Douglas Christopher L, Bowman Grant N, Baghdoyan Helen A, Lydic Ralph
Department of Anesthesiology, University of Michigan, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0615, USA.
J Appl Physiol (1985). 2005 Mar;98(3):918-29. doi: 10.1152/japplphysiol.00900.2004. Epub 2004 Oct 8.
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.
呼吸和觉醒状态控制是小鼠的可遗传性状。B6.V-Lep(ob)(ob)小鼠缺乏瘦素，与C57BL/6J(B6)小鼠的区别在于编码瘦素的基因存在变异。ob小鼠患有病态肥胖和呼吸紊乱，这与肥胖人类的呼吸情况相似。本研究检验了以下假设：向B6和ob小鼠的脑桥网状核嘴侧部(PnO)微量注射新斯的明会改变睡眠和呼吸。在B6和ob小鼠中，新斯的明导致快速眼动(REM)睡眠样状态(REM-Neo)所花费时间的百分比呈浓度依赖性增加(P<0.0001)。相对于生理盐水(对照)，更高浓度的新斯的明增加了B6和ob小鼠的REM-Neo持续时间和REM-Neo发作次数，并减少了觉醒百分比、非快速眼动百分比以及REM-Neo发作的潜伏期(P<0.001)。在B6和ob小鼠中，阿托品可阻断新斯的明对REM睡眠的增强作用。还发现了B6和同源ob小鼠在睡眠和觉醒控制量方面的差异。在PnO注射生理盐水后，ob小鼠清醒时间显著增加(P<0.05)，非快速眼动睡眠时间减少。B6小鼠的基线运动活动比ob小鼠更多(P<0.01)，PnO新斯的明降低了B6和ob小鼠的运动能力(P<0.0001)。全身体积描记法显示，PnO新斯的明使B6和ob小鼠的呼吸受到抑制(P<0.001)，并且对B6小鼠的呼吸抑制作用比对ob小鼠更强(P<0.05)。蛋白质免疫印迹分析表明，在皮质、中脑、小脑和脑桥而非延髓中，ob小鼠的M2毒蕈碱受体蛋白表达量比B6小鼠更高(P<0.05)。综合来看，这些数据首次证明，在已知因编码瘦素的基因自发突变而存在差异的小鼠之间，脑桥胆碱能对睡眠和呼吸的控制有所不同。
