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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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Local pharmacological inactivation of the basal forebrain region reversibly induces a deactivated state and temporarily abolishes state alternations.A) Continuous long duration cortical and hippocampal EEG traces together with spectrographic cortical power at 1 Hz during an infusion of lidocaine in the basal forebrain (BF). Spontaneous state alternations were temporarily abolished in favor of a continuous activated state following inactivation of the BF. B) Expanded EEG traces from neocortical and hippocampal sites prior and following the infusion. Deactivated patterns were elicited during inactivation of the BF and these effects washed out with time. C) Duration of evoked deactivated activity as a function of the amount of lidocaine infused in the BF. D). Histological representation of infusion sites. Open circles indicate ineffective sites. Site marked with arrow and triangle denotes experiment shown in A and B. Abbreviations: B: basal nucleus, CPu: caudate putamen, ec: external capsule, f: fornix, GP: globus pallidus, HDB: horizontal limb of the diagonal band of Broca, ic: internal capsule, mfb: medial forebrain bundle, MPOA: medial preoptic area, POA: preoptic area, SCh: suprachiasmatic nucleus, SI: substantia innominata.
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pone-0002004-g010: Local pharmacological inactivation of the basal forebrain region reversibly induces a deactivated state and temporarily abolishes state alternations.A) Continuous long duration cortical and hippocampal EEG traces together with spectrographic cortical power at 1 Hz during an infusion of lidocaine in the basal forebrain (BF). Spontaneous state alternations were temporarily abolished in favor of a continuous activated state following inactivation of the BF. B) Expanded EEG traces from neocortical and hippocampal sites prior and following the infusion. Deactivated patterns were elicited during inactivation of the BF and these effects washed out with time. C) Duration of evoked deactivated activity as a function of the amount of lidocaine infused in the BF. D). Histological representation of infusion sites. Open circles indicate ineffective sites. Site marked with arrow and triangle denotes experiment shown in A and B. Abbreviations: B: basal nucleus, CPu: caudate putamen, ec: external capsule, f: fornix, GP: globus pallidus, HDB: horizontal limb of the diagonal band of Broca, ic: internal capsule, mfb: medial forebrain bundle, MPOA: medial preoptic area, POA: preoptic area, SCh: suprachiasmatic nucleus, SI: substantia innominata.

Mentions: Since central cholinergic mechanisms appeared to be a major factor in controlling state alternations we next sought to investigate the role of structures in the brain that influence forebrain levels of acetylcholine. The direct source of ACh to the neocortex and the hippocampus emanates from nuclei in the BF that have also been implicated in the elicitation of activated patterns of the EEG during REM sleep [29]. We assessed the role of these nuclei by temporarily inactivating these sites using direct intracerebral infusions of 1 – 4% solutions of lidocaine (22.5±4.5 µg: n = 8). Infusions centered at sites such as the magnocellular preoptic nucleus, the substantia innominata, the horizontal limb of the diagonal band, the basal nucleus, and the ventral aspect of the globus pallidus (for a representation of the actual histological sites see Figure 10D) produced a rapid (61±10 s) onset of a continuous deactivated pattern in the EEG of both the nCTX and HPC that lasted for an average duration of 26.1±7.4 min and resembled patterns elicited during spontaneous deactivation (Figure 10A, C). During this time, no alternations of state took place. Following washout, state alternations returned. Additional equivolume infusions of lidocaine subsequent to washout at sites promoting deactivated states produced identical effects to the initial infusion (n = 2) whereas increased volumes of infusion (n = 5) resulted in an increase of time spent in the deactivated state. In cases in which infusion sites were outside of the BF (placements too lateral or ventral), forebrain EEG was not altered (n = 2, for histological sites see Figure 10D). Thus, as in sleep, the activity of specific nuclei within the BF region appears to be necessary for the expression of activated states and for the alternation of states under urethane anaesthesia.


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)

Local pharmacological inactivation of the basal forebrain region reversibly induces a deactivated state and temporarily abolishes state alternations.A) Continuous long duration cortical and hippocampal EEG traces together with spectrographic cortical power at 1 Hz during an infusion of lidocaine in the basal forebrain (BF). Spontaneous state alternations were temporarily abolished in favor of a continuous activated state following inactivation of the BF. B) Expanded EEG traces from neocortical and hippocampal sites prior and following the infusion. Deactivated patterns were elicited during inactivation of the BF and these effects washed out with time. C) Duration of evoked deactivated activity as a function of the amount of lidocaine infused in the BF. D). Histological representation of infusion sites. Open circles indicate ineffective sites. Site marked with arrow and triangle denotes experiment shown in A and B. Abbreviations: B: basal nucleus, CPu: caudate putamen, ec: external capsule, f: fornix, GP: globus pallidus, HDB: horizontal limb of the diagonal band of Broca, ic: internal capsule, mfb: medial forebrain bundle, MPOA: medial preoptic area, POA: preoptic area, SCh: suprachiasmatic nucleus, SI: substantia innominata.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2289875&req=5

pone-0002004-g010: Local pharmacological inactivation of the basal forebrain region reversibly induces a deactivated state and temporarily abolishes state alternations.A) Continuous long duration cortical and hippocampal EEG traces together with spectrographic cortical power at 1 Hz during an infusion of lidocaine in the basal forebrain (BF). Spontaneous state alternations were temporarily abolished in favor of a continuous activated state following inactivation of the BF. B) Expanded EEG traces from neocortical and hippocampal sites prior and following the infusion. Deactivated patterns were elicited during inactivation of the BF and these effects washed out with time. C) Duration of evoked deactivated activity as a function of the amount of lidocaine infused in the BF. D). Histological representation of infusion sites. Open circles indicate ineffective sites. Site marked with arrow and triangle denotes experiment shown in A and B. Abbreviations: B: basal nucleus, CPu: caudate putamen, ec: external capsule, f: fornix, GP: globus pallidus, HDB: horizontal limb of the diagonal band of Broca, ic: internal capsule, mfb: medial forebrain bundle, MPOA: medial preoptic area, POA: preoptic area, SCh: suprachiasmatic nucleus, SI: substantia innominata.
Mentions: Since central cholinergic mechanisms appeared to be a major factor in controlling state alternations we next sought to investigate the role of structures in the brain that influence forebrain levels of acetylcholine. The direct source of ACh to the neocortex and the hippocampus emanates from nuclei in the BF that have also been implicated in the elicitation of activated patterns of the EEG during REM sleep [29]. We assessed the role of these nuclei by temporarily inactivating these sites using direct intracerebral infusions of 1 – 4% solutions of lidocaine (22.5±4.5 µg: n = 8). Infusions centered at sites such as the magnocellular preoptic nucleus, the substantia innominata, the horizontal limb of the diagonal band, the basal nucleus, and the ventral aspect of the globus pallidus (for a representation of the actual histological sites see Figure 10D) produced a rapid (61±10 s) onset of a continuous deactivated pattern in the EEG of both the nCTX and HPC that lasted for an average duration of 26.1±7.4 min and resembled patterns elicited during spontaneous deactivation (Figure 10A, C). During this time, no alternations of state took place. Following washout, state alternations returned. Additional equivolume infusions of lidocaine subsequent to washout at sites promoting deactivated states produced identical effects to the initial infusion (n = 2) whereas increased volumes of infusion (n = 5) resulted in an increase of time spent in the deactivated state. In cases in which infusion sites were outside of the BF (placements too lateral or ventral), forebrain EEG was not altered (n = 2, for histological sites see Figure 10D). Thus, as in sleep, the activity of specific nuclei within the BF region appears to be necessary for the expression of activated states and for the alternation of states under urethane anaesthesia.

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