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

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

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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非自愿肌肉收缩引起扭曲运动和姿势。许多在女性中，肌张力障碍比男性更常见，但这些性别差异的机制是在很大程度上没有探索。基底神经节功能障碍始终涉及许多形式的肌张力障碍。这基底神经节的主要输入结构是雌激素发挥神经调节作用的纹状体。实际上，已知纹状体棘投射神经元（SPN）的生理特性因生物学而异性别和发情循环阶段。直接途径SPNS（DSPN）向内部Globus Pallidus项目促进移动。间接途径SPNS（ISPN）向外部球形pallidus投影以抑制运动。虽然 DSPN和ISPN被隔离为单独的途径，它们共同作用以调解和完善运动。在肌张力障碍患者中，这种协调的活性被破坏为功能成像研究和微电极记录表明DSPN和ISPN都是功能失调。但是，两者的基础机制 SPN病理生理学和肌张力障碍性差异仍然未知。几个挑战阻碍了我们理解病理生理学的能力以及与生物学的关系肌张力障碍性。首先，通过研究患者获得的信息必然是非常有限的。第二，尽管流行病学研究表明肌张力障碍表达的性别差异，性别为生物学变量很少被纳入研究患者或动物中肌张力障碍基础机制的研究型号。第三，我们缺乏在健康对照中的基础研究，这些研究无法解散生物性别对纹状体细胞类型。实际上，表征正常纹状体生理中性别差异的研究尚未区分SPN亚型，同时研究了DSPN和ISPN的分子特性的研究尚未将性视为生物变量。该建议在知识中解决了这些差距。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与纹状体功能障碍引起的性二态肌张力障碍。为了解决这个差距，我们创建了一个敲门 DOPA反应性肌张力障碍（DRD）的小鼠模型。在患者中，drd是女性的，就像多种形式人类的肌张力障碍。 DRD也是一种原型障碍，用于理解肌张力障碍基底神经节功能障碍 DRD小鼠，纹状体在介导肌张力障碍和DSPN和ISPN信号传导中起着核心作用。此外，男性和女性和女性之间的drd小鼠中肌张力障碍的表现显着差异肌张力障碍随发情周期波动。因此，首次有可能阐明在驱动性别差异的机制的背景下，肌张力障碍。具体目的是：1。确定卵巢激素在肌张力障碍表达中的作用。 2。确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DSPN和ISPN活动的模式雄性和雌性DRD小鼠中的肌张力障碍。