Cortical Pathophysiology in Mouse Models of Huntington's Disease

摘要 亨廷顿病(HD)的致命突变导致猎人体内谷氨酰胺重复扩大 导致神经元功能障碍的蛋白质，通常伴随着选择性神经变性，尤其是在 纹状体和皮质。这些神经元和回路的功能障碍发生在 疾病表型，早在出现明显的细胞丢失之前。最近对动物模型的研究强调了 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，删除 来自大脑皮层的突变亨廷顿蛋白可以改善一些HD症状。这里面的实验 应用程序旨在了解特定人群大脑皮质中发生的功能变化 在HD表型进展过程中的神经元和发现新的靶点和方法 治疗。然而，对皮质神经元的功能变化知之甚少，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 这些似乎依赖于皮层中的异常通讯，可能涉及到 丘脑皮质通路。这些通路从未在HD中被检查过。我们最重要的假设是 感觉和运动皮质区域在HD进展过程中受到不同和不同步的影响。 我们认为，感觉丘脑皮质通路早期下调导致错误的整合和 对感觉信号的解释。反过来，运动皮质变得上调和无序，导致 皮质纹状体通讯和运动症状改变。在这项拨款提案中，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。目标1利用光遗传学和脑片电生理学 观察丘脑感觉核团和运动核团之间机械改变的突触通讯及其相互作用 相应的皮质投影区。AIM 2使用高密度硅微探头记录发射 清醒时感觉和运动皮质区以及丘脑核团中的数百个神经元同时存在 老鼠。AIM 3使用基因编码的钙指示器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，这些研究将提供新的和重要的机制洞察 并将为HD的新的、合理的治疗提供基础 在空间和时间上描绘更多受限目标。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.