Neuronal Mechanisms underlying sex differences in dystonia

肌张力障碍性别差异背后的神经机制

• 批准号: 10701752
• 负责人: ELLEN J. HESS
• 金额: $ 50.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701752
• 关键词: Address; Affinity Chromatography; Animal Model; Basal Ganglia; Biological; Clinical Trials Design; Code; Corpus striatum structure; Data; Diagnosis; Disease; Dopa-Responsive Dystonia; Dopamine; Dystonia; Estradiol; Estrogens; Estrous Cycle; Estrus; Female; Fibrinogen; Foundations; Functional Imaging; Functional disorder; Genes; Globus Pallidus; Hormonal; Human; Hyperactivity; Image; Knock-in Mouse; Knowledge; Mediating; Microelectrodes; Molecular; Molecular Profiling; Movement; Movement Disorders; Mus; Muscle Contraction; Mutation; Neurons; Ovarian hormone; Pathogenesis; Pathway interactions; Patients; Pattern; Phase; Physiological; Physiology; Play; Posture; Process; Property; Ribosomes; Risk Factors; Role; Sample Size; Sex Bias; Sex Differences; Smooth Muscle; Structure; Substantia nigra structure; Testing; Time; Tissues; Translating; biological sex; cell type; epidemiology study; experimental study; imaging study; in vivo; male; mouse model; neural; neuroregulation; neurotransmission; prototype; segregation; sex; sex cycle; sexual dimorphism; translatome

Dystonia is characterized by involuntary muscle contractions that cause twisting movements and postures. Many dystonias are more common in females than in males yet the mechanisms underlying these sex differences are largely unexplored. Basal ganglia dysfunction is consistently implicated across many forms of dystonia. The major input structure of the basal ganglia is the striatum where estrogen exerts neuromodulatory effects. In fact, the physiological properties of striatal spiny projection neurons (SPNs) are known to vary depending on biological sex and estrous cycle phase. Direct pathway SPNs (dSPNs) project to the internal globus pallidus to promote movement. Indirect pathway SPNs (iSPNs) project to the external globus pallidus to inhibit movement. Although dSPNs and iSPNs are segregated into separate pathways, they act in concert to mediate and refine movements. In dystonia patients, this coordinated activity is disrupted as functional imaging studies and microelectrode recordings suggest that both dSPNs and iSPNs are dysfunctional. However, the mechanisms underlying both SPN pathophysiology and sex differences in dystonia remain unknown. Several challenges have stymied our ability to understand the pathophysiology and the relationship to biological sex in dystonia. First, information obtained by studying patients is, by necessity, quite limited. Second, despite the epidemiological studies demonstrating sex differences in the expression of dystonia, sex as a biological variable is rarely incorporated into studies examining mechanisms underlying dystonia in patients or animal models. Third, we lack foundational studies in healthy controls that disentangle the effects of biological sex on striatal cell types. Indeed, studies characterizing sex differences in normal striatal physiology have not distinguished between SPN subtypes, while studies examining the molecular properties of dSPNs and iSPNs have not examined sex as a biological variable. This proposal addresses these gaps in knowledge. Our understanding of the pathophysiology of dystonia has also been hampered by the lack of animal models with sexually dimorphic dystonia caused by striatal dysfunction. To address this gap, we created a knockin mouse model of DOPA-responsive dystonia (DRD). In patients, DRD is female predominant, like many forms of dystonia in humans. DRD is also a prototype disorder for understanding basal ganglia dysfunction in dystonia In DRD mice, the striatum plays a central role in mediating dystonia and dSPN and iSPN signaling is disrupted. Further, the presentation of dystonia in DRD mice is significantly different between males and females and the dystonia fluctuates with the estrus cycle. Thus, for the first time, it is possible to elucidate the neural code of dystonia in the context of the mechanisms that drive the sex differences. The Specific Aims are: 1. to determine the role of ovarian hormones in the expression of dystonia. 2. to identify the molecular signature of dystonia in dSPNs and iSPNs in male and female DRD mice. 3. to define the pattern of dSPN and iSPN activity underlying dystonia in male and female DRD mice.

肌张力障碍的特征是肌肉不自主收缩，导致扭曲的动作和姿势。许多 肌张力障碍在女性中比在男性中更常见，但这些性别差异背后的机制是 很大程度上是未被开发的。基底节功能障碍持续存在于多种形式的肌张力障碍中。这个 基底节的主要输入结构是纹状体，雌激素在纹状体发挥神经调节作用。事实上, 已知纹状体棘突投射神经元(SPN)的生理特性取决于生物学特性。 性周期和发情周期阶段。直接通路SPN(DSPN)投射到苍白球内侧促进 有动静。间接通路SPN(ISPN)投射到苍白球外区以抑制运动。虽然 DSPN和iSPN被分成不同的路径，它们协同作用来调节和优化运动。 在肌张力障碍患者中，这种协调活动随着功能成像研究和微电极的出现而中断。 录音显示dSPN和iSPN都有功能障碍。然而，两者背后的机制 肌张力障碍的SPN病理生理学和性别差异尚不清楚。 一些挑战阻碍了我们理解病理生理学和与生物学的关系的能力。 在肌张力障碍中做爱。首先，通过研究患者获得的信息必然是相当有限的。第二，尽管 流行病学研究表明，性别差异在肌张力障碍的表达中，性别作为一种生物 变量很少被纳入研究患者或动物肌张力障碍的潜在机制 模特们。第三，我们缺乏健康对照的基础性研究，无法揭示生物性行为对健康的影响。 纹状体细胞类型。事实上，在正常纹状体生理中描述性别差异的研究还没有 区分SPN亚型，同时研究dSPN和iSPN的分子特性 还没有将性别作为一个生物变量进行研究。这项提议解决了知识方面的这些差距。 由于缺乏动物模型，我们对肌张力障碍的病理生理学的理解也受到了阻碍。 由纹状体功能障碍引起的性二形肌张力障碍。为了解决这一差距，我们创建了敲门 多巴反应性肌张力障碍(DRD)小鼠模型。在患者中，DRD以女性为主，就像许多形式的 人类的肌张力障碍。DRD也是了解肌张力障碍患者基底节功能障碍的典型障碍 在DRD小鼠中，纹状体在调节肌张力障碍和dSPN和iSPN信号转导方面起着中心作用。 此外，DRD小鼠的肌张力障碍的表现在雄性和雌性之间有显著差异， 肌张力障碍随着发情周期的变化而波动。因此，第一次有可能阐明人的神经密码 在肌张力障碍的背景下，驱动性别差异的机制。具体目标是：1.确定 卵巢激素在肌张力障碍表达中的作用。2.鉴定肌张力障碍的分子特征。 雄性和雌性DRD小鼠的dSPN和iSPN。3.确定dspn和ispn活动的基本模式 雄性和雌性DRD小鼠的肌张力障碍。