Breathing and brain state: Urethane anesthesia as a model for natural sleep

doi:10.1016/j.resp.2013.05.035

Respiratory Physiology & Neurobiology

Volume 188, Issue 3, 15 September 2013, Pages 324-332

https://doi.org/10.1016/j.resp.2013.05.035 Get rights and content

Highlights

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Spontaneous brain state alternations occur under urethane anesthesia.
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State alternations under urethane resemble the natural sleep cycle.
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Respiratory characteristics are correlated with alternations of state.
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Urethane is a useful model for natural sleep.

Abstract

Respiratory control differs dramatically across sleep stages. Indeed, along with rapid eye movements (REM), respiration was one of the first physiological variables shown to be modulated across sleep stages. The study of sleep stages, their physiological correlates, and neurobiological underpinnings present a challenge because of the fragility and unpredictability of individual stages, not to mention sleep itself. Although anesthesia has often substituted as a model for a unitary stage of slow-wave (non-REM) sleep, it is only recently that urethane anesthesia has been proposed to model the full spectrum of sleep given the presence of spontaneous brain state alternations and concurrent physiological correlates that appear remarkably similar to natural sleep. We describe this model, its parallels with natural sleep, and its power for studying modulation of respiration. Specifically, we report data on the EEG characteristics across brain states under urethane anesthesia, the dependence of brain alternations on neurotransmitter systems, and the observations on state dependent modulation of respiration.

Section snippets

Sleep: a dynamic brain process

Sleep is a fundamental and necessary process with a strong circadian rhythm. Sleep, however, is not a unitary process. It exhibits dynamics expressed most prominently as alternations of brain state that can be measured by local or even more global field potential (LFP/EEG) recordings of brain activity which define the sleep cycle. Most important in the context of this review, respiratory control is significantly modulated in concert with changes in brain state during sleep and this has

Anesthesia: a pharmacological parallel to sleep?

Although sleep is the most common metaphor used for anesthesia by physicians and laypersons alike (Shafer, 1995), it is generally accepted that, aside from the loss of consciousness, reduced sensory awareness, and reduction in behavioral responsiveness, typical anesthesia is divergent from sleep; it is imposed by circulating drugs, it suppresses spontaneous arousal, and most importantly, does not allow the cyclical variability of brain states that typifies natural sleep (Tung and Mendelson, 2004

EEG characteristics under urethane anesthesia

Typical brain state alternations occurring at the level of neocortex (nCTX) and hippocampus (HPC) under urethane anesthesia are displayed in Fig. 1. Local field potentials recorded at level of the nCTX (layer V) and the HPC (pyramidal cell layer) display regular alternations between a state characterized by high amplitude, low frequency activity in the nCTX and HPC (with a peak of activity in the range of ∼1 Hz), and a state characterized by low amplitude, high frequency activity in the HPC in

Respiratory characteristics under urethane anesthesia

Breathing is strongly correlated with brain state, and during sleep, as in wakefulness, breathing is under strong metabolic control. In humans, the early stages of non-REM sleep at sleep onset are characterized by breathing patterns that show very little change in frequency but very irregular tidal volumes, that often result in periodic breathing (oscillations in amplitude) (Krieger, 2005). With progression of sleep into deep non-REM sleep (characterized by the typical cortical SWS) breathing

Factors influencing brain state alternations under urethane anesthesia

While most anesthetics produce a relatively uniform level of anesthesia and brain activity with complete suppression of postural tone, urethane is unique in that spontaneous brain state alternations still occur under a constant level of anesthesia, and postural tone changes, although weak, can be detected across states (Clement et al., 2008). Despite the robust demonstration of spontaneous brain state transitions under urethane anesthesia and parallel changes in multiple physiological systems,

Validity of urethane anesthesia as a model of sleep

How good a model of natural sleep is the urethane anesthetized experimental preparation? Is it useful for studying sleep-related state-dependent modulation of breathing? First, it has to be noted that urethane anesthesia does not completely replicate natural sleep. Urethane anesthetized rodents lack the ability to spontaneously rouse from anesthesia. REM-like states also lack the phasic component of REM sleep, and, as seen with other anesthetics, urethane anesthetized rodents lack central

Acknowledgements

Supported by Canadian Institute of Health Research (GDF, CTD), Women and Children Health Research Institute (GDF, SP), Alberta Lung Association (GDF), Natural Science and Engineering Research Council of Canada (CTD), Parker B. Francis Foundation (SP). GDF and CTD are Alberta Innovates Health Solutions funded investigators.

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Deep brain stimulation (DBS) has become an important tool in the management of a wide spectrum of diseases in neurology and psychiatry. Target selection is a vital aspect of DBS so that only the desired areas are stimulated. Segmented leads and current steering have been shown to be promising additions to DBS technology enabling better control of the stimulating electric field. Recently introduced orientation selective DBS (OS-DBS) is a related development permitting sensitization of the stimulus to axonal pathways with different orientations by freely controlling the primary direction of the electric field using multiple contacts. Here, we used OS-DBS to stimulate the subthalamic nucleus (STN) in healthy rats while simultaneously monitoring the induced brain activity with fMRI. Maximal activation of the sensorimotor and basal ganglia-thalamocortical networks was observed when the electric field was aligned mediolaterally in the STN pointing in the lateral direction, while no cortical activation was observed with the electric field pointing medially to the opposite direction. Such findings are consistent with mediolateral main direction of the STN fibers, as seen with high resolution diffusion imaging and histology. The asymmetry of the OS-DBS dipolar field distribution using three contacts along with the potential stimulation of the internal capsule, are also discussed. We conclude that OS-DBS offers an additional degree of flexibility for optimization of DBS of the STN which may enable a better treatment response.
Modulation of Spontaneous and Light-Induced Activity in the Rat Dorsal Lateral Geniculate Nucleus by General Brain State Alterations under Urethane Anesthesia
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Citation Excerpt :
and ‘SWA’ abbreviations were used, which refer to cortical activation and cortical slow wave activity phases of urethane sleep, respectively. Although, they should not be confused with natural sleep stages, several studies emphasised that activation and SWA alternations of urethane naesthesia are valid and commonly used model of natural sleep (Clement et al., 2008; Blasiak et al., 2013; Pagliardini et al., 2013a,b). ECoG signals containing both activated and SWA phases (650 s long recordings, one alteration in ECoG) were subjected to discrete Fast Fourier Transform with the Hann window function.
The thalamic dorsal lateral geniculate nucleus (dLGN) serves as a gating station for the transfer of light information en route to the primary visual cortex (V1). Although the modulatory input arising from the V1 and several brainstem nuclei to the dLGN is well characterised in higher mammals, little is known about its influence on dLGN activity in rodents. Using simultaneous recordings of electrocorticogram (ECoG) and single unit neuronal activity under urethane anesthesia in Long Evans rats, we managed to show that cyclic changes in the general brain state strongly affect spontaneous activity and light encoding properties of dLGN neurons. First, we characterised several groups of dLGN cells: neurons led by ECoG, neurons in which the spike rate preceded ECoG changes and neurons co-occurring or not correlated with ECoG signal. Secondly, we verified that although the general light responsiveness of the dLGN is not influenced by the state of the brain, modulation of types of photoresponses and differences in ability to encode ambient light levels were observed. Cells responding to light in a sustained manner encoded light intensity more accurately during the cortical activation phase of urethane anesthesia. On the other hand, isoflurane anesthesia does not induce such rhythmic changes in ECoG and shuts down the spontaneous neuronal activity in the dLGN. Together, these data suggest a greater modulation of spontaneous activity and dLGN neurons function, than it was previously reported for the rodent dLGN and highlight the role of anesthesia in interpretations of findings from ongoing acute experiments.
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Several lines of evidences show that anesthetics influence neurotoxicity and neuroprotection. The possibility that different anesthetic agents potentially influence the pathophysiological and functional outcome following neurotrauma was examined in a rat model of concussive head injury (CHI). The CHI was produced by an impact of 0.224 N on the right parietal bone by dropping a weight of 114.6 g from a 20 cm height under different anesthetic agents, e.g., inhaled ether anesthesia or intraperitoneally administered ketamine, pentobarbital, equithesin or urethane anesthesia. Five hour CHI resulted in profound volume swelling and brain edema formation in both hemispheres showing disruption of the blood-brain barrier (BBB) to Evans blue and radioiodine. A marked decrease in the cortical CBF and a profound increase in plasma or brain serotonin levels were seen at this time. Neuronal damages were present in several parts of the brain. These pathological changes were most marked in CHI under ether anesthesia followed by ketamine (35 mg/kg, i.p.), pentobarbital (50 mg/kg, i.p.), equithesin (3 mL/kg, i.p.) and urethane (1 g/kg, i.p.). The functional outcome on Rota Rod performances or grid walking tests was also most adversely affected after CHI under ether anesthesia followed by pentobarbital, equithesin and ketamine. Interestingly, the plasma and brain serotonin levels strongly correlated with the development of brain edema in head injured animals in relation to different anesthetic agents used. These observations suggest that anesthetic agents are detrimental to functional and pathological outcomes in CHI probably through influencing the circulating plasma and brain serotonin levels, not reported earlier. Whether anesthetics could also affect the efficacy of different neuroprotective agents in CNS injuries is a new subject that is currently being examined in our laboratory.
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Physiological activity in REM sleep can further be dissociated into two subcategories: tonic features, which are primarily composed of the archetypical REM-induced muscle atony, and phasic features, which are composed of the hallmark rapid saccadic eye movements of REM and muscle twitches in both extremities and middle ear muscles (Aserinsky, 1965; Mashour & Pal, 2012; Rechtschaffen & Siegel, 2000). Both tonic and phasic events occur in a typical REM epoch (Pagliardini, Funk, et al., 2013). All other sleep falls under the broad classification of non-REM (NREM) sleep, which is a state characterized by high-voltage, low-frequency electrophysiological activity (Rechtschaffen & Siegel, 2000).
Sleep is a vital neurobiological process. Yet, despite its fundamental significance, delineating the endogenous neural pathways involved in sleep regulation has been slow to progress, due to a lack of diverse sleep models. Anesthesia, which has direct behavioral parallels to natural sleep, including a reversible loss of consciousness, decreased sensory awareness, and reduced behavioral responsiveness, is a natural choice to model specific components of sleep. Moreover, sleep and anesthesia are linked on both mechanistic and physiological levels. Animal research has demonstrated that anesthetic potency is modulated by sleep deprivation and sleep debt can be depleted by anesthetic interventions. Additionally, the archetypical electrophysiological dynamics of natural sleep, that is, the spontaneous alternations between activated and deactivated forebrain states, can be replicated using urethane anesthesia in rodent models. Increasingly, the overlaps and divergences between components of sleep and specific anesthetic agents are offering insight into the neurochemical mechanisms and fundamental brain circuitry involved in the induction and maintenance of unconsciousness.
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^☆: This paper is part of a special issue entitled “Sleep and Breathing” guest-edited by Dr. James Duffin, Dr. Leszek Kubin and Dr. Jason Mateika.

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Breathing and brain state: Urethane anesthesia as a model for natural sleep☆

Highlights

Abstract

Section snippets

Sleep: a dynamic brain process

Anesthesia: a pharmacological parallel to sleep?

EEG characteristics under urethane anesthesia

Respiratory characteristics under urethane anesthesia

Factors influencing brain state alternations under urethane anesthesia

Validity of urethane anesthesia as a model of sleep

Acknowledgements

Progress in Neurobiology

Respiratory Physiology & Neurobiology

Journal of the Neurological Sciences

Paediatric Respiratory Reviews

Neuroscience

Brain Research

Physiology & Behavior

Cellular Signalling

Respiratory Physiology & Neurobiology

Respiration Physiology

Respiration Physiology

Experimental Neurology

Neuron

Toxicology and Applied Pharmacology

Brain Research

Clinics in Perinatology

Brain Research

Pediatric Neurology

Neuroscience

Experimental Neurology

Respiration Physiology

Experimental Neurology

Neuroscience

Respiratory Physiology & Neurobiology

Sleep Medicine Reviews

Physiology & Behavior

International Review of Neurobiology

Neuroscience Letters

Sleep regulation in rats during early development

American Journal of Physiology

Main trends in rectal temperature during sleep. Hypnogram and thermogram

Neuropsychobiology

How do general anaesthetics work?

Naturwissenschaften

Periodic respiratory pattern occurring in conjunction with eye movements during sleep

Science

Regularly occurring periods of eye motility, and concomitant phenomena, during sleep

Science

Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep–waking cycle

Journal of Neuroscience

Maturation of fetal breathing activity

Biology of the Neonate

Control of sleep and wakefulness

Physiological Reviews