A MODEL OF HUMAN TORSION DYSTONIA

人体扭转肌张力障碍模型

• 批准号: 3398115
• 负责人: JOAN F. LORDEN
• 金额: $ 14.95万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-12-01 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3398115
• 关键词: afferent nerve; autoradiography; autosomal recessive trait; axon; cyclic GMP; disease /disorder model; dystonia; electrophysiology; glutamate decarboxylase; histopathology; neuroanatomy; neurochemistry; neuropharmacology; norepinephrine; psychopharmacology; psychophysiology; radioassay

The dystonic rat is a model of inherited movement disorders discovered in Sprague-Dawley rats. The dt rat displays sustained, twisting movements in the waking state, starting on postnatal days 9-10 following a period of apparently normal development. The movements seen in the dt rat are analogous to those that characterize the disease torsion dystonia in man. Inheritance in the rat model follows an autosomal recessive pattern. As in the human disease, routine histopathological study reveals no evidence of morphological lesions or degenerative processes in the central or peripheral nervous system of rats displaying advanced clinical signs. However, in the rat model application of neurochemical, morphological and psychopharmacological techniques to study noradrenergic, dopaminergic, cholinergic, and GABAergic systems in brain has revealed specific abnormalities including increased GAD activity in the deep cerebellar nuclei, increased steady state levels of cerebellar norepinephrine and decreased cerebellar cGMP. These are not generalized abnormalities in noradrenergic or GABAergic systems. Other evidence of pathology in the cerebellum includes the presence of tubular, honeycombed inclusions of axons seen in electron micrographs. The dt rats are also less sensitive to the tremorogenic effects of harmaline, a drug that acts on one of the major cerebellar afferent systems. The proposed studies are designed to continue a systematic interdisciplinary investigation of the dt rat. Emphasis is given to studies that are designed to provide explanations for previously documented neurochemical and psychopharmacological abnormalities. Specifically, studies are proposed to assess the function to major components of cerebellar circuitry and to determine their relationship to dystonia. Neurochemical, electrophysiological and anatomical techniques will be used. The proposed studies are expected to lead to increased understanding of human torsion dystonia and normal development of motor systems.

肌张力障碍大鼠是一种遗传性运动障碍模型 斯普拉格-道利大鼠。 dt 大鼠表现出持续的、扭曲的运动 清醒状态，从产后 9-10 天开始，经过一段时间后 显然是正常发育。 dt 大鼠的运动是 类似于人类扭转肌张力障碍疾病的特征。 大鼠模型的遗传遵循常染色体隐性遗传模式。 如在 人类疾病，常规组织病理学研究未发现任何证据 中央或中枢的形态病变或退行性过程 显示出晚期临床症状的大鼠的周围神经系统。 然而，在大鼠模型中应用神经化学、形态学和 研究去甲肾上腺素能、多巴胺能、 大脑中的胆碱能和 GABA 能系统揭示了特定的 异常，包括小脑深部 GAD 活性增加 细胞核，小脑去甲肾上腺素稳态水平增加和 小脑 cGMP 降低。 这些并不是普遍的异常现象 去甲肾上腺素能或 GABA 能系统。 其他病理学证据 小脑包括管状、蜂窝状内含物的存在 电子显微照片中看到的轴突。 dt 大鼠对以下物质也不太敏感 骆驼蓬碱的致震颤作用，一种作用于主要神经元之一的药物 小脑传入系统。 拟议的研究旨在继续系统地 dt 大鼠的跨学科研究。 重点是 旨在为先前记录的问题提供解释的研究 神经化学和精神药理学异常。 具体来说， 建议进行研究以评估主要成分的功能 小脑回路并确定其与肌张力障碍的关系。 神经化学、电生理学和解剖学技术将 用过的。 拟议的研究预计将加深理解 人类扭转肌张力障碍和运动系统的正常发育。