Neumbiological basis of the basal ganglia control of sleep

本研究旨在阐明基底节是如何通过从基底节输出核团之一的黑质网状部(SNR)投射到桥中脑被盖的脚桥脑被盖核(PPN)来控制睡眠状态的。为此，我们使用了急性去大脑猫，在这些猫中，纹状体、丘脑和大脑皮层被移除，但SNR被保留。结果表明，重复电刺激(10-40μA，50 Hz)可引起与肌张力(REM)相关的快速眼球运动(REM)。首先，我们试图阐明刺激PPN引起肌肉张力时运动神经元的突触机制。对支配伸肌和屈肌的72个后肢运动神经元进行细胞内记录，观察刺激PPN后运动神经元兴奋性的变化。重复电刺激(20-50μA，50赫兹，5-10…更多的S使伸肌和屈肌运动神经元的膜电位超极化2.0~12 mV(6.0±2.3 mV，n=72)。即使在刺激终止后，膜超极化仍持续10-20秒。在刺激PPN时，膜超极化与运动神经元的放电能力(n=28)和输入电阻(28.5±6.7%，n=14)降低有关。Ia-EPSPS波幅降低(44.1±13.4%，n=14)。在PPN刺激后，尽管膜超极化持续存在，但这些参数立即恢复。在刺激PPN时，向运动神经元内注入氯离子翻转了膜超极化的极性。然而，持续时间较长的超极化的两极并没有逆转。接下来，我们研究了GABA能SNR-PPN投射如何调节PPN诱导的具有张力的REM。电刺激SNR可阻断PPN诱发的具有张力的REM，最佳刺激点混合在SNR的外侧。PPN注射氨基丁酸A受体激动剂L(1.15 mM，0.1-0.25μ)可阻断γ-氨基丁酸A受体激动剂巴氯芬(1-10 mM，0.1-0.25μL)。PPN内注射GABA_A受体拮抗剂荷包牡丹碱(1~15 mM，0.10~0.25μL)，可引起快动眼松弛。另一方面，在SNR背外侧部注射蝇毒酚(0.1-0.25μL)引起快动眼松弛，这种松弛可被进一步注射蝇草酚(5-10 mm，0.2-0.25μL)所消除。这些结果表明，在PPN诱导的体位性张力障碍中，一种由氯离子介导的突触后抑制机制作用于后肢运动神经元。从SNR到PPN的GABA能投射可能参与控制有张力的REM，这是REM睡眠的迹象。帕金森病患者从基底节到PPN的GABA能输出过多可能导致睡眠障碍，包括REM睡眠周期缩短。较少

The present study was designed to elucidate how the basal ganglia control sleep states via projection from the substantia nigra pars reticulata (SNr), one of the basal ganglia output nuclei, to the pedunculopontine tegmental nucleus (PPN) in the mesopontine tegmentum. For this purpose we used acute de cerebrate cats in which the striatum, thalamus, and cerebral cortex were removed, but the SNr was preserved. We have shown that repetitive electrical stimulation (10-40 μA, 50 Hz) applied to the PPN resulted in the generation of rapid eye movements (REM) which were associated with muscular atonia (REM with atonia).First we tried to elucidate synaptic mechanisms acting on motoneurons during muscular atonia induced by PPN stimulation. Intracellular recording was performed from 72 hindlimb motoneurons innervating extensor and flexor muscles, and the changes in excitability of the motoneurons following the PPN stimulation were examined. Repetitive electrical stimulation (20-50 μA, 50 Hz, 5-10 … More s) of the PPN hyperpolarized the membrane potentials of both the extensor and flexor motoneurons by 2.0-12 mV (6.0±2.3 mV, n=72). The membrane hyperpolarization persisted for 10-20 seconds even after termination of the stimulation. During the PPN stimulation, the membrane hyperpolarization was associated with decreases in the firing capability (n=28) and input resistance (28.5±6.7%, n=14) of the motoneurons. Moreover the amplitude of Ia EPSPs was also reduced (44.1±13.4 %, n=14). After the PPN stimulation, these parameters immediately returned despite that the membrane hyperpolarization persisted. Iontophoretic injections of chloride ions into the motoneurons reversed the polarity of the membrane hyperpolarization during the PPN stimulation. The polarity of the outlasting hyperpolarization however was not reversed. Next we examined how the GABAergic SNr-PPN projection regulated the PPN-induced REM with atonia. Electrical stimulation applied to the SNr blocked the PPN-induced REM with atonia, and the optimal stimulus sites for these effects were intermingled within the lateral part of the SNr. Moreover the PPN-induced REM with atonia was abolished by an injection into the PPN of muscimol (1.15 mM, 0.1-0.25 μl), a γ-amino butyric acid (GABA)_A receptor agonist, but not altered by an injection of baclofen (1-10 mM, 0.1-0.25μl), a GABA_B receptor agonist. Moreover, an injection of bicuculline (1-15 mM, 0.1-0.25 μl), a GABA_A receptor antagonist, into the PPN, resulted in REM with atonia. On the other hand, an injection of muscimol into the dorsolateral part of the SNr (1.15 mM, 0.1-0.25 μl) induced REM with atonia, which was in turn eliminated by a further injection of muscimol into the PPN (5-10 mM, 0.2-0.25 μl). ThenThese findings suggest that a postsynaptic inhibitory mechanism, which was mediated by chloride ions, was acting on hindlimb motoneurons during PPN-induced postural atonia. A GABAergic projection from the SNr to the PPN could be involved in the control of REM with atonia, signs which indicate REM sleep. An excessive GABAergic output from the basal ganglia to the PPN in parkinsonian patients may induce sleep disturbances, including a reduction of REM sleep periods. Less