice ◽  
Functional Gastrointestinal Disorders ◽  
Inhibitory Effect ◽  
Gastrointestinal Disorders ◽  
Dependent Manner ◽  
Wild Type ◽  
Trpv1 Receptor ◽  
Alternative Approaches ◽  
Trpv1 Antagonist

Gastric dysmotility is one of the major pathophysiological factors in functional gastrointestinal disorders. Acupuncture, as one of the alternative approaches, is efficacious in the treatment of gastrointestinal motility disorders; however, the mechanism underlying its action is unclear. In the present study, we used both capsazepine, a TRPV1 antagonist, and TRPV1 knockout mice. Animals were divided into wild-type group (WT), capsazepine injection group (CZP, 0.5 mg/kg, i.p.), and TRPV1 knockout mice group (TRPV1−/−). Each of these three groups was divided into three subgroups, which were subjected to EA stimulation at acupoint Zhongwan (CV12) at a different intensity (1, 2, or 4 mA). We demonstrated that electroacupuncture at Zhongwan (CV12) markedly inhibited gastric motility at 2 and 4 mA in an intensity-dependent manner in wild-type mice. The inhibitory effect was also observed in capsazepine-injected and TRPV1−/−mice but was no longer intensity dependent, indicating that TRPV1 is partially involved in the electroacupuncture-mediated modulation of gastric motility.

scholarly journals Novel Role of Brain Stem Pedunculopontine Tegmental Adenylyl Cyclase in the Regulation of Spontaneous REM Sleep in the Freely Moving Rat

2005 ◽  
Vol 94 (3) ◽  
pp. 1928-1937 ◽  
Author(s):  
Subimal Datta ◽  
Sarah L. Prutzman
Keyword(s):  
Adenylyl Cyclase ◽  
Signaling Pathway ◽  
Rem Sleep ◽  
Slow Wave Sleep ◽  
Kainate Receptors ◽  
Camp Signaling ◽  
Dependent Manner ◽  
Camp Signaling Pathway ◽  
Freely Moving ◽  
Different Doses

Physiological activation of kainate receptors and GABAB receptors within the pedunculopontine tegmentum (PPT) is involved in regulation of rapid-eye-movement (REM) sleep. Because these two types of receptors may also directly and/or indirectly activate the intracellular cyclic adenosine monophosphate (cAMP) signaling pathway, we hypothesized that this signaling pathway may be involved in the PPT to regulate spontaneous REM sleep. To test this hypothesis, four different doses (0.25, 0.50, 0.75, and 1.0 nmol) of a specific adenylyl cyclase (AC) inhibitor, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536), were microinjected bilaterally (100 nl/site) into the PPT, and the effects on REM sleep in freely moving chronically instrumented rats were quantified. By comparing alterations in the patterns of REM sleep after control injections of vehicle or one of the four different doses of SQ22536, the contributions made by each dose of SQ22536 to REM sleep were evaluated. The results demonstrated that the local microinjection of AC inhibitor SQ22536 into the PPT decreased the total amount of REM sleep for 3 h and increased slow-wave sleep (SWS) for 2 h in a dose-dependent manner. This reduction in REM sleep was due to increased latency and decreased frequency of REM sleep episodes. These results provide evidence that inhibition of AC within the PPT can successfully reduce REM sleep. These findings suggest that activation of the cAMP-signaling pathway within the cholinergic cell compartment of the PPT is an intracellular biochemical/molecular step for generating REM sleep in the freely moving rat.

Short-Duration Epileptic Discharges Show a Distinct Phase Preference During Ongoing Hippocampal Slow Oscillations

2010 ◽  
Vol 104 (4) ◽  
pp. 2194-2202 ◽  
Author(s):  
Philip H. de Guzman ◽  
Farhang Nazer ◽  
Clayton T. Dickson
Keyword(s):  
Short Duration ◽  
Temporal Lobe ◽  
Slow Wave ◽  
Rem Sleep ◽  
Slow Wave Sleep ◽  
Epileptiform Activity ◽  
Epileptic Activity ◽  
Network Synchronization ◽  
State Dependent ◽  
Oscillatory Pattern

Non-REM (slow-wave) sleep has been shown to facilitate temporal lobe epileptiform events, whereas REM sleep seems more restrictive. This state-dependent modulation may be the result of the enhancement of excitatory synaptic transmission and/or the degree of network synchronization expressed within the hippocampus of the temporal lobe. The slow oscillation (SO), a ∼1 Hz oscillatory pattern expressed during non-REM sleep and urethane anesthesia, has been recently shown to facilitate the generation, maintenance, and propagation of stimulus-evoked epileptiform activity in the hippocampus. To further address the state-dependent modulation of epileptic activity during the SO, we studied the properties of short-duration interictal-like activity generated by focal application of penicillin in the hippocampus of urethane-anesthetized rats. Epileptiform spikes were larger but only slightly more prevalent during the SO as opposed to the theta (REM-like) state. More notably, however, epileptic spikes had a significant tendency to occur just following the peak negativity of ongoing SO cycles. Because of the known phase-dependent changes in 1) synaptic excitability (just following the positive peak of the SO) and 2) network synchronization (during the negative peak of the SO), these results suggest that it is the synchrony and not the changes in synaptic excitability that lead to the facilitation of epileptiform activity during sleep-like slow wave states.

scholarly journals State-dependent pontine ensemble dynamics and interactions with cortex across sleep states

2019 ◽  
Author(s):  
Tomomi Tsunematsu ◽  
Amisha A Patel ◽  
Arno Onken ◽  
Shuzo Sakata
Keyword(s):  
Rem Sleep ◽  
Hippocampal Neurons ◽  
Specific Activity ◽  
Nrem Sleep ◽  
Dependent Manner ◽  
Sleep Regulation ◽  
Population Activity ◽  
P Waves ◽  
State Dependent ◽  
Global Coordination

AbstractThe pontine nuclei play a crucial role in sleep-wake regulation. However, pontine ensemble dynamics underlying sleep regulation remain poorly understood. By monitoring population activity in multiple pontine and adjacent brainstem areas, here we show slow, state-predictive pontine ensemble dynamics and state-dependent interactions between the pons and the cortex in mice. On a timescale of seconds to minutes, pontine populations exhibit diverse firing across vigilance states, with some of these dynamics being attributed to cell type-specific activity. Pontine population activity can predict pupil dilation and vigilance states: pontine neurons exhibit longer predictable power compared with hippocampal neurons. On a timescale of sub-seconds, pontine waves (P-waves) are observed as synchronous firing of pontine neurons primarily during rapid eye movement (REM) sleep, but also during non-REM (NREM) sleep. Crucially, P-waves functionally interact with cortical activity in a state-dependent manner: during NREM sleep, hippocampal sharp wave-ripples (SWRs) precede P-waves. On the other hand, P-waves during REM sleep are phase-locked with ongoing hippocampal theta oscillations and are followed by burst firing in a subset of hippocampal neurons. Thus, the directionality of functional interactions between the hippocampus and pons changes depending on sleep states. This state-dependent global coordination between pontine and cortical regions implicates distinct functional roles of sleep.

scholarly journals Chemokine Receptor CXCR-2 Initiates Atrial Fibrillation by Triggering Monocyte Mobilization in Mice

Hypertension ◽  
2020 ◽  
Vol 76 (2) ◽  
pp. 381-392 ◽  
Author(s):  
Yun-Long Zhang ◽  
Hua-Jun Cao ◽  
Xiao Han ◽  
Fei Teng ◽  
Chen Chen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Bone Marrow ◽  
Chemokine Receptor ◽  
Knockout Mice ◽  
Bone Marrow Cells ◽  
Atrial Remodeling ◽  
Dependent Manner ◽  
Ang Ii ◽  
Wild Type ◽  
Chemokine Ligands

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2 + immune cells markedly increased in Ang II–infused atria in a time-dependent manner. Moreover, Ang II–infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2 + monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.

scholarly journals Control of breathing during sleep assessed by proportional assist ventilation

1998 ◽  
Vol 84 (1) ◽  
pp. 3-12 ◽  
Author(s):  
S. Meza ◽  
E. Giannouli ◽  
M. Younes
Keyword(s):  
Rem Sleep ◽  
Slow Wave Sleep ◽  
Minute Ventilation ◽  
Upper Airway ◽  
Normal Subjects ◽  
Progressive Increase ◽  
Control Of Breathing ◽  
Respiratory Drive ◽  
Proportional Assist Ventilation ◽  
End Tidal

Meza, S., E. Giannouli, and M. Younes. Control of breathing during sleep assessed by proportional assist ventilation. J. Appl. Physiol. 84(1): 3–12, 1998.—We used proportional assist ventilation (PAV) to evaluate the sources of respiratory drive during sleep. PAV increases the slope of the relation between tidal volume (Vt) and respiratory muscle pressure output (Pmus). We reasoned that if respiratory drive is dominated by chemical factors, progressive increase of PAV gain should result in only a small increase in Vt because Pmus would be downregulated substantially as a result of small decreases in[Formula: see text]. In the presence of substantial nonchemical sources of drive [believed to be the case in rapid-eye-movement (REM) sleep] PAV should result in a substantial increase in minute ventilation and reduction in [Formula: see text] as the output related to the chemically insensitive drive source is amplified severalfold. Twelve normal subjects underwent polysomnography while connected to a PAV ventilator. Continuous positive air pressure (5.2 ± 2.0 cmH2O) was administered to stabilize the upper airway. PAV was increased in 2-min steps from 0 to 20, 40, 60, 80, and 90% of the subject’s elastance and resistance. Vt, respiratory rate, minute ventilation, and end-tidal CO2pressure were measured at the different levels, and Pmus was calculated. Observations were obtained in stage 2 sleep ( n = 12), slow-wave sleep ( n = 11), and REM sleep ( n = 7). In all cases, Pmus was substantially downregulated with increase in assist so that the increase in Vt, although significant ( P < 0.05), was small (0.08 liter at the highest assist). There was no difference in response between REM and non-REM sleep. We conclude that respiratory drive during sleep is dominated by chemical control and that there is no fundamental difference between REM and non-REM sleep in this regard. REM sleep appears to simply add bidirectional noise to what is basically a chemically controlled respiratory output.

scholarly journals Neural Correlates of Wakefulness, Sleep, and General Anesthesia

2016 ◽  
Vol 125 (5) ◽  
pp. 929-942 ◽  
Author(s):  
Dinesh Pal ◽  
Brian H. Silverstein ◽  
Heonsoo Lee ◽  
George A. Mashour
Keyword(s):  
General Anesthesia ◽  
Rem Sleep ◽  
Slow Wave Sleep ◽  
Transfer Entropy ◽  
Sprague Dawley ◽  
Behavioral Arousal ◽  
State Dependent ◽  
Sprague Dawley Rats ◽  
Dependent Change ◽  
Symbolic Transfer Entropy

Abstract Background Significant advances have been made in our understanding of subcortical processes related to anesthetic- and sleep-induced unconsciousness, but the associated changes in cortical connectivity and cortical neurochemistry have yet to be fully clarified. Methods Male Sprague–Dawley rats were instrumented for simultaneous measurement of cortical acetylcholine and electroencephalographic indices of corticocortical connectivity—coherence and symbolic transfer entropy—before, during, and after general anesthesia (propofol, n = 11; sevoflurane, n = 13). In another group of rats (n = 7), these electroencephalographic indices were analyzed during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. Results Compared to wakefulness, anesthetic-induced unconsciousness was characterized by a significant decrease in cortical acetylcholine that recovered to preanesthesia levels during recovery wakefulness. Corticocortical coherence and frontal–parietal symbolic transfer entropy in high γ band (85 to 155 Hz) were decreased during anesthetic-induced unconsciousness and returned to preanesthesia levels during recovery wakefulness. Sleep-wake states showed a state-dependent change in coherence and transfer entropy in high γ bandwidth, which correlated with behavioral arousal: high during wakefulness, low during SWS, and lowest during REM sleep. By contrast, frontal–parietal θ connectivity during sleep-wake states was not correlated with behavioral arousal but showed an association with well-established changes in cortical acetylcholine: high during wakefulness and REM sleep and low during SWS. Conclusions Corticocortical coherence and frontal–parietal connectivity in high γ bandwidth correlates with behavioral arousal and is not mediated by cholinergic mechanisms, while θ connectivity correlates with cortical acetylcholine levels.

Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and emptying

2010 ◽  
Vol 299 (5) ◽  
pp. G1078-G1086 ◽  
Author(s):  
Sumito Mizuguchi ◽  
Takashi Ohno ◽  
Youichiro Hattori ◽  
Takako Ae ◽  
Tsutomu Minamino ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Motor Activity ◽  
Continuous Infusion ◽  
Knockout Mice ◽  
Smooth Muscles ◽  
Dependent Manner ◽  
Wild Type ◽  
Gastric Artery ◽  
Myoelectrical Activity ◽  
Gastric Motor Activity

It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not endogenous PGs, which can protect the stomach from noxious stimuli, affect gastric motor activity and emptying. The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of over 2 cmH2O. Replacement of intragastric physiological saline with 1 M NaCl solution significantly increased PGI2 and PGE2 in stomach and suppressed the myoelectrical activity under a pressure of 2 cmH2O by 70%. Indomethacin inhibited the suppression of myoelectrical activity by 1 M NaCl. The myoelectrical activity under a pressure of 2 cmH2O was suppressed by continuous infusion of a selective EP1 agonist (ONO-DI-004, 3–100 nmol·kg−1·min−1) into the gastric artery in a dose-dependent manner, but not by that of the PGI receptor agonist beraprost sodium (100 nmol·kg−1·min−1). Suppression of myoelectrical activity with 1 M NaCl was inhibited by continuous infusion of a selective EP1 antagonist (ONO-8711, 100 nmol·kg−1·min−1) into the gastric artery. Furthermore, gastric emptying was tested in EP1 knockout mice and their wild-type counterparts. Gastric emptying was strongly suppressed with intragastric 1 M NaCl in wild-type mice, but this 1 M NaCl-induced suppression was not seen in EP1 knockout mice. These results suggest that PGE2-EP1 signaling has crucial roles in suppression of myoelectrical activity of gastric smooth muscles and inhibition of gastric emptying and that EP1 is an obvious target for drugs that control gastric emptying.

scholarly journals Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Toshiya Nishi ◽  
Shinichi Kondo ◽  
Maki Miyamoto ◽  
Sayuri Watanabe ◽  
Shigeo Hasegawa ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Brain Slice ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Wild Type ◽  
Short Life Span ◽  
Premature Deaths ◽  
Knockout Animals ◽  
Dose Dependent ◽  
The Brain

Abstract Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.

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