Qiu Mei-Hong, Yao Qiao-Ling, Vetrivelan Ramalingam, Chen Michael C, Lu Jun
State key Laboratory of Medical Neurobiology and Department of Neurobiology, School of Basic Medical Science, Fudan University, Shanghai 200032, China Department of Neurology and Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Cereb Cortex. 2016 Apr;26(4):1430-9. doi: 10.1093/cercor/bhu241. Epub 2014 Oct 14.
Lesions of the globus pallidus externa (GPe) produce a profound sleep loss (∼45%) in rats, suggesting that GPe neurons promote sleep. As GPe neuronal activity is enhanced by dopamine (DA) from the substantia nigra pars compacta (SNc), we hypothesized that SNc DA via the GPe promotes sleep. To test this hypothesis, we selectively destroyed the DA afferents to the caudoputamen (CPu) using 6-hydroxydopamine and examined changes in sleep-wake profiles in rats. Rats with 80-90% loss of SNc neurons displayed a significant 33.7% increase in wakefulness (or sleep reduction). This increase significantly correlated with the extent of SNc DA neuron loss. Furthermore, these animals exhibited sleep-wake fragmentation and reduced diurnal variability of sleep. We then optogenetic-stimulated SNc DA terminals in the CPu and found that 20-Hz stimulation from 9 to 10 PM increased total sleep by 69% with high electroencephalograph (EEG) delta power. We finally directly optogenetic-stimulated GPe neurons and found that 20-Hz stimulation of the GPe from 9 to 10 PM increased total sleep by 66% and significantly increased EEG delta power. These findings elucidate a novel circuit for DA control of sleep and the mechanisms of abnormal sleep in BG disorders such as Parkinson's disease and Huntington's disease.
外侧苍白球（GPe）损伤会导致大鼠出现严重的睡眠丧失（约45%），这表明GPe神经元促进睡眠。由于黑质致密部（SNc）释放的多巴胺（DA）可增强GPe神经元的活性，我们推测SNc DA通过GPe促进睡眠。为验证这一假设，我们使用6-羟基多巴胺选择性地破坏了投射到尾壳核（CPu）的DA传入纤维，并检测了大鼠睡眠-觉醒模式的变化。SNc神经元损失80%-90%的大鼠清醒时间显著增加了33.7%（或睡眠减少）。这种增加与SNc DA神经元损失的程度显著相关。此外，这些动物表现出睡眠-觉醒碎片化以及睡眠的昼夜变异性降低。然后，我们对CPu中的SNc DA终末进行光遗传学刺激，发现晚上9点到10点20赫兹的刺激使总睡眠时间增加了69%，且脑电图（EEG）δ波功率较高。我们最后直接对GPe神经元进行光遗传学刺激，发现晚上9点到10点对GPe进行20赫兹的刺激使总睡眠时间增加了66%，并显著增加了EEG δ波功率。这些发现阐明了一种新的DA控制睡眠的神经回路以及帕金森病和亨廷顿病等基底神经节疾病中异常睡眠的机制。
