title: Optogenetic stimulation of adrenergic C1 neurons causes sleep state-dependent cardiorespiratory stimulation and arousal with sighs in rats.
abstract: BACKGROUND
  The rostral ventrolateral medulla (RVLM) contains central respiratory chemoreceptors (retrotrapezoid nucleus, RTN) and the sympathoexcitatory, hypoxia-responsive C1 neurons. Simultaneous optogenetic stimulation of these neurons produces vigorous cardiorespiratory stimulation, sighing, and arousal from non-REM sleep.
  
  
  OBJECTIVE
  To identify the effects that result from selectively stimulating C1 cells.
  
  
  METHODS
  A Cre-dependent vector expressing channelrhodopsin 2 (ChR2) fused with enhanced yellow fluorescent protein or mCherry was injected into the RVLM of tyrosine hydroxylase (TH)-Cre rats. The response of ChR2-transduced neurons to light was examined in anesthetized rats. ChR2-transduced C1 neurons were photoactivated in conscious rats while EEG, neck muscle EMG, blood pressure (BP), and breathing were recorded.
  
  
  RESULTS
  Most ChR2-expressing neurons (95%) contained C1 neuron markers and innervated the spinal cord. RTN neurons were not transduced. While the rats were under anesthesia, the C1 cells were faithfully activated by each light pulse up to 40 Hz. During quiet resting and non-REM sleep, C1 cell stimulation (20 s, 2-20 Hz) increased BP and respiratory frequency and produced sighs and arousal from non-REM sleep. Arousal was frequency-dependent (85% probability at 20 Hz). Stimulation during REM sleep increased BP, but had no effect on EEG or breathing. C1 cell-mediated breathing stimulation was occluded by hypoxia (12% FIO2), but was unchanged by 6% FiCO2.
  
  
  CONCLUSIONS
  C1 cell stimulation reproduces most effects of acute hypoxia, specifically cardiorespiratory stimulation, sighs, and arousal. C1 cell activation likely contributes to the sleep disruption and adverse autonomic consequences of sleep apnea. During hypoxia (awake) or REM sleep, C1 cell stimulation increases BP but no longer stimulates breathing.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
authors.forename: Peter G R
authors.initials: PG
authors.lastname: Burke
authors.forename: Stephen B G
authors.initials: SB
authors.lastname: Abbott
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Coates
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Viar
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Stornetta
authors.forename: Patrice G
authors.initials: PG
authors.lastname: Guyenet
mesh_terms: D059331:Adrenergic Neurons / Q000502:physiology*; D000818:Animals; D001143:Arousal / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology*; D002628:Chemoreceptor Cells / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D000860:Hypoxia / Q000150:complications; D008297:Male; D008526:Medulla Oblongata / Q000502:physiology*; D062308:Optogenetics / Q000379:methods*; D051381:Rats; D012119:Respiration / Q000187:drug effects*; D012890:Sleep / Q000502:physiology*; D059246:Tachypnea / Q000209:etiology
keywords: EEG; hypoxia; medulla oblongata; respiration; rostral ventrolateral medulla