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

描述(申请人提供)：亨廷顿病(HD)是一种主要遗传的、不可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的发生和发展中发挥作用。17--3-雌二醇(E_2)的神经保护作用表明它可能是导致这些性别差异的原因之一。这项研究的目的是研究雌二醇对雌性小鼠神经病理生理学和HD行为表型的影响。由于HD导致皮质纹状体通路的神经活动受损和改变，皮质功能障碍很可能导致纹状体神经元活动过度和抗氧化剂维生素C(维生素C；AA)的缺乏。雌二醇对谷氨酸(GLU)传递的影响可能使雌性HD小鼠的皮质神经元活动正常化，防止纹状体AA丢失，并导致雌性HD发病较晚和/或进展缓慢。电生理学和伏安法将被用来记录前额叶皮质(PFC)的神经活动，并监测行为HD小鼠和接受卵巢切除(OVX)+安慰剂、OVX+E2或假手术+安慰剂的野生型对照组(WT)纹状体中AA的释放。在皮层记录过程中，小鼠将参与一项反向学习任务，因为这是一项涉及PFC的皮质-纹状体依赖任务。E2神经保护的一种机制可能是通过上调胶质细胞GLU转运体，如GLT1。这可能会阻止HD中发生的GLU兴奋毒性，并增加雌性HD小鼠的GLU清除量。将使用免疫组织化学和行为评估来确定E2是否上调了皮质和纹状体中的GLT1，从而改善了雌性小鼠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丢失的影响，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，在HD小鼠中观察到的性别差异是否与E2对GLU传播的影响有关。美国有3万人患有先天性心脏病，还有15万人面临遗传这种基因的风险。如果E2在HD模型中具有神经保护作用，它可能是一种合适的治疗方法，特别是对患有HD的女性。此外，对E2在调节大脑运动回路中的作用的评估将提供对这种激素如何调节正常和病理性运动控制的更好的理解。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关键作用，并可能代表一种治疗运动障碍和神经退行性疾病的方法，目前还没有得到很好的研究。

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.