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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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State alternations were dependent upon central muscarinic neurotransmission.A) Long duration cortical EEG traces in addition to spectrographic cortical power at 1 Hz demonstrating the effects of agonism and subsequent antagonism of muscarinic receptor mediated transmission. Following an i.p. injection of oxotremorine (4.0 mg/kg) spontaneous alternations between activated and deactivated states were abolished in favor of the activated state. This induced activated state was abolished in favor of the deactivated state with a subsequent i.p. injection of atropine sulfate (ATSO4: 50 mg/kg). B) Expansions of EEG traces from neocortical sites show the similarity of activated and deactivated patterns induced by cholinergic agonism and antagonism, respectively. C) A scatter plots demonstrating the duration of the oxotremorine effect as a function of dosage. The effects of oxotremorine were longer than those of physostigmine (Figure 6C). As in Figure 6, the effects of atropine showed no reversal.
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pone-0002004-g008: State alternations were dependent upon central muscarinic neurotransmission.A) Long duration cortical EEG traces in addition to spectrographic cortical power at 1 Hz demonstrating the effects of agonism and subsequent antagonism of muscarinic receptor mediated transmission. Following an i.p. injection of oxotremorine (4.0 mg/kg) spontaneous alternations between activated and deactivated states were abolished in favor of the activated state. This induced activated state was abolished in favor of the deactivated state with a subsequent i.p. injection of atropine sulfate (ATSO4: 50 mg/kg). B) Expansions of EEG traces from neocortical sites show the similarity of activated and deactivated patterns induced by cholinergic agonism and antagonism, respectively. C) A scatter plots demonstrating the duration of the oxotremorine effect as a function of dosage. The effects of oxotremorine were longer than those of physostigmine (Figure 6C). As in Figure 6, the effects of atropine showed no reversal.

Mentions: Systemic manipulations using the acetylcholinesterase inhibitor physostigmine (2.39±0.9 mg/kg, n = 16) promoted a long lasting activated forebrain state (36.3±6.2 minutes), similar to the spontaneous activated state (Figure S1). Treatments using the muscarinic receptor agonist oxotremorine (11.17±3.96 mg/kg, n = 11) also elicited activated forebrain EEG patterns similar to spontaneous activated patterns (Figure 8A, B) and this effect had a longer duration (70.1±13.2 minutes, Figure 8A, C). Treatments with the muscarinic antagonist atropine sulphate (50 mg/kg, n = 17) produced a deactivated state similar in spectral characteristics to spontaneous deactivated patterns (Figure 8B and Figure S1). This effect appeared non-reversible since no washout occurred over recording times as long as 100 minutes (average recording duration: 46.9±6.9 minutes). All of the above manipulations resulted in the abolition of state alternations, although as physostigmine was metabolized, a return to alternations into the deactivated state began taking place (Figure S1). These results demonstrate that spontaneous alternations of state in the urethane-anaesthetized animal, like natural sleep, are also dependent on central muscarinic mechanisms.


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)

State alternations were dependent upon central muscarinic neurotransmission.A) Long duration cortical EEG traces in addition to spectrographic cortical power at 1 Hz demonstrating the effects of agonism and subsequent antagonism of muscarinic receptor mediated transmission. Following an i.p. injection of oxotremorine (4.0 mg/kg) spontaneous alternations between activated and deactivated states were abolished in favor of the activated state. This induced activated state was abolished in favor of the deactivated state with a subsequent i.p. injection of atropine sulfate (ATSO4: 50 mg/kg). B) Expansions of EEG traces from neocortical sites show the similarity of activated and deactivated patterns induced by cholinergic agonism and antagonism, respectively. C) A scatter plots demonstrating the duration of the oxotremorine effect as a function of dosage. The effects of oxotremorine were longer than those of physostigmine (Figure 6C). As in Figure 6, the effects of atropine showed no reversal.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2289875&req=5

pone-0002004-g008: State alternations were dependent upon central muscarinic neurotransmission.A) Long duration cortical EEG traces in addition to spectrographic cortical power at 1 Hz demonstrating the effects of agonism and subsequent antagonism of muscarinic receptor mediated transmission. Following an i.p. injection of oxotremorine (4.0 mg/kg) spontaneous alternations between activated and deactivated states were abolished in favor of the activated state. This induced activated state was abolished in favor of the deactivated state with a subsequent i.p. injection of atropine sulfate (ATSO4: 50 mg/kg). B) Expansions of EEG traces from neocortical sites show the similarity of activated and deactivated patterns induced by cholinergic agonism and antagonism, respectively. C) A scatter plots demonstrating the duration of the oxotremorine effect as a function of dosage. The effects of oxotremorine were longer than those of physostigmine (Figure 6C). As in Figure 6, the effects of atropine showed no reversal.
Mentions: Systemic manipulations using the acetylcholinesterase inhibitor physostigmine (2.39±0.9 mg/kg, n = 16) promoted a long lasting activated forebrain state (36.3±6.2 minutes), similar to the spontaneous activated state (Figure S1). Treatments using the muscarinic receptor agonist oxotremorine (11.17±3.96 mg/kg, n = 11) also elicited activated forebrain EEG patterns similar to spontaneous activated patterns (Figure 8A, B) and this effect had a longer duration (70.1±13.2 minutes, Figure 8A, C). Treatments with the muscarinic antagonist atropine sulphate (50 mg/kg, n = 17) produced a deactivated state similar in spectral characteristics to spontaneous deactivated patterns (Figure 8B and Figure S1). This effect appeared non-reversible since no washout occurred over recording times as long as 100 minutes (average recording duration: 46.9±6.9 minutes). All of the above manipulations resulted in the abolition of state alternations, although as physostigmine was metabolized, a return to alternations into the deactivated state began taking place (Figure S1). These results demonstrate that spontaneous alternations of state in the urethane-anaesthetized animal, like natural sleep, are also dependent on central muscarinic mechanisms.

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