Analysis of sleep disorders under pain using an optogenetic tool: possible involvement of the activation of dorsal raphe nucleus-serotonergic neurons.
Analysis of sleep disorders under pain using an optogenetic tool: possible involvement of the activation of dorsal raphe nucleus-serotonergic neurons.
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DOI：
10.1186/1756-6606-6-59
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发表时间：
2013-12-26
期刊：
影响因子：
3.6
通讯作者：
Narita M
中科院分区：
文献类型：
--
作者：
Ito H;Yanase M;Yamashita A;Kitabatake C;Hamada A;Suhara Y;Narita M;Ikegami D;Sakai H;Yamazaki M;Narita M
一些病因学报告表明，慢性疼痛严重干扰睡眠。由于慢性疼痛导致的睡眠不足可能会导致生活在疼痛中的压力负面后果。然而，慢性疼痛影响睡眠-觉醒模式的神经生理机制尚不清楚。虽然5-羟色胺（5-HT）被认为是负责睡眠调节，在中缝背核（DRN）的5-HT能神经元的活动是否受到慢性疼痛的影响已经很少被研究。另一方面，光遗传学工具的最新发展提供了一个宝贵的机会，以高空间和时间精度调节遗传靶向神经群体的活性。在本研究中，我们调查了慢性疼痛是否可以诱导睡眠失调，同时改变DRN-5-HTergic神经元的活动。此外，我们试图用通道视紫红质-2（ChR 2）生理激活DRN，以确定DRN-5-HT系统在使用光遗传学促进和维持觉醒中的因果作用。我们通过在坐骨神经直径的大约三分之一到二分之一周围系紧结扎线来产生坐骨神经结扎模型。在神经结扎的小鼠中，我们证实了脑电图（EEG）监测的觉醒增加和非快速眼动（NREM）睡眠减少。将荧光金（FG）逆行示踪剂注入前额叶皮层（PFC），发现DRN内有几个逆行标记细胞。本研究的关键发现是，在坐骨神经结扎的小鼠中，电刺激DRN神经元后，前额叶皮质中释放的5-HT水平显着增加。在小鼠中使用光遗传学工具，我们发现DRN神经元放电，皮质活动和睡眠到觉醒过渡之间存在因果关系。特别是，DRN-5-HTergic神经元的激活产生了觉醒的显着增加和NREM睡眠的显着减少。在这些小鼠的光刺激过程中，NREM睡眠发作的持续时间显著减少。这些结果表明，神经病理性疼痛加速DRN-5-HTergic神经元的活动。虽然需要进一步的功能丧失实验，我们假设，这种激活在DRN神经元可能，至少部分，与睡眠失调下的神经性疼痛样状态。
Several etiological reports have shown that chronic pain significantly interferes with sleep. Inadequate sleep due to chronic pain may contribute to the stressful negative consequences of living with pain. However, the neurophysiological mechanism by which chronic pain affects sleep-arousal patterns is as yet unknown. Although serotonin (5-HT) was proposed to be responsible for sleep regulation, whether the activity of 5-HTergic neurons in the dorsal raphe nucleus (DRN) is affected by chronic pain has been studied only infrequently. On the other hand, the recent development of optogenetic tools has provided a valuable opportunity to regulate the activity in genetically targeted neural populations with high spatial and temporal precision. In the present study, we investigated whether chronic pain could induce sleep dysregulation while changing the activity of DRN-5-HTergic neurons. Furthermore, we sought to physiologically activate the DRN with channelrhodopsin-2 (ChR2) to identify a causal role for the DRN-5-HT system in promoting and maintaining wakefulness using optogenetics. We produced a sciatic nerve ligation model by tying a tight ligature around approximately one-third to one-half the diameter of the sciatic nerve. In mice with nerve ligation, we confirmed an increase in wakefulness and a decrease in non-rapid eye movement (NREM) sleep as monitored by electroencephalogram (EEG). Microinjection of the retrograde tracer fluoro-gold (FG) into the prefrontal cortex (PFC) revealed several retrogradely labeled-cells in the DRN. The key finding of the present study was that the levels of 5-HT released in the PFC by the electrical stimulation of DRN neurons were significantly increased in mice with sciatic nerve ligation. Using optogenetic tools in mice, we found a causal relationship among DRN neuron firing, cortical activity and sleep-to-wake transitions. In particular, the activation of DRN-5-HTergic neurons produced a significant increase in wakefulness and a significant decrease in NREM sleep. The duration of NREM sleep episodes was significantly decreased during photostimulation in these mice. These results suggest that neuropathic pain accelerates the activity of DRN-5-HTergic neurons. Although further loss-of-function experiments are required, we hypothesize that this activation in DRN neurons may, at least in part, correlate with sleep dysregulation under a neuropathic pain-like state.
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影响因子：
13.9
作者：
Fenno L;Yizhar O;Deisseroth K
通讯作者：
Deisseroth K
影响因子：
2.9
作者：
Andersen, ML;Tufik, S
通讯作者：
Tufik, S
影响因子：
25
作者：
Boyden, ES;Zhang, F;Deisseroth, K
通讯作者：
Deisseroth, K
影响因子：
2.5
作者：
CESPUGLIO, R;WALKER, E;MUSOLINO, R
通讯作者：
MUSOLINO, R
影响因子：
0.3
作者：
DAI, JL;ZHU, YH;XU, SF
通讯作者：
XU, SF