Cortical Pathophysiology in Mouse Models of Huntington's Disease

摘要 亨廷顿病（HD）中的致命突变导致亨廷顿蛋白内谷氨酰胺重复序列扩增 一种蛋白质，引起神经元功能障碍，通常随后是选择性神经变性，特别是在 纹状体和皮质这些神经元和回路的功能障碍发生在发育过程中， 疾病表型，以及之前有显着的细胞损失。最近的动物模型研究强调， 突触细胞间的相互作用在这种疾病的病理生理学中起作用。例如移除 来自大脑皮层的突变亨廷顿蛋白改善了某些HD症状。其中的实验 应用程序的目的是了解发生在特定人群的皮质功能的变化， 在HD表型的进展过程中的神经元，并发现新的目标和方法， 治疗然而，对皮层神经元的功能变化知之甚少，尽管这些神经元也 在HD中退化。在运动症状变得明显之前， 发生，这些似乎取决于异常的沟通，在皮层，可能涉及 丘脑皮质通路这些途径从未在HD中进行过检查。我们的首要假设是 感觉和运动皮质区在HD进展过程中受到不同和异步的影响。 我们认为，感觉丘脑皮层通路在早期下调，导致错误的整合， 解读感官信号反过来，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。在这个拨款申请中，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。AIM1使用光遗传学和切片电生理学， 研究丘脑感觉和运动核团之间的突触通讯机制的改变， 对应的皮质投射区。Aim 2使用高密度硅微探针记录 在清醒状态下，感觉和运动皮质区以及丘脑核团中同时存在数百个神经元， 小鼠AIM3使用遗传编码的钙指标来可视化感觉和运动神经元的活动 清醒小鼠的皮质区。总之，这些研究将提供新的和重要的机械见解， 未充分研究皮质功能障碍，并将为HD的新型合理治疗提供基础， 在空间和时间上描绘出更多受限的目标。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。

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.