Department of Neurosurgery, Emory University, USA.
Department of Neurosurgery, Emory University, USA; Department of Neurology, Emory University, USA.
Brain Stimul. 2020 Sep-Oct;13(5):1305-1316. doi: 10.1016/j.brs.2020.04.006. Epub 2020 Apr 19.
Narcolepsy type 1 (NT1, narcolepsy with cataplexy) is a disabling neurological disorder caused by loss of excitatory orexin neurons from the hypothalamus and is characterized by decreased motivation, sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS) during wake, and abrupt loss of muscle tone, called cataplexy, in response to sudden emotions.
We investigated whether subcortical stimulation, analogous to clinical deep brain stimulation (DBS), would ameliorate NT1 using a validated transgenic mouse model with postnatal orexin neuron degeneration.
Using implanted electrodes in freely behaving mice, the immediate and prolonged effects of DBS were determined upon behavior using continuous video-electroencephalogram-electromyogram (video/EEG/EMG) and locomotor activity, and neural activation in brain sections, using immunohistochemical labeling of the immediate early gene product c-Fos.
Brief 10-s stimulation to the region of the lateral hypothalamus and zona incerta (LH/ZI) dose-responsively reversed established sleep and cataplexy episodes without negative sequelae. Continuous 3-h stimulation increased ambulation, improved sleep-wake consolidation, and ameliorated cataplexy. Brain c-Fos from mice sacrificed after 90 min of DBS revealed dose-responsive neural activation within wake-active nuclei of the basal forebrain, hypothalamus, thalamus, and ventral midbrain.
Acute and continuous LH/ZI DBS enhanced behavioral state control in a mouse model of NT1, supporting the feasibility of clinical DBS for NT1 and other sleep-wake disorders.
1 型发作性睡病（NT1，伴有猝倒的发作性睡病）是一种由下丘脑兴奋性食欲素神经元丧失引起的使人丧失能力的神经疾病，其特征是动机降低、睡眠-觉醒碎片化、觉醒时快速眼动睡眠（REMS）侵入和肌肉张力突然丧失，称为猝倒，这是对突然情绪的反应。
我们使用一种经过验证的具有出生后食欲素神经元退化的转基因小鼠模型，研究了类似临床深部脑刺激（DBS）的皮质下刺激是否可以改善 NT1。
使用植入的自由活动小鼠中的电极，通过连续视频-脑电图-肌电图（video/EEG/EMG）和运动活动，以及使用即时早期基因产物 c-Fos 的免疫组织化学标记，在脑切片中检测 DBS 的即时和长期影响。
短暂的 10 秒刺激外侧下丘脑和未定带（LH/ZI）区域剂量依赖性地逆转了已建立的睡眠和猝倒发作，没有负面后果。连续 3 小时刺激增加了活动度，改善了睡眠-觉醒整合，并改善了猝倒。在 DBS 后 90 分钟处死的小鼠的脑 c-Fos 显示出与基础前脑、下丘脑、丘脑和腹侧中脑的觉醒活性核内剂量反应性的神经激活。
急性和连续的 LH/ZI DBS 增强了 NT1 小鼠模型的行为状态控制，支持了 NT1 和其他睡眠-觉醒障碍的临床 DBS 的可行性。
