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: 9543575
• 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/9543575
• 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 亨廷顿氏病（HD）的致命突变导致亨廷顿蛋白中的谷氨酰胺重复膨胀 引起神经元功能障碍的蛋白质通常是选择性神经退行性的，尤其是在 纹状体和皮质。神经元和电路中的这些功能障碍发生在开发过程中 疾病表型，在明显的细胞丧失之前。动物模型的最新研究强调了 这种突触细胞 - 细胞相互作用在该疾病的病理生理中起作用。例如，删除 来自大脑皮质的突变亨廷汀可以改善一些高清症状。其中的实验 应用旨在了解皮质特定种群中发生的功能变化 HD表型进展过程中的神经元，并发现新的目标和方法 疗法。然而，尽管这些神经元也 在高清中退化。在运动症状变得明显之前，感觉，认知和情绪障碍 发生了，这些似乎取决于皮质中的异常沟通可能涉及 丘脑皮层途径。这些途径从未在HD中检查。我们的总体假设是 在HD进展过程中，该感觉和运动皮质区域差异和异步影响。 我们建议感觉丘脑皮层途径早期下调，导致整合错误和 感觉信号的解释。反过来，运动皮层变得上调和混乱，导致 皮质纹状体通信和运动症状的改变。在此赠款建议中，我们将使用最先进的 加州大学洛杉矶分校的三个不同实验室的技术。 AIM 1使用光遗传学和切片电生理学 检查丘脑感觉与运动核之间的机械改变的突触通信及其 相应的皮质投影区域。 AIM 2使用高密度的硅微探针记录发射 在感觉和运动皮质区域以及丘脑核中同时存在数百个神经元 老鼠。 AIM 3使用遗传编码的钙指标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。研究将共同​​提供对有关的新的重要机械见解 研究皮质功能障碍，将为HD的新颖和合理处理提供基础 在空间和时间上描述更多受限制的目标。这些研究也将与 了解其他CAG三胞胎重复疾病和神经退行性疾病。