Neuropathology of Hypocretin

下丘脑泌素的神经病理学

• 批准号: 7788107
• 负责人: JEROME M SIEGEL
• 金额: $ 28.03万
• 依托单位: SEPULVEDA RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-02-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788107
• 关键词: Abbreviations; Acetylcholine; Agonist; Amygdaloid structure; Anatomy; Antigens; Arousal; Basal Nucleus of Meynert; Brain; Brain Stem; Cataplexy; Cell Count; Cell Nucleus; Cell Size; Cells; Cellular Structures; Cerebrospinal Fluid; Characteristics; Chronic; Data; Deletion Mutation; Diagnosis; Disease; Dopamine; Dorsal; Down-Regulation; Effectiveness; Etiology; Fc Receptor; Felis catus; Gliosis; Golgi Apparatus; Grant; Heterozygote; Histamine; Histidine Decarboxylase; Human; Hypothalamic structure; Immunohistochemistry; Impairment; In Situ Hybridization; Incidence; Knockout Mice; Label; Link; Location; Measures; Mental Depression; Messenger RNA; Modeling; Morphology; Mus; Narcolepsy; Nature; Neurodegenerative Disorders; Neurons; Output; Parkinson Disease; Pathology; Patients; Peptides; Phenotype; Posterior Hypothalamus; Process; Prosencephalon; Proteins; REM Sleep Behavior Disorder; Radioimmunoassay; Relative (related person); Reporting; Research; Shapes; Sleep; Sleeplessness; Symptoms; Syndrome; System; Testing; Time; Tissue Stains; Trees; Tyrosine 3-Monooxygenase; Universities; Ventral Tegmental Area; Work; basal forebrain; base; cholinergic; cholinergic neuron; disease classification; dopaminergic neuron; hypocretin; improved; locus ceruleus structure; melanin-concentrating hormone; neuropathology; noradrenergic; orexin A receptor; orexin B receptor; postsynaptic; public health relevance; raphe nuclei; receptor; response

DESCRIPTION (provided by applicant): In work first reported in 2000 and supported entirely by the current grant, we identified the cause of human narcolepsy as a loss of cells containing hypocretin (Hcrt, or orexin). Similar results were reported by the group at Stanford University at the same time. While these discoveries have been a major advance in our understanding of narcolepsy, important questions remain unanswered. Despite the discovery of a link between Hcrt cell loss and narcolepsy, the anatomical bases of several major symptoms of narcolepsy remain unexplained. For example, narcoleptics have disrupted nighttime sleep and an increased incidence of REM sleep behavior disorder, symptoms that appear to be opposite to the sleepiness and cataplexy that are the best known characteristics of narcolepsy. It is likely that other brain systems are altered in narcolepsy either by the process that removes Hcrt cells or by the direct and indirect postsynaptic effects of the loss of these cells. We will look for anatomical clues to the changes occurring in narcolepsy by measuring, in Hcrt KO mice and in human narcoleptics, Hcrt receptor numbers and in the number, size, dendritic fields and morphology of cholinergic, monoaminergic and other cells normally receiving Hcrt axonal projections. We will determine which of these changes can be reversed by Hcrt administration to Hcrt knockout mice. Changes in Hcrt receptors and in the structure of the cells receiving Hcrt projections will determine the effect of Hcrt administration as a treatment for narcolepsy. It is unclear whether narcolepsy without cataplexy is the same disease as narcolepsy with cataplexy. Up to half of all narcoleptics diagnosed according to current nosology do not have cataplexy and have normal levels of Hcrt in the cerebrospinal fluid. We will determine the number, distribution and morphology of Hcrt neurons in these patients. Narcolepsy appears to be the simplest neurodegenerative disease, in terms of the very restricted pathology that seems to underlie it. Analysis of how the loss of only 60,000 Hcrt cells causes the varied symptoms of narcolepsy by altering brain anatomy may well serve as a model for comprehending the symptoms of, and developing treatments for, other neurodegenerative diseases, including Parkinson's disease, which we have recently shown is also accompanied by a loss of Hcrt neurons. PUBLIC HEALTH RELEVANCE This work may help clarify the nature of the processes that cause Hcrt cell loss in narcolepsy. It will also help us better understand the sleep symptoms of narcolepsy and may have general relevance for understanding symptoms that are common in narcolepsy, but that are not restricted to narcoleptics, including depression, daytime sleepiness, insomnia and REM sleep behavior disorder.

描述（由申请人提供）：在2000年首次报道的工作中，完全得到当前赠款的支持，我们确定了人类性睡病的原因是含有低螺旋蛋白（HCRT或Orexin）细胞的损失。斯坦福大学的小组同时报告了类似的结果。尽管这些发现是我们对睡病的理解的重大进步，但重要的问题仍未得到解决。尽管发现了HCRT细胞损失与发作性睡病之间存在联系，但发作性疾病的几种主要症状的解剖基础仍然无法解释。例如，麻醉剂破坏了夜间睡眠和REM睡眠行为障碍的发病率增加，似乎与昏昏欲睡和瘫痪的症状相反，这些症状是麻醉症的最著名特征。通过去除HCRT细胞的过程，或通过这些细胞丧失的直接和间接突触后作用来改变其他大脑系统在麻醉症中的变化。我们将通过测量，HCRT KO小鼠和人类麻醉剂，HCRT受体数量以及在胆碱能，单氨基能和其他正常接受HCRT HCRT Axonal Projections的数量，大小，树突状场和形态。我们将通过HCRT给药到HCRT敲除小鼠可以确定这些变化中的哪些变化。 HCRT受体和接受HCRT投影的细胞结构的变化将确定HCRT给药作为对睡病的治疗的影响。目前尚不清楚没有瘫痪的睡病疗中与患有脱囊的睡病是同一疾病。根据当前疾病学诊断的所有麻醉剂中，多达一半的麻醉剂没有瘫痪，并且在脑脊液中的HCRT水平正常。我们将确定这些患者中HCRT神经元的数量，分布和形态。就似乎是基础的非常有限的病理学而言，睡病似乎是最简单的神经退行性疾病。分析仅60,000个HCRT细胞的损失如何通过改变脑解剖结构来引起鼻疗症状的各种症状，可以很好地作为理解其他神经退行性疾病的症状，包括帕金森氏病的症状，以及最近显示的其他神经退行性疾病的症状，这些疾病最近也伴有HCRT神经元的丧失。公共卫生相关性这项工作可能有助于阐明导致睡病hcrt细胞损失的过程的性质。这也将帮助我们更好地了解睡眠的睡眠症状，并可能与理解在麻醉症中常见的症状具有一般意义，但不仅限于麻醉药，包括抑郁症，白天嗜睡，失眠和REM睡眠行为障碍。