Neural basis of locomotor dysfunction in Down Syndrome

唐氏综合症运动功能障碍的神经基础

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要唐氏综合症（DS）是最常见的染色体状况，也是最常见的遗传美国智力残疾的原因。 DS影响儿童的一系列行为领域，包括电动机和认知功能。虽然非典型认知处理在DS中进行了很好的研究，但运动功能障碍相对低估了。临床评估表明DS中的一系列运动缺陷以及较慢自适应控制。纵向数据还表明从儿童期到成年的步态进化发生了改变。小脑在DS中一直观察到病理学，被认为会导致运动和运动功能障碍自适应运动技能。 DS动物模型中的研究也表明小脑加工不足。但是，运动不足和小脑电路的底层特定途径被破坏 DS的理解仍然很差。定义运动行为的特定异常，并识别大脑功能涉及的区域和神经元将为开发潜在疗法的基础治疗DS患者的运动问题。该提案的主要目标是确定特定的更改在小脑的电路中，导致ds的运动功能障碍。我们的初步数据显示 TS65DN中的运动误差，自适应运动学习缺陷和小脑突触改变 DS的鼠标模型。为了量化运动行为，我们使用了Erasmusladder，这是一种高级工具测量运动的协调和自适应小脑学习。我们在产后TS65DN小鼠中的分析表明Purkinje细胞（PC）是小脑皮层的唯一输出从攀爬纤维（CFS）的突触比正常突触。这一发现很重要，因为小脑依赖于学习取决于从CFS到PC树突的强烈单突触兴奋性输入。根据我们的数据，我们假设DS的TS65DN小鼠模型中的运动功能障碍和自适应运动缺陷为由CF输入对PC的破坏引起。为了检验这一假设，在AIM 1中，我们将定义PC电路的变化与TS65DN小鼠中PC的异常突触输入以及运动缺陷有关。我们将分析运动功能障碍并确定小脑回路中的分子变化，以定义潜在的突触小脑皮质的改变。在AIM 2中，我们将建立在自由行为动物的PC活性和运动异常的病理生理变化，以及确定增强对PC的兴奋性输入是否会恢复TS65DN小鼠中的运动功能。我们将使用在我们的实验室中建立的高级技术，该技术采用GCAMP6F纤维光度法，以便时间将小脑中的PC活动锁定到Erasmusladder行为数据。我们将尝试营救异常在TS65DN小鼠中PC活动和运动行为中 TS65DN小鼠的下橄榄（IO； CFS的唯一起源），然后注入氯氮平N-氧化物（CNO）激活IO，从而通过CFS引起PC的持续和增强兴奋性输入。