Early-onset narcolepsy: A role for histamine

早发性嗜睡症：组胺的作用

• 批准号: 9906984
• 负责人: Alissa A Coffey
• 金额: $ 6.45万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-17 至 2021-04-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906984
• 关键词: Acute; Address; Adult; Affect; Age; Age of Onset; Animals; Behavior; Behavioral; Brain region; Cataplexy; Cerebrospinal Fluid; Cessation of life; Child; Childhood; Chronic; Conscious; Data; Diet; Diphtheria Toxin; Doxycycline; Drowsiness; Excision; Exhibits; Fiber; Goals; Histamine; Histidine Decarboxylase; Hypothalamic structure; Lateral; Lead; Measures; Mus; Muscle; Narcolepsy; Neuromodulator; Neurons; Onset of illness; Paralysed; Photometry; Pontine structure; REM Sleep; Regulation; Reporting; Research; Research Personnel; Role; Signal Transduction; Sleep; Sleep Disorders; Symptoms; System; Tegmentum Mesencephali; Testing; Time; Wakefulness; alpha Toxin; early onset; effective therapy; experience; experimental study; falls; hypocretin; mammilloinfundibular nucleus structure; midbrain central gray substance; mouse model; neuron loss; novel; targeted treatment; young adult

PROJECT SUMMARY/ABSTRACT Narcolepsy is a sleep disorder caused by the selective death of orexin neurons that commonly occurs in childhood. Orexin neuron loss disinhibits REM sleep during the active period and produces cataplexy, an abnormal behavioral state between REM sleep and wake. Cataplexy is much more severe in children who develop narcolepsy than in adults, but the underlying mechanisms remain unknown. Histamine is a wake-promoting neuromodulator produced solely in the tuberomammillary nucleus. Histamine neurons are active during cataplexy, possibly maintaining consciousness during this REM sleep-like state. Mice lacking both orexins and histamine exhibit far less cataplexy than mice lacking only orexins, suggesting that histamine is necessary for cataplexy. In children with narcolepsy, cerebrospinal fluid histamine levels are higher than in healthy controls, whereas histamine levels are normal or low in adults with narcolepsy. Our pilot data indicate that orexin neuron loss in mice at age 4 weeks (young-onset) results in very severe cataplexy, whereas orexin neuron loss at age 14 weeks (adult-onset) results in little cataplexy but more REM sleep. We hypothesize that the abundant cataplexy in young mice is caused by a compensatory increase in histamine signaling. We will test this hypothesis by first analyzing sleep-wake behavior in young-onset and adult-onset mice acutely and chronically after orexin neuron loss to confirm that young-onset mice experience more cataplexy. Then, we will use photometry to measure histamine neuron activity during cataplexy and across sleep/wake states in young-onset mice to confirm whether histamine neurons are active during cataplexy. Finally, we will chemogenetically inhibit or activate histamine neurons to test whether elevated histamine neuron activity promotes cataplexy. These experiments will define the role of histamine neurons in the regulation of cataplexy in mice with young-onset or adult-onset orexin neuron loss. Ultimately, elucidating this mechanism of severe cataplexy should enable more targeted treatments for children with narcolepsy.

项目摘要/摘要 睡病是由Orexin神经元的选择性死亡引起的睡眠障碍，通常发生 在童年时期。 Orexin神经元丧失在活动期间dissive rem睡眠，并产生崩溃 REM睡眠和唤醒之间的异常行为状态。在儿童中，脱圈要严重得多 与成年人相比，发展发育迟缓，但潜在的机制仍然未知。 组胺是仅在结核氨基核中产生的唤醒神经调节剂。 组胺神经元在瘫痪期间活跃，可能在这种rem睡眠状时保持意识 状态。缺乏奥甲蛋白和组胺的小鼠表现出比仅缺少奥甲蛋白的小鼠的瘫痪远不那么少。 表明组胺对于脱囊是必需的。在患有发肠炎的儿童中，脑脊液组胺 水平高于健康对照，而患有睡病的成年人的组胺水平正常或低。 我们的试点数据表明，4周时小鼠的奥甲释蛋白神经元丧失（年轻发病）导致非常 严重的脱弹性，而​​在14周龄时奥甲释蛋白神经元丧失（成人发言）导致脱弹性，但更多 REM睡觉。我们假设年轻小鼠的大量脱囊是由补偿性增加引起的 在组胺信号传导中。 我们将通过首先分析年轻人和成人发作的小鼠的睡眠效果行为来检验这一假设 在Orexin神经元丧失后，急性和慢性地确认年轻的小鼠会经历更多的瘫痪。 然后，我们将使用光度法来测量瘫痪和贯穿睡眠/唤醒期间组胺神经元活性 年轻小鼠中的状态以确认组胺神经元在脱发过程中是否活跃。最后，我们会的 化学上抑制或激活组胺神经元，以测试是否升高组胺神经元活性 促进催化性。 这些实验将定义组胺神经元在调节小鼠中的作用 年轻人发作或成人发作的Orexin神经元丧失。最终，阐明了这种严重瘫痪机制 应该为患有睡病的儿童提供更多针对性的治疗方法。