Effects of estrogen on neuropathophysiology and behavior in Huntington's disease

雌激素对亨廷顿病神经病理生理学和行为的影响

• 批准号: 7529201
• 负责人: Jenelle Lynn Dorner
• 金额: $ 3.98万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2010-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529201
• 关键词: Accounting; Affect; Antioxidants; Area; Ascorbic Acid; Behavior; Behavior assessment; Behavioral; Brain; Condition; Corpus striatum structure; Disease Progression; Disease model; Electrophysiology (science); Estradiol; Estrogens; Evaluation; Event; Exhibits; Female; Functional disorder; Genes; Glutamate Transporter; Glutamates; Goals; Gonadal Steroid Hormones; Hormones; Human; Huntington Disease; Immunohistochemistry; Inherited; Ischemia; Lesion; Modeling; Monitor; Motor; Movement Disorders; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Ovariectomy; Oxidative Stress; Pathway interactions; Phenotype; Placebos; Play; Prefrontal Cortex; Research; Reversal Learning; Risk; Role; Scanning; Sex Characteristics; Testing; Transgenic Organisms; United States; Up-Regulation; Vitamins; Wild Type Mouse; Woman; ascorbate; excitotoxicity; extracellular; improved; male; motor control; neuroprotection; prevent; relating to nervous system; sham surgery; steroid hormone; transmission process

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a dominantly inherited, incurable neurodegenerative disease affecting primarily the striatum and corticostriatal pathway. Sex differences in mice and humans with HD suggest that gonadal steroid hormones may play a role in the onset and progression of HD. Neuroprotective effects of 17--3-estradiol (E2) suggest that it may contribute to these sex differences. The goal of the proposed research is to characterize the effects of E2 on neural pathophysiology and the behavioral phenotype of HD in female mice. Because HD results in damage and altered neural activity of the corticostriatal pathway, it is likely that cortical dysfunction contributes to excessive neuronal activity and a deficit of the antioxidant vitamin, ascorbate (vitamin C; AA) in the striatum. E2 effects on glutamate (GLU) transmission may normalize cortical neuronal activity in female HD mice preventing striatal AA loss and resulting in later onset and/or slower progression of HD in females. Electrophysiology and voltammetry will be used to record neural activity in the prefrontal cortex (PFC) and monitor AA release in the striatum of behaving HD mice and wild-type controls (WT) receiving either ovariectomy (OVX) + .placebo, OVX + E2, or sham surgery + placebo. During cortical recordings, mice will be engaged in a reversal learning task as this is a cortico- striatal dependent task involving PFC. One mechanism of E2 neuroprotection may be via upregulation of glial GLU transporters such as GLT1. This may prevent the GLU excitotoxicity believed to occur in HD and increase GLU clearance in female HD mice. Immunohistochemistry and behavioral assessments will be used to determine whether E2 upregulates GLT1 in the cortex and striatum, improving the behavioral phenotype of HD in female mice. Results of this study will indicate whether E2 may protect female HD mice from striatal AA loss, normalize cortical neuronal activity and improve the behavioral phenotype associated with HD. Furthermore, results will suggest whether E2 effects on GLU transmission contribute to sex differences observed in HD mice. HD affects -30,000 people in the United States and -150,000 more are at risk for inheriting the gene. If E2 is neuroprotective in HD models, it may be a suitable therapy, particularly for women with HD. Furthermore, evaluation of the role of E2 in regulating motor circuits in the brain will provide a better understanding of how this hormone regulates normal and pathological motor control. This is particularly important because more than 40 million U.S. citizens are affected by movement disorders. E2 likely plays a critical role in motor function and neuroprotection and may represent a therapy for movement disorders and neurodegenerative conditions that is currently not well investigated.

描述（由申请人提供）：亨廷顿病（HD）是一种显性遗传的、无法治愈的神经退行性疾病，主要影响纹状体和皮质纹状体通路。患有 HD 的小鼠和人类的性别差异表明，性腺类固醇激素可能在 HD 的发病和进展中发挥作用。 17--3-雌二醇 (E2) 的神经保护作用表明它可能导致这些性别差异。本研究的目的是表征 E2 对雌性小鼠 HD 神经病理生理学和行为表型的影响。由于 HD 会导致皮质纹状体通路的损伤和神经活动改变，因此皮质功能障碍可能会导致神经元活动过度以及纹状体中抗氧化维生素抗坏血酸（维生素 C；AA）的缺乏。 E2 对谷氨酸 (GLU) 传输的影响可能会使雌性 HD 小鼠的皮质神经元活动正常化，防止纹状体 AA 损失，并导致雌性 HD 较晚发作和/或进展较慢。电生理学和伏安法将用于记录行为 HD 小鼠和接受卵巢切除术 (OVX) + 安慰剂、OVX + E2 或假手术 + 安慰剂的野生型对照 (WT) 前额皮质 (PFC) 的神经活动，并监测纹状体中 AA 的释放。在皮质记录期间，小鼠将从事逆转学习任务，因为这是涉及 PFC 的皮质纹状体依赖性任务。 E2 神经保护的一种机制可能是通过上调神经胶质 GLU 转运蛋白（例如 GLT1）。这可能会阻止 HD 中发生的 GLU 兴奋性毒性，并增加雌性 HD 小鼠的 GLU 清除率。免疫组织化学和行为评估将用于确定 E2 是否上调皮质和纹状体中的 GLT1，从而改善雌性小鼠 HD 的行为表型。这项研究的结果将表明 E2 是否可以保护雌性 HD 小鼠免受纹状体 AA 损失、使皮质神经元活动正常化并改善与 HD 相关的行为表型。此外，结果将表明 E2 对 GLU 传输的影响是否会导致 HD 小鼠中观察到的性别差异。 HD 影响美国 -30,000 人，还有 -150,000 人面临遗传该基因的风险。如果 E2 在 HD 模型中具有神经保护作用，那么它可能是一种合适的疗法，特别是对于患有 HD 的女性。此外，评估 E2 在调节大脑运动回路中的作用将有助于更好地理解这种激素如何调节正常和病理性运动控制。这一点尤其重要，因为超过 4000 万美国公民受到运动障碍的影响。 E2可能在运动功能和神经保护中发挥着关键作用，并且可能代表一种目前尚未得到充分研究的运动障碍和神经退行性疾病的治疗方法。