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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：
10784385
负责人：
ELLEN J. HESS
金额：
$ 5.95万
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/10784385
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

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不随意的肌肉收缩，引起扭曲的运动和姿势。许多