C57BL/6J and B6.V-LEPOB mice differ in the cholinergic modulation of sleep and breathing.
Respiratory and arousal state control are heritable traits in mice. B6.V-Lep(ob) (ob) mice are leptin deficient and differ from C57BL/6J (B6) mice by a variation in the gene coding for leptin. The ob mouse has morbid obesity and disordered breathing that is homologous to breathing of obese humans. This study tested the hypothesis that microinjecting neostigmine into the pontine reticular nucleus, oral part (PnO), of B6 and ob mice alters sleep and breathing. In B6 and ob mice, neostigmine caused a concentration-dependent increase (P < 0.0001) in percentage of time spent in a rapid eye movement (REM) sleeplike state (REM-Neo). Relative to saline (control), higher concentrations of neostigmine increased REM-Neo duration and the number of REM-Neo episodes in B6 and ob mice and decreased percent wake, percent non-REM, and latency to onset of REM-Neo (P < 0.001). In B6 and ob mice, REM sleep enhancement by neostigmine was blocked by atropine. Differences in control amounts of sleep and wakefulness between B6 and the congenic ob mice also were identified. After PnO injection of saline, ob mice spent significantly (P < 0.05) more time awake and less time in non-REM sleep. B6 mice displayed more (P < 0.01) baseline locomotor activity than ob mice, and PnO neostigmine decreased locomotion (P < 0.0001) in B6 and ob mice. Whole body plethysmography showed that PnO neostigmine depressed breathing (P < 0.001) in B6 and ob mice and caused greater respiratory depression in B6 than ob mice (P < 0.05). Western blot analysis identified greater (P < 0.05) expression of M2 muscarinic receptor protein in ob than B6 mice for cortex, midbrain, cerebellum, and pons, but not medulla. Considered together, these data provide the first evidence that pontine cholinergic control of sleep and breathing varies between mice known to differ by a spontaneous mutation in the gene coding for leptin.
Department of Anesthesiology, University of Michigan, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0615, USA.
Christopher L
CL
Douglas
Grant N
GN
Bowman
Helen A
HA
Baghdoyan
Ralph
R
Lydic
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001143:Arousal; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009388:Neostigmine / Q000008:administration & dosage*; D009765:Obesity / Q000378:metabolism*; D012119:Respiration; D012890:Sleep / Q000502:physiology*; D013045:Species Specificity
D002800:Cholinesterase Inhibitors; D009388:Neostigmine; D000109:Acetylcholine