Cortical Pathophysiology in Mouse Models of Huntington's Disease

亨廷顿病小鼠模型的皮质病理生理学

• 批准号: 9761585
• 负责人: Michael S. Levine
• 金额: $ 50.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761585
• 关键词: Affect; Animal Model; Anterior; Applications Grants; Area; Automobile Driving; Basal Ganglia; Behavioral; Calcium; Cell Communication; Cell Nucleus; Cells; Cerebral cortex; Cognitive deficits; Collaborations; Communication; Complex; Corpus striatum structure; Development; Disease; Disease Progression; Disinhibition; Dorsal; Electrophysiology (science); Emotional Disturbance; Evaluation; Functional disorder; Genes; Genetic; Genetic Diseases; Glutamine; Goals; Grant; Huntington Disease; Huntington gene; Huntington protein; Image; Impaired cognition; In Vitro; Individual; Interneurons; Joints; Laboratories; Lead; Locomotion; Methodology; Modeling; Morphology; Motor; Motor Activity; Motor Cortex; Movement; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Nuclear; Pathway interactions; Patients; Phenotype; Play; Population; Publications; Rest; Role; Sensory; Signal Transduction; Silicon; Slice; Somatosensory Cortex; Symptoms; Synapses; Synaptic Transmission; Techniques; Technology; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Trinucleotide Repeats; Vacuum; Ventroposterior Medial Nucleus of the Thalamus; Vibrissae; awake; calcium indicator; density; design; disease phenotype; experimental study; hippocampal pyramidal neuron; in vivo; in vivo imaging; insight; motor deficit; motor disorder; motor symptom; mouse model; mutant; nervous system disorder; new therapeutic target; novel; optogenetics; patch clamp; reduce symptoms; response; sensory input; sensory integration; somatosensory

Abstract The fatal mutation in Huntington's disease (HD) leads to an expanded glutamine repeat within the huntingtin protein which causes neuronal dysfunction typically followed by selective neurodegeneration especially within the striatum and cortex. These dysfunctions in neurons and circuits occur during the development of the disease phenotype, well before there is significant cell loss. Recent studies in animal models have emphasized that synaptic cell-cell interactions play a role in the pathophysiology of this disease. For example, removing mutant huntingtin from the cerebral cortex ameliorates some HD symptoms. The experiments in this application are designed to understand the functional changes that occur in specific populations of cortical neurons during the progression of the HD phenotype and to uncover new targets and approaches for therapies. However, little is known about functional changes in cortical neurons, although these neurons also degenerate in HD. Before motor symptoms become apparent, sensory, cognitive and emotional disturbances occur and these seem to depend on aberrant communication in the cortex that probably involves thalamocortical pathways. These pathways have never been examined in HD. Our overarching hypothesis is that sensory and motor cortical areas are differentially and asynchronously affected during HD progression. We propose that sensory thalamocortical pathways are downregulated early leading to faulty integration and interpretation of sensory signals. In turn, the motor cortex becomes upregulated and disorganized, leading to altered corticostriatal communication and motor symptoms. In this grant proposal we will use state-of-the-art techniques in three different laboratories at UCLA. Aim 1 uses optogenetics and slice electrophysiology to examine mechanistically altered synaptic communication between thalamic sensory and motor nuclei and their corresponding cortical projection areas. Aim 2 uses high-density silicon microprobes to record firing of hundreds of neurons simultaneously in sensory and motor cortical areas as well as thalamic nuclei in awake mice. Aim 3 uses genetically encoded calcium indicators to visualize neuronal activity in sensory and motor cortical areas in awake mice. Together, the studies will provide new and important mechanistic insights into the understudied cortical dysfunction and will provide the basis for novel and rational treatments for HD by delineating more restricted targets spatially and temporally. These studies also will be relevant for understanding other CAG triplet repeat diseases and neurodegenerative disorders.

抽象的 亨廷顿病 (HD) 的致命突变导致亨廷顿蛋白内谷氨酰胺重复序列扩大 引起神经元功能障碍的蛋白质通常会导致选择性神经变性，尤其是在 纹状体和皮质。这些神经元和电路的功能障碍发生在发育过程中 疾病表型，早在出现显着细胞损失之前就已确定。最近的动物模型研究强调 突触细胞间相互作用在这种疾病的病理生理学中发挥作用。例如，删除 来自大脑皮层的突变亨廷顿蛋白可改善亨廷顿舞蹈症的一些症状。本次实验中 应用程序旨在了解特定皮质群体中发生的功能变化 HD表型进展过程中的神经元，并发现新的靶点和方法 疗法。然而，人们对皮质神经元的功能变化知之甚少，尽管这些神经元也 HD 中退化。在运动症状变得明显之前，感觉、认知和情绪障碍 发生，这些似乎取决于皮质中的异常通信，这可能涉及 丘脑皮质通路。这些通路从未在 HD 中被检查过。我们的总体假设是 感觉和运动皮层区域在 HD 进展过程中受到不同程度的异步影响。 我们认为感觉丘脑皮质通路早期下调导致错误的整合和 感觉信号的解释。反过来，运动皮层变得上调和混乱，导致 改变皮质纹状体通讯和运动症状。在此拨款提案中，我们将使用最先进的技术 加州大学洛杉矶分校三个不同实验室的技术。目标 1 使用光遗传学和切片电生理学 检查丘脑感觉核和运动核之间机械改变的突触通讯及其 相应的皮质投影区域。 Aim 2 使用高密度硅微探针来记录 感觉和运动皮层区域以及清醒状态下的丘脑核中同时有数百个神经元 老鼠。目标 3 使用基因编码的钙指示剂来可视化感觉和运动中的神经元活动 清醒小鼠的皮质区域。总之，这些研究将为这一问题提供新的、重要的机制见解。 皮质功能障碍的研究不足，将为 HD 的新颖合理的治疗提供基础 在空间和时间上描绘更受限制的目标。这些研究也将与 了解其他 CAG 三联体重复疾病和神经退行性疾病。