Morrison Janna L, Sood Sandeep, Liu Hattie, Park Eileen, Liu Xia, Nolan Philip, Horner Richard L
Departments of Medicine and Physiology, University of Toronto, Toronto, Canada M5S 1A8.
J Physiol. 2003 Nov 1;552(Pt 3):975-91. doi: 10.1113/jphysiol.2003.052357. Epub 2003 Aug 22.
The hypoglossal motor nucleus innervates the genioglossus (GG) muscle of the tongue, a muscle that helps maintain an open airway for effective breathing. Rapid-eye-movement (REM) sleep, however, recruits powerful neural mechanisms that can abolish GG activity even during strong reflex stimulation such as by hypercapnia, effects that can predispose to sleep-related breathing problems in humans. We have developed an animal model to chronically manipulate neurotransmission at the hypoglossal motor nucleus using in vivo microdialysis in freely behaving rats. This study tests the hypothesis that glycine receptor antagonism at the hypoglossal motor nucleus, either alone or in combination with GABAA receptor antagonism, will prevent suppression of GG activity in natural REM sleep during room air and CO2-stimulated breathing. Rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid (ACSF) and strychnine (glycine receptor antagonist, 0.1 mM) either alone or combined with bicuculline (GABAA antagonist, 0.1 mM) during room air and CO2-stimulated breathing. Compared to ACSF controls, glycine receptor antagonism at the hypoglossal motor nucleus increased respiratory-related GG activity in room air (P = 0.010) but not hypercapnia (P = 0.221). This stimulating effect of strychnine in room air did not depend on the prevailing sleep-wake state (P = 0.625) indicating removal of a non-specific background inhibitory glycinergic tone. Nevertheless, GG activity remained minimal in those REM sleep periods without phasic twitches in GG muscle, with GG suppression from non-REM (NREM) sleep being > 85 % whether ACSF or strychnine was at the hypoglossal motor nucleus or the inspired gas was room air or 7 % CO2. While GG activity was minimal in these REM sleep periods, there was a small but measurable increase in GG activity after strychnine (P < 0.05). GG activity was also minimal, and effectively abolished, in the REM sleep periods without GG twitches with combined glycine and GABAA receptor antagonism at the hypoglossal motor nucleus. We conclude that these data in freely behaving rats confirm that inhibitory glycine and GABAA receptor mechanisms are present at the hypoglossal motor nucleus and are tonically active, but that such inhibitory mechanisms make only a small contribution to the marked suppression of GG activity and reflex responses observed in periods of natural REM sleep.
舌下运动神经核支配舌部的颏舌肌（GG），该肌肉有助于维持开放气道以实现有效呼吸。然而，快速眼动（REM）睡眠会启动强大的神经机制，即使在诸如高碳酸血症等强烈反射刺激下，这些机制也能消除GG活动，这些影响可能使人类易患与睡眠相关的呼吸问题。我们开发了一种动物模型，通过在自由活动的大鼠体内进行微透析，长期操纵舌下运动神经核的神经传递。本研究检验了以下假设：单独或与GABAA受体拮抗剂联合阻断舌下运动神经核的甘氨酸受体，将预防在室内空气和二氧化碳刺激呼吸期间自然REM睡眠中GG活动的抑制。给大鼠植入脑电图和颈部肌肉电极以记录睡眠-觉醒状态，以及用于记录呼吸肌的GG和膈肌电极。在室内空气和二氧化碳刺激呼吸期间，将微透析探针植入舌下运动神经核，以灌注人工脑脊液（ACSF）和士的宁（甘氨酸受体拮抗剂，0.1 mM），单独使用或与荷包牡丹碱（GABAA拮抗剂，0.1 mM）联合使用。与ACSF对照组相比，舌下运动神经核的甘氨酸受体拮抗剂在室内空气中增加了与呼吸相关的GG活动（P = 0.010），但在高碳酸血症时没有增加（P = 0.221）。士的宁在室内空气中的这种刺激作用不依赖于当时的睡眠-觉醒状态（P = 0.625），表明消除了非特异性背景抑制性甘氨酸能张力。然而，在那些GG肌肉没有相位性抽搐的REM睡眠期，GG活动仍然最小，无论ACSF或士的宁是否在舌下运动神经核，或者吸入气体是室内空气还是7%二氧化碳，GG从非快速眼动（NREM）睡眠中的抑制都> 85%。虽然在这些REM睡眠期GG活动最小，但士的宁处理后GG活动有小幅但可测量的增加（P < 0.05）。在舌下运动神经核联合甘氨酸和GABAA受体拮抗剂的情况下，在没有GG抽搐的REM睡眠期，GG活动也最小且实际上被消除。我们得出结论，这些自由活动大鼠的数据证实，抑制性甘氨酸和GABAA受体机制存在于舌下运动神经核且呈紧张性活动，但这种抑制机制对在自然REM睡眠期观察到的GG活动和反射反应的显著抑制仅起很小的作用。
