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1.
Br J Anaesth ; 2023 Dec 08.
Article in English | MEDLINE | ID: mdl-38071152

ABSTRACT

BACKGROUND: Sleep disruption is a common occurrence during medical care and is detrimental to patient recovery. Long-term sedation in the critical care setting is a modifiable factor that affects sleep, but the impact of different sedative-hypnotics on sleep homeostasis is not clear. METHODS: We conducted a systematic comparison of the effects of prolonged sedation (8 h) with i.v. and inhalational agents on sleep homeostasis. Adult Sprague-Dawley rats (n=10) received dexmedetomidine or midazolam on separate days. Another group (n=9) received propofol or sevoflurane on separate days. A third group (n=12) received coadministration of dexmedetomidine and sevoflurane. Wakefulness (wake), slow-wave sleep (SWS), and rapid eye movement (REM) sleep were quantified during the 48-h post-sedation period, during which we also assessed wake-associated neural dynamics using two electroencephalographic measures: theta-high gamma phase-amplitude coupling and high gamma weighted phase-lag index. RESULTS: Dexmedetomidine-, midazolam-, or propofol-induced sedation increased wake and decreased SWS and REM sleep (P<0.0001) during the 48-h post-sedation period. Sevoflurane produced no change in SWS, decreased wake for 3 h, and increased REM sleep for 6 h (P<0.02) post-sedation. Coadministration of dexmedetomidine and sevoflurane induced no change in wake (P>0.05), increased SWS for 3 h, and decreased REM sleep for 9 h (P<0.02) post-sedation. Dexmedetomidine, midazolam, and coadministration of dexmedetomidine with sevoflurane reduced wake-associated phase-amplitude coupling (P≤0.01). All sedatives except sevoflurane decreased wake-associated high gamma weighted phase-lag index (P<0.01). CONCLUSIONS: In contrast to i.v. drugs, prolonged sevoflurane sedation produced minimal changes in sleep homeostasis and neural dynamics. Further studies are warranted to assess inhalational agents for long-term sedation and sleep homeostasis.

2.
Front Neurosci ; 14: 567849, 2020.
Article in English | MEDLINE | ID: mdl-33328847

ABSTRACT

The role of the brainstem cholinergic system in the regulation of sleep-wake states has been studied extensively but relatively little is known about the role of cholinergic mechanisms in prefrontal cortex in the regulation of sleep-wake states. In a recent study, we showed that prefrontal cholinergic stimulation in anesthetized rat can reverse the traits associated with anesthesia and restore a wake-like state, thereby providing evidence for a causal role for prefrontal cholinergic mechanisms in modulating level of arousal. However, the effect of increase in prefrontal cholinergic tone on spontaneous sleep-wake states has yet to be demonstrated. Therefore, in this study, we tested the hypothesis that delivery of cholinergic agonists - carbachol or nicotine - into prefrontal cortex of rat during slow wave sleep (SWS) would produce behavioral arousal and increase the time spent in wake state. We show that unilateral microinjection (200 nL) of carbachol (1 mM) or nicotine (100 mM) into prefrontal cortex during SWS decreased the latency to the onset of wake state (p = 0.03 for carbachol, p = 0.03 for nicotine) and increased the latency to the onset of rapid eye movement sleep (p = 0.008 for carbachol, p = 0.006 for nicotine). Although the infusion of 1 mM carbachol increased the time spent in wake state (p = 0.01) and decreased the time spent in SWS (p = 0.01), infusion of 10 or 100 mM nicotine did not produce any statistically significant change in sleep-wake architecture. These data demonstrate a differential role of prefrontal cholinergic receptors in modulating spontaneous sleep-wake states.

3.
J Chem Neuroanat ; 100: 101651, 2019 10.
Article in English | MEDLINE | ID: mdl-31128245

ABSTRACT

In obstructive sleep apnea (OSA) patients, contraction of the muscles of the tongue is needed to protect the upper airway from collapse. During wakefulness, norepinephrine directly excites motoneurons that innervate the tongue and other upper airway muscles but its excitatory effects decline during sleep, thus contributing to OSA. In addition to motoneurons, NE may regulate activity in premotor pathways but little is known about these upstream effects. To start filling this void, we injected a retrograde tracer (beta-subunit of cholera toxin-CTb; 5-10 nl, 1%) into the hypoglossal (XII) motor nucleus in 7 rats. We then used dual immunohistochemistry and brightfield microscopy to count dopamine beta-hydroxylase (DBH)-positive axon terminals closely apposed to CTb cells located in five anatomically distinct XII premotor regions. In different premotor groups, we found on the average 2.2-4.3 closely apposed DBH terminals per cell, with ˜60% more terminals on XII premotor neurons located in the ventrolateral pontine parabrachial region and ventral medullary gigantocellular region than on XII premotor cells of the rostral or caudal intermediate medullary reticular regions. This difference suggests stronger control by norepinephrine of the interneurons that mediate complex behavioral effects than of those mediating reflexes or respiratory drive to XII motoneurons.


Subject(s)
Adrenergic Neurons/cytology , Brain Stem/cytology , Hypoglossal Nerve/cytology , Presynaptic Terminals , Tongue/innervation , Animals , Female , Interneurons/cytology , Male , Rats , Rats, Long-Evans
4.
Respir Physiol Neurobiol ; 260: 105-113, 2019 02.
Article in English | MEDLINE | ID: mdl-30447306

ABSTRACT

Hypoglossal (XII) motoneurons are activated by type 2 receptors for serotonin (5-HT). This activation is especially strong during wakefulness which facilitates diverse motor functions of the tongue, including the maintenance of upper airway patency in obstructive sleep apnea (OSA) patients. We tested whether 5-HT2 receptor levels in the XII nucleus vary with intensity of tongue use. Three groups of rats were housed overnight under conditions of increasing oromotor activity: W-water available ad lib; S-sweetened water to stimulate drinking; S + O-sweetened water + oil applied on fur to increase grooming. After the exposures, immunostaining for 5-HT2C, but not 5-HT2A, receptors was higher in the XII nucleus in S + O than in W rats (65 ± 1.8 (SE) vs. 60 ± 2.0 arbitrary units; p = 0.008). In the medullary raphé obscurus region, the percentage of c-Fos-positive 5-HT cells was 13% higher (p = 0.03) in S + O than in W rats. The positive feedback between tongue use and 5-HT2C receptor immunostaining reveals a novel mechanism potentially relevant for OSA and neuromuscular disorders.


Subject(s)
Gene Expression Regulation/physiology , Hypoglossal Nerve/physiology , Medulla Oblongata/metabolism , Motor Neurons/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Tongue/physiology , Analysis of Variance , Animals , Diaphragm/physiology , Drinking , Electromyography , Locomotion , Male , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley
5.
J Neurosci ; 34(4): 1105-14, 2014 Jan 22.
Article in English | MEDLINE | ID: mdl-24453303

ABSTRACT

Improved understanding of the interaction between state of vigilance (SOV) and seizure onset has therapeutic potential. Six rats received injections of tetanus toxin (TeTX) in the ventral hippocampus that resulted in chronic spontaneous seizures. The distribution of SOV before 486 seizures was analyzed for a total of 19 d of recording. Rapid eye movement sleep (REM) and exploratory wake, both of which express prominent hippocampal theta rhythm, preceded 47 and 34%, for a total of 81%, of all seizures. Nonrapid eye movement sleep (NREM) and nonexploratory wake, neither of which expresses prominent theta, preceded 6.8 and 13% of seizures. We demonstrate that identification of SOV yields significant differentiation of seizure susceptibilities, with the instantaneous seizure rate during REM nearly 10 times higher than baseline and the rate for NREM less than half of baseline. Survival analysis indicated a shorter duration of preseizure REM bouts, with a maximum transition to seizure at ∼90 s after the onset of REM. This study provides the first analysis of a correlation between SOV and seizure onset in the TeTX model of temporal lobe epilepsy, as well as the first demonstration that hippocampal theta rhythms associated with natural behavioral states can serve a seizure-promoting role. Our findings are in contrast with previous studies suggesting that the correlations between SOV and seizures are primarily governed by circadian oscillations and the notion that hippocampal theta rhythms inhibit seizures. The documentation of significant SOV-dependent seizure susceptibilities indicates the potential utility of SOV and its time course in seizure prediction and control.


Subject(s)
Arousal/physiology , Epilepsy, Temporal Lobe/physiopathology , Hippocampus/physiopathology , Sleep, REM/physiology , Theta Rhythm/physiology , Animals , Disease Models, Animal , Epilepsy, Temporal Lobe/chemically induced , Male , Neurotoxins/toxicity , Rats , Rats, Long-Evans , Tetanus Toxin/toxicity
6.
J Biol Chem ; 285(35): 27411-27417, 2010 Aug 27.
Article in English | MEDLINE | ID: mdl-20551319

ABSTRACT

Potassium fluxes integrate mitochondria into cellular activities, controlling their volume homeostasis and structural integrity in many pathophysiological mechanisms. The outer mitochondrial membrane (OMM) is thought to play a passive role in this process because K(+) is believed to equilibrate freely between the cytosol and mitochondrial intermembrane space. By patch clamping mitochondria isolated from the central nervous systems of adult mitoCFP transgenic mice, we discovered the existence of I(OMMKi), a novel voltage-dependent inwardly rectifying K(+) conductance located in the OMM. I(OMMKi) is regulated by osmolarity, potentiated by cAMP, and activated at physiological negative potentials, allowing K(+) to enter the mitochondrial intermembrane space in a controlled regulated fashion. The identification of I(OMMKi) in the OMM supports the notion that a membrane potential could exist across this membrane in vivo and suggests that the OMM possesses regulated pathways for K(+) uptake.


Subject(s)
Membrane Potential, Mitochondrial/physiology , Mitochondrial Membranes/metabolism , Neurons/metabolism , Potassium Channels, Inwardly Rectifying/metabolism , Potassium/metabolism , Animals , Mice , Mice, Transgenic , Potassium Channels, Inwardly Rectifying/genetics
7.
Neurobiol Dis ; 25(1): 17-26, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17011204

ABSTRACT

This study sought to determine the role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology. We studied the effect of the HIV envelope protein gp120 on the expression of E2F1-dependent apoptotic proteins in human and rodent neurons and examined the expression pattern of E2F1 in the brain of HIV-infected individuals. Our findings suggest that in cultured neurons gp120 increased E2F1 levels in the nucleus, stimulated its transcriptional activity and enhanced the expression of the E2F1 target proteins Cdc2 and Puma. Studies with neuronal cultures from E2F1 deficient mice demonstrated that the transcription factor is required for gp120-induced neurotoxicity and up-regulation of Cdc2 and Puma. Levels of E2F1 protein were greater in the nucleus of neurons in brains of HIV-infected patients exhibiting dementia when compared to HIV-negative subjects or HIV-positive neurologically normal patients. Overall, these studies indicate that E2F1 is primarily involved in CXCR4-mediated neurotoxicity and HIV neuropathogenesis.


Subject(s)
AIDS Dementia Complex/pathology , E2F1 Transcription Factor/physiology , Neurotoxicity Syndromes/pathology , Receptors, CXCR4/physiology , Adult , Aged , Animals , Apoptosis/genetics , Blotting, Western , Brain/pathology , Cell Nucleus/metabolism , Cells, Cultured , E2F1 Transcription Factor/genetics , Electrophoretic Mobility Shift Assay , Environment , Female , HIV Envelope Protein gp120/genetics , HIV Infections/pathology , Humans , Immunoblotting , Immunohistochemistry , Luciferases/genetics , Male , Mice , Mice, Knockout , Microscopy, Fluorescence , Middle Aged , Neurons/physiology , Rats , Receptor Cross-Talk/physiology , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis , Transfection , Up-Regulation/genetics , Up-Regulation/physiology
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