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On the role of pontine cholinergic neurons in the modulation of rem sleep and its respiratory phenotype 2009

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Serotonin type 1A (5-HT(1A)) receptor-responsive neurons in the pedunculopontine tegmental nucleus (PPTn) become maximally active immediately before and during rapid eye movement (REM) sleep. A prevailing model of REM sleep generation indicates that activation of such neurons contributes significantly to the generation of REM sleep, and if correct then inactivation of such neurons ought to suppress REM sleep. We test this hypothesis using bilateral microperfusion of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 10 μm) into the PPTn; this tool has been shown to selectively silence REM sleep-active PPTn neurons while the activity of wake/REM sleep-active PPTn neurons is unaffected. Contrary to the prevailing model, bilateral microperfusion of 8-OH-DPAT into the PPTn (n = 23 rats) significantly increased REM sleep both as a percentage of the total recording time and sleep time, compared with both within-animal vehicle controls and between-animal time-controls. This increased REM sleep resulted from an increased frequency of REM sleep bouts but not their duration, indicating an effect on mechanisms of REM sleep initiation but not maintenance. Furthermore, an increased proportion of the REM sleep bouts stemmed from periods of low REM sleep drive quantified electrographically. Targeted suppression of 5-HT(1A) receptor-responsive PPTn neurons also increased respiratory rate and respiratory-related genioglossus activity, and increased the frequency and amplitude of the sporadic genioglossus activations occurring during REM sleep. These data indicate that 5-HT(1A) receptor-responsive PPTn neurons normally function to restrain REM sleep by elevating the drive threshold for REM sleep induction, and restrain the expression of respiratory rate and motor activities.
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  • 1. On the Role of Pontine Cholinergic Neurons in the Modulation of REM sleep and its Respiratory Phenotype KP Grace, H Liu, RL Horner Departments of Medicine and Physiology, University of Toronto
  • 2. REM sleepNon-REM sleep Genioglossus EMG EEG Diaphragm EMG Introduction Respiratory control network REM sleep control network Respiratory phenotype of REM sleep Sleep results in fundamental changes in respiratory muscle activity and control mechanisms, changes that can predispose individuals to disordered breathing during sleep.Genioglossus muscle Diaphragm muscle adapted from ref. 4
  • 3. adapted from ref. 1 Genioglossus muscle Maintains open airway for effective ventilation ACh ACh To diaphragm Primary respiratory pump muscle Pedunculopntine Tegmental (PPT) Nucleus ACh Sublaterodorsal region of the pons Hypoglossal Motor Nucleus (HMN) Rostral ventral lateral medulla The cholinergic cell population of the pedunculopontine tegmental (PPT) nucleus fulfills these criteria by having: (i) A population of neurons maximally active during REM sleep (ii) Afferent and efferent connections to the site of REM sleep generation in the pons (iii) Direct cholinergic projections to regions of the medulla containing respiratory neurons and motor neurons Introduction Meandischarge/sec Active Wake Quiet Wake Non- REM REM REM with twitching adapted from ref. 2
  • 4. Objective & Hypotheses To determine whether the cholinergic REM sleep-active cell population of the PPT nucleus is a necessary component of the circuitry responsible for the generation of REM sleep and its respiratory phenotype (i) ↑ endogenous acetylcholine at the hypoglossal motor nucleus ought to suppress genioglossus muscle activity (ii) Targeted inhibition of REM sleep-active cholinergic neurons in the PPT nucleus ought to change: (a) respiratory rate, diaphragm, and genioglossus muscle activities consistent with the PPT having a necessary role in producing the respiratory phenotype of REM sleep. (b)The normal temporal expression of REM sleep Consistent with the PPT having a necessary role in modulating the state of REM sleep
  • 5. EEG Diaphragm Neck muscle EEG Neck EMG Genioglossus EMG Diaphragm EMG Hypoglossal Motor nucleus Genioglossus muscle adapted from ref. 3 PPT nucleus (i) The hypoglossal motor nucleus (unilateral) & perfused with: (A)Artificial cerebral spinal fuild (ACSF) (B)Eserine dissolved in ACSF (100µM) Increases endogenous acetylcholine levels (ii) The PPT nuclei (bilateral) & perfused with: (A)Artificial cerebral spinal fuild (ACSF) (B)8-OH-DPAT dissolved in ACSF (10µM) Produces targeted inhibition of cholinergic REM sleep-active cells 2 or On the day of the experiment, microdialysis probes were inserted into either the: Methods Meandischarge/sec Active Wake Quiet Wake Non- REM REM REM with twitching PPT Wake/REM sleep-active cell population Meandischarge/sec Active Wake Quiet Wake Non- REM REM REM with twitching PPT REM sleep-active cell population adapted from ref. 2
  • 6. Genioglossus EMG EEG Neck EMG 5 sec ACSF Eserine ACSF EserineACSF Eserine Non-REM sleep REM sleepAwake Diaphragm EMG Amplitude (Au) 0 2 4 6 8 10 12 14 Wake Non-REM REM Sleep-wake States Respiratory-Related Genioglossus Activity ACSF Eserine * Denotes significant effect of drug independent of state * * * Amplitude (Au) 0 10 20 30 40 50 60 REM Sleep Specific Genioglossus Muscle Twitching ACSF Eserine * Enhanced Cholinergic activity at the Hypoglossal Motor Nucleus (n=10) 500µm Microdialysis probe site
  • 7. Genioglossus EMG EEG Neck EMG Diaphragm EMG ACSF 8-OH-DPAT ACSF 8-OH-DPATACSF 8-OH-DPAT Non-REM sleep REM sleepAwake Targeted inhibition of Cholinergic REM sleep-active cells at the PPT nuclei 5 sec 500µm Microdialysis probe site 0 5 10 15 20 25 70 75 80 85 90 95 100 Amplitude(Au) Wake Non-REM REM Sleep-wake States Respiratory-Related Genioglossus Activity Amplitude(Au) REM Sleep Specific Genioglossus Muscle Twitching Respiratory Rate Rate(Breaths/min) Wake Non-REM REM Sleep-wake States ACSF 8-OH-DPAT ACSF 8-OH -DPAT * * Denotes significant effect of drug independent of state * * * * * * * Denotes significant effect of drug independent of state 0 20 40 60 80 100 120 140 ACSF 8-OH -DPAT 500µm PPT Cholinergic cells (NADPH diaphorase +) (n=11)
  • 8. ACSF 8-OH-DPAT Targeted inhibition of Cholinergic REM sleep-active cells at the PPT nuclei (n=20) W N R W N R 10min 0 10 20 30 40 50 60 30 35 40 45 50 55 25 30 35 40 45 50 10 15 20 35 30 35 0 5 10 15 20 25 ACSF 8-OH-DPAT ACSF 8-OH-DPAT 65 70 75 80 85 90 ACSF 8-OH-DPATACSF 8-OH-DPAT % of Total Recording Time % of Total Sleep Time (transitions/hr) Sleep-Wake State Transitions Awake Non-REM sleep REM sleep * * * * * * Denotes significant difference relative to control NOTE: Data from sham group not shown. Changes due to time do not account for the changes resulting from 8-OH-DPAT treatment * Accounts for more than 50% of the total increase in sleep time
  • 9. Conclusions • Increased endogenous acetylcholine at the hypoglossal motor nucleus suppresses genioglossus muscle activity in wakefulness and sleep • This effect of increased acetylcholine may contribute to the major suppression of genioglossus muscle activity in REM sleep, since the hypoglossal motor nucleus is innervated by cholinergic cells of the PPT nucleus, a subset of which are maximally active during REM sleep. • Selective inhibition of cholinergic REM sleep-active neurons in the PPT region alleviated suppression of genioglossus activity and respiratory rate across sleep-wake states. • Therefore PPT REM sleep-active neurons are a necessary component of the circuitry responsible for shaping the phenotype of breathing in wakefulness and sleep.
  • 10. Conclusions •Fragmentation of sleep-wake state architecture, reduced wakefulness, and increased REM sleep following inhibition of REM sleep-active neurons in the PPT region shows that this cell population performs essential functions within the neural network controlling vigilance state. • PPT REM sleep-active neurons act to restrain entry into REM sleep, contribute to the generation of wakefulness, and stabilize activity in state switching circuitry thereby limiting the frequency of state transitioning. • These results are in opposition with long-standing models of REM sleep generation which regard the PPT REM sleep-active cholinergic cell population to be an integral part of that which generates REM sleep. •This study provides the most definitive evidence to date regarding the role of this specific cell population within the REM sleep control network and therefore current models ought to be amended to reflect these findings.
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