Spatial and temporal pathophysiology of developmental dystonia

发育性肌张力障碍的时空病理生理学

基本信息

批准号：
10605284
负责人：
Roy Vincent Sillitoe
金额：
$ 40.13万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2022-04-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605284
关键词：
Address Adult Affect Age Animal Model Animals Antipsychotic Agents Area Basal Ganglia Behavior Behavioral Paradigm Birth Blepharospasm Brain Brain Stem Brain region Calcium Channel Cells Cerebellar Cortex Cerebellum Characteristics Child Cues Data Deep Brain Stimulation Defect Dependence Development Disease Dystonia Dystonia Musculorum Deformans Early Onset Dystonia Electrophysiology (science)Embryo Eyelid structure Face Functional disorder Genes Genetic Genetically Engineered Mouse Glutamates Health Healthcare Homeobox Homologous Gene Inherited Injections Kainic Acid Knockout Mice Knowledge Life Limb structure Mediating Midbrain structure Modeling Molecular Molecular Genetics Molecular Probes Morphogenesis Morphology Motor Mus Muscle Muscle Contraction Mutant Strains Mice Mutation Names Nature Neurons Neurotransmitters Onset of illness Ouabain Output P-Q type voltage-dependent calcium channel Pain Parkinson Disease Pathogenesis Pathology Pathway interactions Patients Pattern Persons Pharmaceutical Preparations Phenotype Posture Predisposition Purkinje Cells Quality of life Rattus Regulation Role Severities Structure Symptoms Testing Thalamic structure Therapeutic Tremor Writer&apos s cramp neurosis cell type cholinergic comorbidity conditional mutant design gene function genetic manipulation granule cell hindbrain improved in vivo insight knock-down motor behavior motor disorder mouse model mutant nervous system disorder neural neuropsychiatric disorder new therapeutic target optogenetics pediatric patients postnatal pup repaired small hairpin RNA success therapeutic target virtual

Address Adult Affect Age Animal Model Animals Antipsychotic Agents Area Basal Ganglia Behavior Behavioral Paradigm Birth Blepharospasm Brain Brain Stem Brain region Calcium Channel Cells Cerebellar Cortex Cerebellum Characteristics Child Cues Data Deep Brain Stimulation Defect Dependence Development Disease Dystonia Dystonia Musculorum Deformans Early Onset Dystonia Electrophysiology (science)Embryo Eyelid structure Face Functional disorder Genes Genetic Genetically Engineered Mouse Glutamates Health Healthcare Homeobox Homologous Gene Inherited Injections Kainic Acid Knockout Mice Knowledge Life Limb structure Mediating Midbrain structure Modeling Molecular Molecular Genetics Molecular Probes Morphogenesis Morphology Motor Mus Muscle Muscle Contraction Mutant Strains Mice Mutation Names Nature Neurons Neurotransmitters Onset of illness Ouabain Output P-Q type voltage-dependent calcium channel Pain Parkinson Disease Pathogenesis Pathology Pathway interactions Patients Pattern Persons Pharmaceutical Preparations Phenotype Posture Predisposition Purkinje Cells Quality of life Rattus Regulation Role Severities Structure Symptoms Testing Thalamic structure Therapeutic Tremor Writer&apos s cramp neurosis cell type cholinergic comorbidity conditional mutant design gene function genetic manipulation granule cell hindbrain improved in vivo insight knock-down motor behavior motor disorder mouse model mutant nervous system disorder neural neuropsychiatric disorder new therapeutic target optogenetics pediatric patients postnatal pup repaired small hairpin RNA success therapeutic target virtual

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项目摘要

PROJECT SUMMARY/ABSTRACT Neurological and neuropsychiatric diseases are a growing concern worldwide, as the consequences are often lethal, or at best they leave patients incapacitated. One such disease is dystonia, which overwhelms affected people with severe motor difficulties including painful muscle over-contractions, twisting of the body and tremor in the limbs. Despite recent efforts in identifying the brain circuits that contribute to dystonia, as well as the success of deep brain stimulation (DBS) as a therapy for adults, pediatric patients face unique long-term health concerns, with poor treatment options for many kids since the timing of disease onset is unclear. Such barriers arise as developing circuits are dynamic; and functional changes that promote brain maturation create hurdles for using deep brain stimulation. An overarching problem, however, is that we currently have little insight into how the brain regions and circuits that mediate dystonia emerge during embryonic and early postnatal life. As a first step towards better defining the developmental mechanisms that instigate dystonia, we have found that conditional loss of a single gene, engrailed1 (En1), which is required for brain morphogenesis, results in severe dystonia in mice. En1 and its homolog engrailed 2 (En2) are homeobox-containing genes that cooperate to control midbrain and hindbrain development. The basal ganglia, which are partly located in the midbrain, and the cerebellum, which is entirely located within the hindbrain, are the two main structures that are thought to drive dystonia pathophysiology. Intriguingly, manipulations of En1 alone leave the basal ganglia intact, but alter cerebellar circuit patterning. Based on the cerebellar focus of the En1 conditional phenotype, we argue that severe dystonia originates from genetically- defined defects that disrupt cerebellar circuit maturation. We generated three specific aims to test this hypothesis in vivo. In Aim1, we will use conditional genetic manipulations in combination with in vivo electrophysiology and quantitative behavioral paradigms to uncover the temporal dependence of En1 in setting the severity of developmental dystonia. In Aim2, we will perform cell-type specific deletions of En1 and then conduct in vivo electrophysiology in behaving pups to define the neural signatures of the En1-dependent cerebellar circuits that trigger early-onset dystonia. Although the cerebellum and basal ganglia are present in En1 mutants, it is unclear if their circuits are mis-wired to a point that is beyond repair. In Aim3, we will use the En1 lineage to target optogenetic DBS to the cerebellum and basal ganglia to test which region restores mobility in En1 mutants. Then, we will deliver optogenetic stimulation to the En1 lineage in control mice to test which of these regions can initiate dystonia in otherwise normal young and adult mice. Designing better treatment options for incurable motor diseases will improve healthcare considerations and enhance the quality of life for pediatric patients.

项目摘要/摘要神经系统和神经精神疾病在全球范围内越来越关注，因为后果通常是致命的，或者充其量会使患者无能为力。一种这样的疾病是肌张力障碍，它不知所措影响了严重运动困难的人，包括疼痛的肌肉过度收缩，身体和四肢震颤的扭曲。尽管最近努力确定大脑电路有助于肌张力障碍以及深度脑刺激（DBS）作为成人治疗的成功，小儿患者面临独特的长期健康问题，许多孩子的治疗选择差由于疾病发作的时间尚不清楚。出现这样的障碍，例如开发电路是动态的。促进大脑成熟的功能变化为使用深脑刺激造成了障碍。但是，一个总体问题是，我们目前对大脑区域的方式几乎没有深入的了解以及介导肌张力障碍症的电路在胚胎和产后早期生活期间出现。作为第一步为了更好地定义激发肌张力障碍的发展机制，我们发现单个基因的有条件丧失，构成1（en1），这是脑形态发生所必需的，结果在小鼠的严重肌张力障碍中。 EN1及其同源物插入2（EN2）是含同源的基因合作控制中脑和后脑的发展。基底神经节，部分是位于中脑，小脑完全位于后脑内，是两个被认为驱动肌张力障碍病理生理学的主要结构。有趣的是，EN1的操作单独使基底神经节完好无损，但会改变小脑电路的图案。基于小脑 EN1有条件表型的重点，我们认为严重的肌张力障碍起源于遗传学定义的缺陷破坏小脑电路成熟。我们产生了三个特定的目标来测试这一点体内假设。在AIM1中，我们将使用条件遗传操作与体内结合电生理学和定量行为范例，以发现EN1的时间依赖性在设定发育障碍的严重性时。在AIM2中，我们将执行细胞类型的特定缺失 eN1，然后在行为幼崽中进行体内电生理学来定义 EN1依赖性小脑回路引发早发性肌张力障碍。虽然小脑和基底神经节存在于EN1突变体中，目前尚不清楚它们的电路是否被误导至无法维修。在AIM3中，我们将使用EN1谱系将光遗传学DB靶向小脑和基底神经节测试哪个区域可恢复EN1突变体中的迁移率。然后，我们将提供光学遗传刺激对照小鼠中的EN1谱系，以测试哪些区域可以启动肌张力障碍否则正常的年轻和成年小鼠。设计无法治愈的电机的更好的治疗选择疾病将改善医疗保健考虑因素并提高儿科患者的生活质量。