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Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.

Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT - PLoS ONE (2008)

Bottom Line: Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period).Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep.Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep.

View Article: PubMed Central - PubMed

Affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Background: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.

Methodology/principal findings: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane.

Conclusions/significance: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.

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Related in: MedlinePlus

Monoaminergic depletion affected neither the activated state nor the alternations between states under urethane anaesthesia.A) Continuous hippocampal EEG traces and spectrographic power at theta frequencies under urethane anaesthesia following reserpine (5 mg/kg) pretreatment. Alternations between states were obvious as fluctuations in the amplitude of the raw EEG in addition to the spectrographic theta power (5 Hz). A further supplemental i.p. administration of reserpine (5 mg/kg) was without effect upon either the activated state or the alternations between states. However, a subsequent i.p. injection of atropine (ATSO4: 50 mg/kg) completely abolished the activated state and subsequent alternations between state. Hippocampal B) EEG expansions and C) spectra from before and after reserpine supplement demonstrating intact theta activity in both cases. D) Scatterplots of peak power and frequencies for activated states pre and post reserpine supplement. There were no significant differences between pre and post supplement groups. E) Scatterplots of period lengths pre and post reserpine supplements demonstrating that alternations and rhythmicity were not affected by reserpine.
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pone-0002004-g009: Monoaminergic depletion affected neither the activated state nor the alternations between states under urethane anaesthesia.A) Continuous hippocampal EEG traces and spectrographic power at theta frequencies under urethane anaesthesia following reserpine (5 mg/kg) pretreatment. Alternations between states were obvious as fluctuations in the amplitude of the raw EEG in addition to the spectrographic theta power (5 Hz). A further supplemental i.p. administration of reserpine (5 mg/kg) was without effect upon either the activated state or the alternations between states. However, a subsequent i.p. injection of atropine (ATSO4: 50 mg/kg) completely abolished the activated state and subsequent alternations between state. Hippocampal B) EEG expansions and C) spectra from before and after reserpine supplement demonstrating intact theta activity in both cases. D) Scatterplots of peak power and frequencies for activated states pre and post reserpine supplement. There were no significant differences between pre and post supplement groups. E) Scatterplots of period lengths pre and post reserpine supplements demonstrating that alternations and rhythmicity were not affected by reserpine.

Mentions: A major difference between forebrain activation during wakefulness and during REM sleep is the role of ascending monoaminergic systems, most notably the noradrenergic system [29], [30]. In order to eliminate any possible contribution of these non-cholinergic systems in the elicitation of activated states and state alternations under urethane, we depleted monoaminergic vesicular stores by pre-treating animals with reserpine (5 mg/kg) 14–18 hours prior to our experiments. The pharmacological action of reserpine was confirmed by behavioural observations in the intervening period for sedation, ptosis and akinesia [31]–[33]. Despite successful pre-treatments with reserpine, all subsequently anaesthetized animals displayed spontaneous and rhythmic alternations of brain state demonstrating both activated and deactivated patterns (Figure 9). Furthermore, a supplemental dose of reserpine (5 mg/kg) during anaesthesia affected neither the occurrence nor characteristics of the activated state nor did it affect the ongoing state alternations. Measurements were limited to hippocampal traces as variations in theta frequency and power are a sensitive index of the level of forebrain activation [34]. As shown (Figure 9B, C, D), raw traces and spectral components showed no differences pre- and post-reserpine supplement (p≥0.926 for both power and frequency measures). As well, the period length prior to supplement (8.16±1.04 minutes) was not significantly different from that measured post-supplement (8.23±1.04 minutes: p = 0.44, n = 3) (Figure 9E). Therefore, individual states and their alternations under urethane anaesthesia were not dependent upon the integrity of monoaminergic transmission as they are during the waking state.


Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.

Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT - PLoS ONE (2008)

Monoaminergic depletion affected neither the activated state nor the alternations between states under urethane anaesthesia.A) Continuous hippocampal EEG traces and spectrographic power at theta frequencies under urethane anaesthesia following reserpine (5 mg/kg) pretreatment. Alternations between states were obvious as fluctuations in the amplitude of the raw EEG in addition to the spectrographic theta power (5 Hz). A further supplemental i.p. administration of reserpine (5 mg/kg) was without effect upon either the activated state or the alternations between states. However, a subsequent i.p. injection of atropine (ATSO4: 50 mg/kg) completely abolished the activated state and subsequent alternations between state. Hippocampal B) EEG expansions and C) spectra from before and after reserpine supplement demonstrating intact theta activity in both cases. D) Scatterplots of peak power and frequencies for activated states pre and post reserpine supplement. There were no significant differences between pre and post supplement groups. E) Scatterplots of period lengths pre and post reserpine supplements demonstrating that alternations and rhythmicity were not affected by reserpine.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2289875&req=5

pone-0002004-g009: Monoaminergic depletion affected neither the activated state nor the alternations between states under urethane anaesthesia.A) Continuous hippocampal EEG traces and spectrographic power at theta frequencies under urethane anaesthesia following reserpine (5 mg/kg) pretreatment. Alternations between states were obvious as fluctuations in the amplitude of the raw EEG in addition to the spectrographic theta power (5 Hz). A further supplemental i.p. administration of reserpine (5 mg/kg) was without effect upon either the activated state or the alternations between states. However, a subsequent i.p. injection of atropine (ATSO4: 50 mg/kg) completely abolished the activated state and subsequent alternations between state. Hippocampal B) EEG expansions and C) spectra from before and after reserpine supplement demonstrating intact theta activity in both cases. D) Scatterplots of peak power and frequencies for activated states pre and post reserpine supplement. There were no significant differences between pre and post supplement groups. E) Scatterplots of period lengths pre and post reserpine supplements demonstrating that alternations and rhythmicity were not affected by reserpine.
Mentions: A major difference between forebrain activation during wakefulness and during REM sleep is the role of ascending monoaminergic systems, most notably the noradrenergic system [29], [30]. In order to eliminate any possible contribution of these non-cholinergic systems in the elicitation of activated states and state alternations under urethane, we depleted monoaminergic vesicular stores by pre-treating animals with reserpine (5 mg/kg) 14–18 hours prior to our experiments. The pharmacological action of reserpine was confirmed by behavioural observations in the intervening period for sedation, ptosis and akinesia [31]–[33]. Despite successful pre-treatments with reserpine, all subsequently anaesthetized animals displayed spontaneous and rhythmic alternations of brain state demonstrating both activated and deactivated patterns (Figure 9). Furthermore, a supplemental dose of reserpine (5 mg/kg) during anaesthesia affected neither the occurrence nor characteristics of the activated state nor did it affect the ongoing state alternations. Measurements were limited to hippocampal traces as variations in theta frequency and power are a sensitive index of the level of forebrain activation [34]. As shown (Figure 9B, C, D), raw traces and spectral components showed no differences pre- and post-reserpine supplement (p≥0.926 for both power and frequency measures). As well, the period length prior to supplement (8.16±1.04 minutes) was not significantly different from that measured post-supplement (8.23±1.04 minutes: p = 0.44, n = 3) (Figure 9E). Therefore, individual states and their alternations under urethane anaesthesia were not dependent upon the integrity of monoaminergic transmission as they are during the waking state.

Bottom Line: Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period).Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep.Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep.

View Article: PubMed Central - PubMed

Affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Background: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.

Methodology/principal findings: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane.

Conclusions/significance: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.

Show MeSH
Related in: MedlinePlus