Spatial and temporal pathophysiology of developmental dystonia

发育性肌张力障碍的时空病理生理学

• 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
• 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' 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

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.

项目总结/摘要 神经系统和神经精神疾病是全世界日益关注的问题， 通常是致命的，或者最多让病人丧失能力。其中一种疾病是肌张力障碍， 痉挛症影响严重运动障碍的人，包括疼痛的肌肉过度收缩， 身体的扭曲和四肢的颤抖尽管最近在识别大脑回路方面做出了努力， 有助于肌张力障碍，以及脑深部电刺激（DBS）作为成人治疗的成功， 儿科患者面临着独特的长期健康问题，许多儿童的治疗选择很差 因为疾病发作的时间尚不清楚。当发展中的电路是动态的时，这种障碍就会出现; 促进大脑成熟的功能变化为使用脑深部电刺激创造了障碍。 然而，一个首要的问题是，我们目前对大脑区域如何 并且介导肌张力障碍的回路在胚胎期和出生后早期出现。作为第一步 为了更好地定义引起肌张力障碍的发育机制，我们发现， 一个单一的基因，enrailed 1（En 1），这是必要的脑形态发生的条件性损失，结果 严重肌张力障碍。En 1及其同源物enrailed 2（En 2）是含有同源框的基因 共同控制中脑和后脑的发育基底神经节，部分是 位于中脑和小脑，这是完全位于后脑，是两个 被认为是驱动肌张力障碍病理生理学的主要结构。有趣的是，操纵En 1 单独使用时，基底神经节完好无损，但改变了小脑回路模式。根据小脑 En 1条件性表型的焦点，我们认为，严重的肌张力障碍起源于遗传- 破坏小脑回路成熟的明确缺陷。我们生成了三个具体目标来测试这个 体内假说在Aim 1中，我们将使用条件遗传操作结合体内 电生理学和定量行为范例，以揭示En 1的时间依赖性 来确定发育性肌张力障碍的严重程度。在Aim 2中，我们将执行细胞类型特异性删除 然后在行为幼崽中进行体内电生理学，以确定 触发早发性肌张力障碍的En 1依赖性小脑回路。虽然小脑和 基底神经节存在于En 1突变体中，目前还不清楚它们的电路是否错误连接到一个点， 无法修复在Aim 3中，我们将使用En 1谱系将光遗传学DBS靶向小脑， 基底神经节，以测试哪一个区域恢复了En 1突变体的活动性。然后，我们会将光遗传学 刺激对照小鼠中的En 1谱系，以测试这些区域中的哪一个可以引发肌张力障碍。 其他方面正常的年轻和成年小鼠。为无法治愈的运动设计更好的治疗方案 疾病将改善医疗保健考虑并提高儿科患者的生活质量。