Enhanced Thalamic Spillover Inhibition during Non–rapid-eye-movement Sleep Triggers an Electrocortical Signature of Anesthetic Hypnosis

2016 ◽  
Vol 125 (5) ◽  
pp. 964-978 ◽  
Author(s):  
Lia Mesbah-Oskui ◽  
Richard L. Horner
Keyword(s):  
Eye Movement ◽  
Rem Sleep ◽  
Aminobutyric Acid ◽  
Rapid Eye Movement ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Brain Wave ◽  
Electrocortical Activity

Abstract Background Alterations in thalamic γ-aminobutyric acid–mediated signaling are thought to underlie the increased frontal α-β frequency electrocortical activity that signals anesthetic-induced loss of consciousness with γ-aminobutyric acid receptor type A (GABAAR)–targeting general anesthetics. The general anesthetic etomidate elicits phasic extrasynaptic GABAAR activation (“spillover” inhibition) at thalamocortical neurons in vitro. We hypothesize that this action of etomidate at the thalamus is sufficient to trigger an increase in frontal α-β frequency electrocortical activity and that this effect of etomidate is fully recapitulated by enhanced thalamic spillover inhibition in vivo. Methods We recorded electrocortical activity and sleep–wake behavior in freely behaving wild-type (n = 33) and extrasynaptic δ-subunit–containing GABAAR knockout mice (n = 9) during bilateral microperfusion of the thalamus with etomidate and/or other pharmacologic agents that influence GABAAR or T-type Ca2+ channel activity. Results Microperfusion of etomidate into the thalamus elicited an increase in α-β frequency electrocortical activity that occurred only during non–rapid-eye-movement (REM) sleep (11.0 ± 11.8% and 16.0 ± 14.2% greater 8 to 12- and 12 to 30-Hz power, respectively; mean ± SD; both P < 0.031) and was not affected by blockade of thalamic T-type Ca2+ channels. Etomidate at the thalamus also increased spindle-like oscillations during non-REM sleep (4.5 ± 2.4 spindle per minute with etomidate vs. 3.2 ± 1.7 at baseline; P = 0.002). These effects of etomidate were fully recapitulated by enhanced thalamic extrasynaptic GABAAR-mediated spillover inhibition. Conclusions These findings identify how a prototypic GABAAR-targeting general anesthetic agent can elicit the characteristic brain wave pattern associated with anesthetic hypnosis when acting at the thalamus by promoting spillover inhibition and the necessity of a preexisting non-REM mode of activity in the thalamus to generate this effect.

GABAergic Regulation of REM Sleep in Reticularis Pontis Oralis and Caudalis in Rats

2003 ◽  
Vol 90 (2) ◽  
pp. 938-945 ◽  
Author(s):  
Larry D. Sanford ◽  
Xiangdong Tang ◽  
Jihua Xiao ◽  
Richard J. Ross ◽  
Adrian R. Morrison
Keyword(s):  
Eye Movement ◽  
Rem Sleep ◽  
Escape Behavior ◽  
Aminobutyric Acid ◽  
Rapid Eye Movement ◽  
Rapid Eye Movement Sleep ◽  
Sprague Dawley ◽  
Site Specific ◽  
Guide Cannulae ◽  
Nucleus Reticularis

The nucleus reticularis pontis oralis (RPO) and nucleus reticularis pontis caudalis (RPC) are implicated in the generation of rapid eye movement sleep (REM). Work in cats has indicated that GABA in RPO plays a role in the regulation of REM. We assessed REM after local microinjections into RPO and RPC of the γ-aminobutyric acid-A (GABAA) agonist, muscimol (MUS), and the GABAA antagonist, bicuculline (BIC). Rats (90-day-old male Sprague-Dawley) were implanted with electrodes for recording electroencephalographs (EEG) and electromyographs (EMG). Guide cannulae were aimed into RPO ( n = 9) and RPC ( n = 8) for microinjecting MUS (200, 1,000.0 μM) and BIC (0.056, 0.333, 1.0, 1,000.0, and 10,000.0 μM). Animals received bilateral microinjections of saline, MUS, and BIC (0.2 μl microinjected at 0.1 μl/min) into each region followed by 6-h sleep recordings. In RPO, MUS (1,000.0 μM) suppressed REM and BIC (1,000.0 μM) enhanced REM. In RPC, MUS (200, 1,000.0 μM) suppressed REM, but BIC (1,000.0 μM and less) did not significantly affect REM. Higher concentrations of BIC (10,000.0 μM) injected into RPO ( n = 9) and RPC ( n = 4) produced wakefulness and escape behavior. The results indicate that GABA in RPO/RPC is involved in the regulation of REM and suggest site-specific differences in this regulation.

scholarly journals Computational model of brain-stem circuit for state-dependent control of hypoglossal motoneurons

2018 ◽  
Vol 120 (1) ◽  
pp. 296-305 ◽  
Author(s):  
Mohsen Naji ◽  
Maxim Komarov ◽  
Giri P. Krishnan ◽  
Atul Malhotra ◽  
Frank L. Powell ◽  
...  
Keyword(s):  
Eye Movement ◽  
Neuronal Network ◽  
Rem Sleep ◽  
Rapid Eye Movement ◽  
Hypoglossal Motoneurons ◽  
State Dependent ◽  
Obstructive Sleep ◽  
Pharyngeal Muscles ◽  
Serotonergic Drugs

In patients with obstructive sleep apnea (OSA), the pharyngeal muscles become relaxed during sleep, which leads to a partial or complete closure of upper airway. Experimental studies suggest that withdrawal of noradrenergic and serotonergic drives importantly contributes to depression of hypoglossal motoneurons and, therefore, may contribute to OSA pathophysiology; however, specific cellular and synaptic mechanisms remain unknown. In this new study, we developed a biophysical network model to test the hypothesis that, to explain experimental observations, the neuronal network for monoaminergic control of excitability of hypoglossal motoneurons needs to include excitatory and inhibitory perihypoglossal interneurons that mediate noradrenergic and serotonergic drives to hypoglossal motoneurons. In the model, the state-dependent activation of the hypoglossal motoneurons was in qualitative agreement with in vivo data during simulated rapid eye movement (REM) and non-REM sleep. The model was applied to test the mechanisms of action of noradrenergic and serotonergic drugs during REM sleep as observed in vivo. We conclude that the proposed minimal neuronal circuit is sufficient to explain in vivo data and supports the hypothesis that perihypoglossal interneurons may mediate state-dependent monoaminergic drive to hypoglossal motoneurons. The population of the hypothesized perihypoglossal interneurons may serve as novel targets for pharmacological treatment of OSA. NEW & NOTEWORTHY In vivo studies suggest that during rapid eye movement sleep, withdrawal of noradrenergic and serotonergic drives critically contributes to depression of hypoglossal motoneurons (HMs), which innervate the tongue muscles. By means of a biophysical model, which is consistent with a broad range of empirical data, we demonstrate that the neuronal network controlling the excitability of HMs needs to include excitatory and inhibitory interneurons that mediate noradrenergic and serotonergic drives to HMs.

Inflammation Increases Neuronal Sensitivity to General Anesthetics

2016 ◽  
Vol 124 (2) ◽  
pp. 417-427 ◽  
Author(s):  
Sinziana Avramescu ◽  
Dian-Shi Wang ◽  
Irene Lecker ◽  
William T. H. To ◽  
Antonello Penna ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Cortical Neurons ◽  
Receptor Activity ◽  
Aminobutyric Acid ◽  
General Anesthetics ◽  
Enhanced Sensitivity ◽  
Behavioral Sensitivity ◽  
Underlying Mechanisms

Abstract Background Critically ill patients with severe inflammation often exhibit heightened sensitivity to general anesthetics; however, the underlying mechanisms remain poorly understood. Inflammation increases the number of γ-aminobutyric acid type A (GABAA) receptors expressed on the surface of neurons, which supports the hypothesis that inflammation increases up-regulation of GABAA receptor activity by anesthetics, thereby enhancing the behavioral sensitivity to these drugs. Methods To mimic inflammation in vitro, cultured hippocampal and cortical neurons were pretreated with interleukin (IL)-1β. Whole cell patch clamp methods were used to record currents evoked by γ-aminobutyric acid (GABA) (0.5 μM) in the absence and presence of etomidate or isoflurane. To mimic inflammation in vivo, mice were treated with lipopolysaccharide, and several anesthetic-related behavioral endpoints were examined. Results IL-1β increased the amplitude of current evoked by GABA in combination with clinically relevant concentrations of either etomidate (3 μM) or isoflurane (250 μM) (n = 5 to 17, P < 0.05). Concentration–response plots for etomidate and isoflurane showed that IL-1β increased the maximal current 3.3-fold (n = 5 to 9) and 1.5-fold (n = 8 to 11), respectively (P < 0.05 for both), whereas the half-maximal effective concentrations were unchanged. Lipopolysaccharide enhanced the hypnotic properties of both etomidate and isoflurane. The immobilizing properties of etomidate, but not isoflurane, were also increased by lipopolysaccharide. Both lipopolysaccharide and etomidate impaired contextual fear memory. Conclusions These results provide proof-of-concept evidence that inflammation increases the sensitivity of neurons to general anesthetics. This increase in anesthetic up-regulation of GABAA receptor activity in vitro correlates with enhanced sensitivity for GABAA receptor–dependent behavioral endpoints in vivo.

scholarly journals Vesicular GABA-transporter neurons in the zona incerta are maximally active during non rapid-eye movement (NREM) and rapid-eye movement (REM) sleep

2020 ◽  
Author(s):  
Carlos Blanco-Centurion ◽  
SiWei Luo ◽  
Aurelio Vidal-Ortiz ◽  
Priyattam J. Shiromani
Keyword(s):  
Eye Movement ◽  
Lateral Hypothalamus ◽  
Rem Sleep ◽  
Sleep Onset ◽  
Nrem Sleep ◽  
Zona Incerta ◽  
Imaging Method ◽  
Rapid Eye Movement ◽  
Gaba Transporter

AbstractSleep and wake are opposing behavioral states controlled by the activity of specific neurons. The neurons responsible for sleep/wake control have not been fully identifed due to the lack of in-vivo high throughput technology. We use the deep-brain calcium (Ca2+) imaging method to identify activity of hypothalamic neurons expressing the vesicular GABA transporter (vGAT), a marker of GABAergic neurons. vGAT-cre mice (n=5) were microinjected with rAAV-FLEX-GCaMP6M into the lateral hypothalamus and 21d later the Ca2+ influx in vGAT neurons (n=372) was recorded in freely-behaving mice during waking (W), NREM and REM sleep. Post-mortem analysis revealed the lens tip located in the zona incerta/lateral hypothalamus (ZI-LH) and the change in fluorescence of neurons in the field of view was as follows: 54.9% of the vGAT neurons had peak fluorescence during REM sleep (REM-max), 17.2% were NREM-max, 22.8% were wake-max while 5.1% were both wake+REM max. Thus, three quarters of the recorded vGAT neurons in the ZI-LH were most active during sleep. In the NREM-max group Ca2+ fluorescence anticipated the initiation of NREM sleep onset and remained high throughout sleep (NREM and REM sleep). In the REM-max neurons Ca2+fluorescence increased before the onset of REM sleep and stayed elevated during the episode. Activation of the vGAT NREM-max neurons in the zona incerta and dorsal lateral hypothalamus would inhibit the arousal neurons to initiate and maintain sleep.

Halothane-induced synaptic depression at both in vivo and in vitro reconstructed synapses between identified Lymnaea neurons

1995 ◽  
Vol 74 (6) ◽  
pp. 2604-2613 ◽  
Author(s):  
G. E. Spencer ◽  
N. I. Syed ◽  
K. Lukowiak ◽  
W. Winlow
Keyword(s):  
Synaptic Transmission ◽  
Lymnaea Stagnalis ◽  
Cell Types ◽  
Inhibitory Synapses ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Presynaptic Neuron ◽  
Novel Approach

1. In the present study we tested the ability of the general anesthetic, halothane, to affect synaptic transmission at in vivo and in vitro reconstructed peptidergic synapses between identified neurons of Lymnaea stagnalis. 2. An identified respiratory interneuron, visceral dorsal 4 (VD4), innervates a number of postsynaptic cells in the central ring ganglia of Lymnaea. Because VD4 has previously been shown to exhibit immunoreactivity for FMRFamide-related peptides, it was hypothesized that these peptides may be utilized by VD4 during synaptic transmission. In the intact, isolated CNS of Lymnaea, we have identified novel connections between VD4 and the pedal A (PeA) cells. We demonstrate that VD4 makes inhibitory connections with the PeA neurons, in particular PeA4, and that these synaptic responses are mimicked by exogenous application of FMRFamide. 3. The synaptic transmission between VD4 and the PeA cells in an intact, isolated CNS preparation was completely blocked in 2%, but not 1% halothanc. Interestingly, the postsynaptic responses (PeA) to exogenous FMRFamide were maintained in the presence of both 1 and 2% halothane. 4. To determine the specificity of the observed responses and to determine the precise synaptic site of anesthetic action, we reconstructed the VD4/PeA synapses in vitro. After isolation from their respective ganglia, both cell types extended processes and established neuritic contact. We demonstrated that not only did the presynaptic neuron reestablish the appropriate inhibitory synapses with the PeA neurons, but that the PeA cells also maintained their responsiveness to exogenous FMRFamide. 5. Superfusion of the in vitro synaptically connected VD4 and PeA cells with 2% halothane completely abolished the synaptic transmission between these cells. However, even higher concentrations of 4% halothane failed to block the responsiveness of the PeA neurons to exogenous FMRFamide. Moreover, both 1 and 2% halothane enhanced the duration of the postsynaptic response to exogenously applied FMRFamide. These data suggest that the halothane-induced depression of synaptic transmission most likely occurred at the presynaptic level. 6. This study provides the first direct evidence that peptidergic transmission in the nervous system may also be susceptible to the actions of general anesthetics. In addition, we utilized a novel approach of in vitro reconstructed synapses for studying the effects of general anesthetics on monosynaptic transmission in the absence of other synaptic influences.

scholarly journals General Anesthetic Isoflurane Modulates Inositol 1,4,5-Trisphosphate Receptor Calcium Channel Opening

2014 ◽  
Vol 121 (3) ◽  
pp. 528-537 ◽  
Author(s):  
J. Donald Joseph ◽  
Yi Peng ◽  
Don-On Daniel Mak ◽  
King-Ho Cheung ◽  
Horia Vais ◽  
...  
Keyword(s):  
Single Channel ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Minimal Alveolar Concentration ◽  
Open Probability ◽  
Recombinant Type ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Abstract Background: Pharmacological evidence suggests that inhalational general anesthetics induce neurodegeneration in vitro and in vivo through overactivation of inositol trisphosphate receptor (InsP3R) Ca2+-release channels, but it is not clear whether these effects are due to direct modulation of channel activity by the anesthetics. Methods: Using single-channel patch clamp electrophysiology, the authors examined the gating of rat recombinant type 3 InsP3R (InsP3R-3) Ca2+-release channels in isolated nuclei (N = 3 to 15) from chicken lymphocytes modulated by isoflurane at clinically relevant concentrations in the absence and presence of physiological levels of the agonist inositol 1,4,5-trisphosphate (InsP3). The authors also examined the effects of isoflurane on InsP3R-mediated Ca2+ release from the endoplasmic reticulum and changes in intracellular Ca2+ concentration ([Ca2+]i). Results: Clinically relevant concentrations (approximately 1 minimal alveolar concentration) of the commonly used general anesthetic, isoflurane, activated InsP3R-3 channels with open probability similar to channels activated by 1 µM InsP3 (Po ≈ 0.2). This isoflurane modulation of InsP3R-3 Po depended biphasically on [Ca2+]i. Combination of isoflurane with subsaturating levels of InsP3 in patch pipettes resulted in at least two-fold augmentations of InsP3R-3 channel Po compared with InsP3 alone. These effects were not noted in the presence of saturating [InsP3]. Application of isoflurane to DT40 cells resulted in a 30% amplification of InsP3R-mediated [Ca2+]i oscillations, whereas InsP3-induced increase in [Ca2+]i and cleaved caspase-3 activity were enhanced by approximately 2.5-fold. Conclusion: These results suggest that the InsP3R may be a direct molecular target of isoflurane and plays a role in the mechanisms of anesthetic-mediated pharmacological or neurotoxic effects.

scholarly journals GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice

2019 ◽  
Author(s):  
Srikanta Chowdhury ◽  
Takanori Matsubara ◽  
Toh Miyazaki ◽  
Daisuke Ono ◽  
Manabu Abe ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Eye Movement ◽  
Rem Sleep ◽  
Nrem Sleep ◽  
Neural Circuitry ◽  
Acid Decarboxylase ◽  
Rapid Eye Movement ◽  
Population Activity ◽  
Ventral Tegmental

AbstractThe daily sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed neural circuitry mediating sleep is far from understood. Here, we found that glutamic acid decarboxylase 67 (Gad67)-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ neurons project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH) and dorsal raphe nucleus. Chemogenetic activation of VTAGad67+ neurons promoted NREM sleep with higher delta power whereas optogenetic inhibition of these neurons induced prompt arousal from NREM sleep under highly somnolescent conditions, but not during REM sleep. In vivo fiber photometry recordings revealed that VTAGad67+ neurons showed the highest population activity in NREM sleep and the lowest activity in REM sleep. Acute brain slice electrophysiology combined with optogenetics revealed that VTAGad67+ neurons directly innervate and inhibit wake-promoting orexin/hypocretin neurons in the LH by releasing GABA. Taken together, we reveal that VTAGad67+ neurons play a crucial role in the regulation of NREM sleep.

Does general anesthesia affect neurodevelopment in infants and children?

BMJ ◽  
2019 ◽  
pp. l6459 ◽  
Author(s):  
Mary Ellen McCann ◽  
Sulpicio G Soriano
Keyword(s):  
General Anesthesia ◽  
Pediatric Anesthesia ◽  
Neuronal Cell ◽  
Abnormal Development ◽  
In Vivo Studies ◽  
General Anesthetics ◽  
Neurocognitive Deficits ◽  
General Anesthetic

AbstractGeneral anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these retrospective studies have shown an association between anesthesia exposure at a young age and neurocognitive deficits, but others have not. Practitioners and families should be reassured that although general anesthetics have the potential to induce neurotoxicity, very little clinical evidence exists to support this.

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