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.

项目概要/摘要 神经系统和神经精神疾病在全世界范围内日益受到关注，因为其后果 通常是致命的，或者充其量会使患者丧失行为能力。其中一种疾病是肌张力障碍，它 使受影响的人不堪重负，患有严重的运动困难，包括痛苦的肌肉过度收缩， 身体扭曲和四肢颤抖。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，以及深部脑刺激（DBS）作为成人疗法的成功， 儿科患者面临着独特的长期健康问题，许多孩子的治疗选择很差 因为疾病发作的时间尚不清楚。当开发电路是动态的时，就会出现这种障碍。 促进大脑成熟的功能变化为使用深层大脑刺激带来了障碍。 然而，一个首要问题是，我们目前对大脑区域如何运作知之甚少。 介导肌张力障碍的回路在胚胎和产后早期出现。作为第一步 为了更好地定义引发肌张力障碍的发育机制，我们发现 结果是大脑形态发生所需的单个基因 engrailed1 (En1) 有条件丢失 在小鼠严重肌张力障碍中。 En1 及其同源物 engrailed 2 (En2) 是含有同源盒的基因 合作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，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 的操纵 单独留下基底神经节完整，但改变小脑回路模式。基于小脑 En1 条件表型的焦点，我们认为严重的肌张力障碍源于遗传- 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一点 体内假设。在Aim1中，我们将结合体内条件遗传操作 电生理学和定量行为范式揭示 En1 的时间依赖性 确定发育性肌张力障碍的严重程度。在 Aim2 中，我们将执行细胞类型特异性删除 En1，然后对表现良好的幼崽进行体内电生理学，以确定 En1 的神经特征 引发早发性肌张力障碍的 En1 依赖性小脑回路。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错误连接到某个点 无法修复。在 Aim3 中，我们将使用 En1 谱系将光遗传学 DBS 靶向小脑和 基底神经节来测试哪个区域恢复了 En1 突变体的活动性。然后，我们将提供光遗传学 刺激对照小鼠的 En1 谱系，以测试这些区域中的哪些区域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。