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.

项目概要唐氏综合症 (DS) 是最常诊断的染色体疾病，也是最常见的遗传性疾病美国智力障碍的原因。 DS 影响儿童的一系列行为领域，包括运动和认知功能。虽然 DS 中的非典型认知处理已得到充分研究，但运动功能障碍相对而言，研究较少。临床评估表明 DS 存在一系列运动缺陷，并且速度较慢自适应控制。纵向数据还表明从童年到成年的步态进化发生了变化。小脑在 DS 中一直观察到病理学变化，并被认为是导致运动和运动功能障碍的原因之一。适应性运动技能。 DS 动物模型研究也表明小脑处理缺陷。然而，运动缺陷和小脑回路的具体通路在 DS 仍然知之甚少。定义运动行为的特定异常并识别大脑功能相关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。该提案的主要目标是确定具体变更导致 DS 运动功能障碍的小脑回路。我们的初步数据显示运动失调、适应性运动学习缺陷和 Ts65Dn 中的小脑突触改变 DS小鼠模型。为了量化运动行为，我们使用了 ErasmusLadder，这是一种能够测量运动协调和适应性小脑学习。我们对出生后 Ts65Dn 小鼠的分析表明浦肯野细胞（PC）是小脑皮质的唯一输出，接收到的兴奋性较少来自攀爬纤维（CF）的突触比正常情况要多。这一发现很重要，因为小脑依赖性学习依赖于从 CF 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适应性运动缺陷是由 PC 的 CF 输入中断引起。为了检验这个假设，在目标 1 中，我们将定义 PC 电路的变化与 Ts65Dn 小鼠的 PC 突触输入异常和运动学习缺陷有关。我们将分析运动功能障碍并识别小脑回路的分子变化以定义潜在的突触小脑皮质的改变。在目标 2 中，我们将建立之间的精确关联自由行为动物中 PC 活性和运动异常的病理生理变化，以及确定增强 PC 的兴奋性输入是否会恢复 Ts65Dn 小鼠的运动功能。我们将使用我们实验室建立的先进技术，该技术采用 GCaMP6f 光纤光度测定法来计时将小脑中的 PC 活动锁定到 ErasmusLadder 行为数据。我们将尝试挽救异常情况通过在 Ts65Dn 小鼠中特异性表达兴奋性 DREADDs 来影响 PC 活动和运动行为 Ts65Dn 小鼠的下橄榄（IO；CF 的唯一来源），然后选择性注射氯氮平 N-氧化物（CNO）激活 IO，通过 CF 对 PC 产生持续和增强的兴奋性输入。