Neuronal Mechanisms underlying sex differences in dystonia

肌张力障碍性别差异背后的神经机制

基本信息

批准号：
10518475
负责人：
ELLEN J. HESS
金额：
$ 50.78万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10518475
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 Libido 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 Signal Transduction 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 neuroregulation prototype relating to nervous system sex sex cycle sexual dimorphism therapy design translatome

项目摘要

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，导致扭转运动和姿势。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尚未探索。基底神经节功能障碍始终与多种形式的肌张力障碍有关。这基底神经节的主要输入结构是纹状体，雌激素在纹状体中发挥神经调节作用。实际上，已知纹状体棘投射神经元 (SPN) 的生理特性会根据生物学特性而变化性和动情周期阶段。直接通路 SPN (dSPN) 投射到内部苍白球以促进移动。间接通路 SPN (iSPN) 投射到外部苍白球以抑制运动。虽然 dSPN 和 iSPN 被分成不同的通路，它们协同作用来调节和完善运动。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使用而被破坏。记录表明 dSPN 和 iSPN 均出现功能障碍。然而，两者背后的机制 SPN 病理生理学和肌张力障碍的性别差异仍然未知。一些挑战阻碍了我们理解病理生理学及其与生物学关系的能力肌张力障碍中的性行为。首先，通过研究患者获得的信息必然是相当有限的。其次，尽管流行病学研究表明肌张力障碍的表达存在性别差异，性别作为一种生物因素变量很少被纳入研究患者或动物肌张力障碍的潜在机制的研究中模型。第三，我们缺乏健康控制方面的基础研究，无法阐明生物性别对健康的影响。纹状体细胞类型。事实上，描述正常纹状体生理学性别差异的研究尚未发现区分 SPN 亚型，同时研究检查 dSPN 和 iSPN 的分子特性尚未将性别作为生物学变量进行研究。该提案解决了这些知识差距。我们对肌张力障碍病理生理学的理解也因缺乏动物模型而受到阻碍纹状体功能障碍引起的性二形性肌张力障碍。为了解决这个差距，我们创建了一个敲击多巴反应性肌张力障碍（DRD）小鼠模型。与许多形式的 DRD 患者一样，DRD 患者以女性为主人类肌张力障碍。 DRD 也是了解肌张力障碍中基底神经节功能障碍的原型疾病 DRD 小鼠的纹状体在介导肌张力障碍中发挥核心作用，dSPN 和 iSPN 信号传导被破坏。此外，DRD 小鼠的肌张力障碍表现在雄性和雌性之间存在显着差异，并且肌张力障碍随发情周期而波动。因此，第一次有可能阐明驱动性别差异的机制背景下的肌张力障碍。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. 定义底层 dSPN 和 iSPN 活动的模式雄性和雌性 DRD 小鼠的肌张力障碍。