Microinjection of neostigmine into the pontine reticular formation of C57BL/6J mouse enhances rapid eye movement sleep and depresses breathing

Ralph Lydic, Christopher L. Douglas, Helen Baghdoyan

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Study Objectives: The cholinergic model of rapid eye movement (REM) sleep has contributed significantly to understanding sleep neurobiology and sleep-dependent respiratory depression. The model has been used extensively in cat and rat, but no previous studies have demonstrated cholinergic REM sleep enhancement in mouse. The present study used microinjection of neostigmine into pontine reticular formation of mouse to test the hypothesis that enhancing pontine cholinergic neurotransmission would cause increased REM sleep and sleep disordered breathing. Design: Mice (n=8) were anesthetized and implanted with electrodes for measuring cortical electroencephalogram (EEG). Stainless steel cannulae were stereotaxically implanted to permit subsequent microinjections of 50 nl neostigmine (0.133 μg; 8.8 mM) or saline into the pontine reticular formation. Following recovery, an intensive within-subjects design was used to obtain measures of sleep/wake states, breathing, and locomotor activity. Inferential statistics were provided by t-tests. A probability value of < 0.05 indicated statistical significance. Setting: NA Patients or Participants: NA Interventions: NA Measurements and Results: Behavioral observations and manual scoring of polygraphic recordings showed that neostigmine produced a REM sleep-like state. EEG power analysis using Fast Fourier Transformation confirmed that pontine neostigmine caused EEG activation. Plethysmography demonstrated significantly disordered breathing. Compared to waking, pontine microinjection of neostigmine decreased respiratory rate (-64%) and minute ventilation (-75%). Pontine neostigmine significantly increased duration of inspiration (138%) and expiration (140%) above waking levels and decreased inspiratory flow (-69%). Additional studies showed that pontine neostigmine significantly depressed locomotor activity. Conclusions: This study is the first to demonstrate cholinergic REM sleep enhancement in unanesthetized, intact mouse. The results encourage future studies to characterize similarities and differences in cholinergic REM sleep enhancement in additional inbred strains and in transgenic mice. Such comparisons will help characterize sleep and breathing as intermediate phenotypes that are determined, in part, by the lower level phenotype of pontine cholinergic neurotransmission.

Original languageEnglish (US)
Pages (from-to)835-841
Number of pages7
JournalSleep
Volume25
Issue number8
DOIs
StatePublished - Dec 15 2002
Externally publishedYes

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Neostigmine
REM Sleep
Microinjections
Inbred C57BL Mouse
Sleep
Respiration
Cholinergic Agents
Electroencephalography
Locomotion
Synaptic Transmission
Pontine Tegmentum
Phenotype
Implanted Electrodes
Plethysmography
Neurobiology
Stainless Steel
Sleep Apnea Syndromes
Respiratory Rate
Respiratory Insufficiency
Transgenic Mice

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Physiology (medical)

Cite this

Microinjection of neostigmine into the pontine reticular formation of C57BL/6J mouse enhances rapid eye movement sleep and depresses breathing. / Lydic, Ralph; Douglas, Christopher L.; Baghdoyan, Helen.

In: Sleep, Vol. 25, No. 8, 15.12.2002, p. 835-841.

Research output: Contribution to journalArticle

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abstract = "Study Objectives: The cholinergic model of rapid eye movement (REM) sleep has contributed significantly to understanding sleep neurobiology and sleep-dependent respiratory depression. The model has been used extensively in cat and rat, but no previous studies have demonstrated cholinergic REM sleep enhancement in mouse. The present study used microinjection of neostigmine into pontine reticular formation of mouse to test the hypothesis that enhancing pontine cholinergic neurotransmission would cause increased REM sleep and sleep disordered breathing. Design: Mice (n=8) were anesthetized and implanted with electrodes for measuring cortical electroencephalogram (EEG). Stainless steel cannulae were stereotaxically implanted to permit subsequent microinjections of 50 nl neostigmine (0.133 μg; 8.8 mM) or saline into the pontine reticular formation. Following recovery, an intensive within-subjects design was used to obtain measures of sleep/wake states, breathing, and locomotor activity. Inferential statistics were provided by t-tests. A probability value of < 0.05 indicated statistical significance. Setting: NA Patients or Participants: NA Interventions: NA Measurements and Results: Behavioral observations and manual scoring of polygraphic recordings showed that neostigmine produced a REM sleep-like state. EEG power analysis using Fast Fourier Transformation confirmed that pontine neostigmine caused EEG activation. Plethysmography demonstrated significantly disordered breathing. Compared to waking, pontine microinjection of neostigmine decreased respiratory rate (-64{\%}) and minute ventilation (-75{\%}). Pontine neostigmine significantly increased duration of inspiration (138{\%}) and expiration (140{\%}) above waking levels and decreased inspiratory flow (-69{\%}). Additional studies showed that pontine neostigmine significantly depressed locomotor activity. Conclusions: This study is the first to demonstrate cholinergic REM sleep enhancement in unanesthetized, intact mouse. The results encourage future studies to characterize similarities and differences in cholinergic REM sleep enhancement in additional inbred strains and in transgenic mice. Such comparisons will help characterize sleep and breathing as intermediate phenotypes that are determined, in part, by the lower level phenotype of pontine cholinergic neurotransmission.",
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