title: Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice.
abstract: The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states.
  
  
  
  More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep-wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our understanding of how the PPT nucleus regulates cortical activity and behavioral states.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kroeger
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Loris L
authors.initials: LL
authors.lastname: Ferrari
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and.|École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Gaetan
authors.identifier: 0000-0002-7667-7849
authors.initials: G
authors.lastname: Petit
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Mahoney
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Patrick M
authors.identifier: 0000-0002-7017-583X
authors.initials: PM
authors.lastname: Fuller
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Elda
authors.initials: E
authors.lastname: Arrigoni
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and tscammel@bidmc.harvard.edu.
authors.forename: Thomas E
authors.identifier: 0000-0002-7231-8558
authors.initials: TE
authors.lastname: Scammell
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D059329:Cholinergic Neurons / Q000502:physiology*; D004569:Electroencephalography; D004576:Electromyography; D059330:GABAergic Neurons / Q000502:physiology*; D005971:Glutamates / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000502:physiology*; D045042:Pedunculopontine Tegmental Nucleus / Q000166:cytology / Q000502:physiology*; D012890:Sleep / Q000502:physiology*; D012895:Sleep, REM / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D014851:Wakefulness / Q000502:physiology*
chemical_list: D005971:Glutamates; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2
keywords: PPT; chemogenetic; mouse; sleep