Neural basis of locomotor dysfunction in Down Syndrome

唐氏综合症运动功能障碍的神经基础

• 批准号: 10091905
• 负责人: Vittorio Gallo
• 金额: $ 49.09万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091905
• 关键词: Adolescent; Adult; Affect; Age; Anatomy; Animal Model; Animals; Behavior; Behavioral; Behavioral Mechanisms; Behavioral Paradigm; Brain; Brain region; Cerebellar Cortex; Cerebellum; Child; Childhood; Clinical assessments; Clozapine; Cognitive; Confocal Microscopy; Data; Dendrites; Designer Drugs; Development; Diagnosis; Doctor of Philosophy; Down Syndrome; Evolution; Excitatory Synapse; Fiber; Fiber Optics; Fluorescence; Functional disorder; Gait; Genetic; Goals; Immunohistochemistry; Individual; Inferior; Injections; Intellectual functioning disability; Learning; Light; Link; Maps; Measures; Microscopy; Modeling; Molecular; Motor; Motor Skills; Movement; Musculoskeletal Equilibrium; Neocortex; Neural Pathways; Neurodevelopmental Disorder; Neurologic Deficit; Neurons; Olives - dietary; Output; Oxides; Pathology; Pathway interactions; Photometry; Physiological; Purkinje Cells; Reporting; Synapses; Synaptic Potentials; System; Techniques; Testing; Therapeutic Agents; Three-dimensional analysis; Time; Work; base; clinical diagnostics; clinical translation; clinically relevant; cognitive function; designer receptors exclusively activated by designer drugs; in vivo; intervention effect; locomotor deficit; motor behavior; motor deficit; motor learning; mouse Ts65Dn; mouse model; neonatal brain; postnatal; pre-clinical; relating to nervous system; response; synaptogenesis; tool; young adult

PROJECT SUMMARY Down syndrome (DS) is the most commonly diagnosed chromosomal condition and the most common genetic cause of intellectual disability in the US. DS affects a range of behavioral domains in children, including motor and cognitive function. While atypical cognitive processing has been well studied in DS, locomotor dysfunction is relatively understudied. Clinical assessments indicate a range of locomotor deficits in DS, as well as slower adaptive control. Longitudinal data also indicates altered gait evolution from childhood to adulthood. Cerebellar pathology has been consistently observed in DS, and is thought to contribute to dysfunction in locomotor and adaptive motor skills. Studies in animal models of DS have also indicated deficient cerebellar processing. However, the specific pathways underlying locomotor deficits and the cerebellar circuits that are disrupted in DS remain poorly understood. Defining specific abnormalities in motor behavior, and identifying the brain regions and neurons which are functionally involved will provide the basis for developing potential therapies for treating motor problems in individuals with DS. The main goal of this proposal is to identify specific alterations in the circuitry of the cerebellum that result in locomotor dysfunction in DS. Our preliminary data show locomotor miscoordination, adaptive motor learning deficits, and cerebellar synaptic alterations in the Ts65Dn mouse model of DS. To quantify locomotor behavior, we used the ErasmusLadder, an advanced tool capable of measuring locomotor coordination and adaptive cerebellar learning. Our analysis in postnatal Ts65Dn mice shows that Purkinje cells (PCs), which are the sole output of the cerebellar cortex, receive fewer excitatory synapses from climbing fibers (CFs) than normal. This finding is significant, as cerebellar-dependent learning depends on strong monosynaptic excitatory input from CFs onto PC dendrites. Based on our data, we hypothesize that locomotor dysfunction and adaptive motor deficits in the Ts65Dn mouse model of DS are caused by disruption of CF input to PCs. To test this hypothesis, in Aim 1 we will define changes in PC circuitry that are linked to abnormal synaptic input to PCs and to locomotor learning deficits in Ts65Dn mice. We will analyze locomotor dysfunction and identify molecular changes in cerebellar circuitry to define potential synaptic alterations in the cerebellar cortex. In Aim 2, we will establish the precise correlation between pathophysiological changes in PC activity and locomotor abnormalities in freely-behaving animals, and determine whether enhancing excitatory input to PCs will restore locomotor function in Ts65Dn mice. We will use an advanced technique established in our lab that employs GCaMP6f fiber photometry in order to time- lock PC activity in the cerebellum to ErasmusLadder behavioral data. We will attempt at rescuing abnormalities in PC activity and locomotor behavior in Ts65Dn mice by specifically expressing excitatory DREADDs in the inferior olive (IO; the sole origin of CFs) of Ts65Dn mice and then inject clozapine N-oxide (CNO) to selectively activate the IO, causing sustained and enhanced excitatory input to PCs via CFs.

项目摘要 唐氏综合征（DS）是最常见的染色体疾病，也是最常见的遗传病。 美国的智力残疾。DS影响儿童的一系列行为领域，包括运动 和认知功能。虽然非典型认知处理已经在DS中得到了很好的研究， 相对来说研究不足。临床评估表明，DS存在一系列运动缺陷， 自适应控制纵向数据也表明从儿童到成年步态演变的改变。小脑 在DS中一直观察到病理学，并认为其导致运动功能障碍， 适应性运动技能在DS动物模型中的研究也表明小脑处理缺陷。 然而，运动缺陷和小脑回路被破坏的具体途径， DS仍然知之甚少。定义运动行为中的特定异常，并识别大脑 功能上涉及的区域和神经元将为开发潜在的治疗方法提供基础， 治疗DS患者的运动问题。本提案的主要目标是确定具体的改动 导致DS患者运动功能障碍的小脑回路。我们的初步数据显示 Ts 65 Dn的运动失调、适应性运动学习缺陷和小脑突触改变 DS小鼠模型为了量化运动行为，我们使用了ErasmusLadder，一种先进的工具， 测量运动协调性和小脑适应性学习能力。我们在出生后Ts 65 Dn小鼠中的分析 显示浦肯野细胞（PC），这是小脑皮层的唯一输出，接受较少的兴奋性 从攀爬纤维（CF）的突触比正常。这一发现意义重大，因为小脑依赖性学习 依赖于从CF到PC树突的强单突触兴奋性输入。根据我们的数据， 假设DS Ts 65 Dn小鼠模型中运动功能障碍和适应性运动缺陷是 由于CF输入到PC的中断而导致。为了验证这一假设，在目标1中，我们将定义PC电路的变化 与异常突触输入到PC和Ts 65 Dn小鼠的运动学习缺陷有关。我们将 分析运动功能障碍，并确定小脑回路中的分子变化，以确定潜在的突触 小脑皮质的改变在目标2中，我们将建立以下各项之间的精确关联： PC活动的病理生理学变化和自由行为动物的运动异常，以及 确定增强对PC的兴奋性输入是否会恢复Ts 65 Dn小鼠的运动功能。我们将 使用我们实验室建立的先进技术，采用GCaMP 6 f纤维光度法，以时间- 将小脑中的PC活动锁定到ErasmusLadder行为数据。我们将尝试拯救异常 在Ts 65 Dn小鼠的PC活动和运动行为中通过特异性表达兴奋性DREADD来调节 下橄榄（IO; CFs的唯一来源），然后注射氯氮平N-氧化物（CNO）以选择性地 激活IO，通过CF引起对PC的持续和增强的兴奋性输入。