Mechanisms of Motor Skill Learning in the Fragile X Mouse Model

脆性 X 小鼠模型的运动技能学习机制

• 批准号: 8438418
• 负责人: Anna Dunaevsky
• 金额: $ 29.24万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438418
• 关键词: Affect; Autistic Disorder; Behavioral; Behavioral Paradigm; Brain; Child; Communication; Dendritic Spines; Development; Disease; Dopamine; Dopamine Receptor; FMR1 Gene; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genes; Genetic; Glutamate Receptor; Goals; Image; Impairment; Inherited; Intellectual functioning disability; Intervention; Knockout Mice; Knowledge; Lead; Learning; Long-Term Potentiation; Measures; Mediating; Memory; Mental Retardation; Mission; Modeling; Molecular; Morphology; Motor; Motor Cortex; Motor Skills; Movement; Mus; Mutation; Neurobiology; Neurodevelopmental Disorder; Neurons; Patients; Performance; Photons; Physiological; Receptor Signaling; Regulation; Reporting; Role; Signal Transduction; Slice; Staging; Synapses; Synaptic plasticity; Testing; Therapeutic; Training; United States National Institutes of Health; Vertebral column; Whole-Cell Recordings; Work; autism spectrum disorder; base; experience; improved; in vivo; limb movement; molecular imaging; motor learning; motor skill learning; mouse model; response; skills; synaptic function; therapeutic target; therapy development; trafficking

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited form of an intellectual disability. Children with FXS have been found to have a developmental impairment in the performance of learned skilled limb movements. Motor skill learning is thought to require synaptic plasticity in the primary motor cortex (M1). To better understand how neuronal communication changes with motor learning, it is necessary to determine if learning can induce changes in number, morphology, efficacy, and molecular composition of synapses. FXS results from mutation that causes silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP). Here we will use the fmr1 KO mouse, a murine model for FXS, to study the mechanisms of learning in the primary motor cortex. Our goal is to understand how fmr1 contributes to regulation of synaptic plasticity in the motor cortex and thus elucidate the mechanisms of motor skill learning deficits in the fmr1 KO. We will combine behavioral, electrophysiological, pharmacological, 2-photon imaging and molecular approaches to characterize the changes that occur at synapses in M1 following the learning of a new motor skill in the fmr1 KO mouse. This work is expected to provide important knowledge to develop therapies for FXS and other neurodevelopmental disorders such as autism, a mission of the NIH. !

描述（由申请人提供）：脆性X综合征（FXS）是智力残疾的最常见遗传形式。已发现患有FXS的儿童在学习熟练肢体运动的表现方面存在发育障碍。运动技能学习被认为需要初级运动皮层（M1）中的突触可塑性。为了更好地理解神经元通信如何随着运动学习而改变，有必要确定学习是否可以诱导突触的数量，形态，功效和分子组成的变化。FXS是由编码脆性X智力低下蛋白（FMRP）的FMR1基因沉默突变引起的。在这里，我们将使用fmr1 KO小鼠，FXS的小鼠模型，研究初级运动皮层的学习机制。我们的目标是了解如何fmr1有助于调节运动皮层的突触可塑性，从而阐明在fmr1 KO运动技能学习缺陷的机制。我们将结合联合收割机的行为，电生理，药理学，双光子成像和分子的方法来表征的变化，发生在突触在M1的fmr1基因敲除小鼠学习一种新的运动技能。这项工作有望为开发FXS和其他神经发育障碍（如自闭症）的疗法提供重要知识，这是NIH的一项使命。!