Chronic alterations in monoaminergic cells in the locus coeruleus in orexin neuron-ablated narcoleptic mice.
Chronic alterations in monoaminergic cells in the locus coeruleus in orexin neuron-ablated narcoleptic mice.
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DOI：
10.1371/journal.pone.0070012
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sakurai T
中科院分区：
文献类型：
--
作者：
Tsujino N;Tsunematsu T;Uchigashima M;Konno K;Yamanaka A;Kobayashi K;Watanabe M;Koyama Y;Sakurai T
发作性睡病患者除了白天过度嗜睡外，还经常失眠。发作性睡病的动物也表现出行为不稳定，其特征是在所有警戒状态之间频繁转换，表现出非常短的NREM睡眠和清醒。发作性睡病患者觉醒状态的不稳定被认为是由于下丘脑外侧神经元产生的神经肽-食欲素缺乏所致，食欲素在维持觉醒中起着非常重要的作用。然而，这种疾病中睡眠不稳定的机制仍有待阐明。由于健康动物睡眠期间食欲素神经元的放电停止，食欲素缺乏并不能解释睡眠异常。我们推测，蓝斑(LC)和中缝背核(DR)神经生理活动的慢性代偿性变化是内源性增食欲素张力进行性丧失的基础，是睡眠/清醒状态的病理调节。为了评估这一假说，我们研究了脑干中5-羟色胺(5-HT)能神经元和去甲肾上腺素(NA)能神经元的放电模式，这两类神经元在调节睡眠/觉醒状态方面具有重要作用。我们记录了食欲素神经元损毁的发作性睡病小鼠DR核和LC内5-羟色胺能神经元和NA能神经元的单位活动。我们发现，虽然发作性睡病小鼠5-羟色胺神经元的放电模式与野生型小鼠相似，但NA神经元的放电模式与野生型小鼠有显著不同。在发作性睡病小鼠中，与野生型小鼠相比，NA神经元在清醒和NREM睡眠中都显示出更高的放电频率。对发作性睡病小鼠NA神经元的体外膜片钳研究表明，对这些神经元的GABA能输入功能减少。这些改变可能在发作性睡病的睡眠异常中起作用。
Narcolepsy patients often suffer from insomnia in addition to excessive daytime sleepiness. Narcoleptic animals also show behavioral instability characterized by frequent transitions between all vigilance states, exhibiting very short bouts of NREM sleep as well as wakefulness. The instability of wakefulness states in narcolepsy is thought to be due to deficiency of orexins, neuropeptides produced in the lateral hypothalamic neurons, which play a highly important role in maintaining wakefulness. However, the mechanism responsible for sleep instability in this disorder remains to be elucidated. Because firing of orexin neurons ceases during sleep in healthy animals, deficiency of orexins does not explain the abnormality of sleep. We hypothesized that chronic compensatory changes in the neurophysiologica activity of the locus coeruleus (LC) and dorsal raphe (DR) nucleus in response to the progressive loss of endogenous orexin tone underlie the pathological regulation of sleep/wake states. To evaluate this hypothesis, we examined firing patterns of serotonergic (5-HT) neurons and noradrenergic (NA) neurons in the brain stem, two important neuronal populations in the regulation of sleep/wakefulness states. We recorded single-unit activities of 5-HT neurons and NA neurons in the DR nucleus and LC of orexin neuron-ablated narcoleptic mice. We found that while the firing pattern of 5-HT neurons in narcoleptic mice was similar to that in wildtype mice, that of NA neurons was significantly different from that in wildtype mice. In narcoleptic mice, NA neurons showed a higher firing frequency during both wakefulness and NREM sleep as compared with wildtype mice. In vitro patch-clamp study of NA neurons of narcoleptic mice suggested a functional decrease of GABAergic input to these neurons. These alterations might play roles in the sleep abnormality in narcolepsy.
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