Targeted Circuit Manipulation for Ameliorating Huntington's Disease Pathogenesis

改善亨廷顿病发病机制的靶向电路操作

• 批准号: 10646867
• 负责人: UTE H HOCHGESCHWENDER
• 金额: $ 21.08万
• 依托单位: CENTRAL MICHIGAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646867
• 关键词: Address; Adenine; Affect; BRAIN initiative; Behavior; Behavioral; Behavioral Research; Brain; Brain Diseases; Cell Survival; Cellular Morphology; Chimeric Proteins; Cognition; Cognitive deficits; Collaborations; Communication; Compensation; Complex; Corpus striatum structure; Cytosine; DNA Sequence Alteration; Development; Disease; Disease Progression; Disease model; Early Intervention; Electrophysiology (science); Event; Excitatory Synapse; Exons; Genes; Genetic; Goals; Guanine; Human; Huntington Disease; Huntington gene; Hyperactivity; Interneurons; Intervention; Ion Channel; Light; Link; Luciferases; Mental Health; Movement; Mus; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Neocortex; Neurodegenerative Disorders; Neurons; Opsin; Output; Parvalbumins; Pathogenesis; Pathologic; Patients; Peripheral; Persons; Phase; Physiological; Population; Process; Regulation; Research; Research Personnel; Symptoms; Synapses; Synaptic Transmission; Target Populations; Testing; Therapeutic; Time; Transgenes; Transgenic Mice; Triplet Multiple Birth; efficacious treatment; hippocampal pyramidal neuron; light emission; luciferin; mouse model; neocortical; neural; neural circuit; neuronal circuitry; neuropathology; novel; novel therapeutics; optogenetics; postsynaptic; postsynaptic neurons; preservation; presynaptic; prevent; sensor; tool; tool development; translational progress

PROJECT SUMMARY/ABSTRACT This exploratory project is a collaboration between Huntington's disease (HD) researchers and BRAIN tool developers and will utilize novel interventional tools for changing neural circuit dynamics to causally link brain activity to behavior in the context of HD. Almost 30 years after identifying the genetic mutation causing this debilitating neurodegenerative disease, treatments remain limited to managing late-stage symptoms of motoric, psychiatric, and cognitive deficits. Findings from patients and mouse models of HD point to pre-symptomatic imbalances in neuronal circuit activity, well before any overt symptoms are observed. This project will explore modulating specific microcircuits in the HD brain using tools developed under the BRAIN initiative. Our central hypothesis is that manipulating the firing activity within selected microcircuits before the onset of symptoms by chemogenetic inhibition and/or excitation of key target populations will slow HD disease progression. A crucial early event in HD is the pathological increase in the overall excitatory output from cortex onto striatum. Underlying mechanisms could be enhanced excitability of cortical pyramidal neurons (PNs) and/or decreased inhibition by cortical parvalbumin interneurons (PVs) that provide the main inhibitory drive onto PNs. Stimulating PVs offers a physiologically relevant approach, as it restores this critical input while preserving other modulating synaptic inputs to the PNs (Aim 1). A second, and more direct, correction is to decrease the firing of the PNs themselves (Aim 2). Finally, a third approach will convert excitatory synapses into inhibitory ones at the PN terminals which would directly reduce the hyperactivity of specific striatal neurons during the prodromal phase of the disease process (Aim 3). Our major goal will be to determine which of the three key entry points provides the most efficacious strategy for preventing or delaying and mitigating the behavioral deficits in the R6/2 transgenic mouse model of HD. For manipulation of neuronal activity this project will utilize the bioluminescent optogenetic (BL- OG) platform that employs light emitting luciferases to activate light sensing opsins, including the recently developed ‘interluminescence’ approach that enables controlling synaptic transmission by expressing the light emitter and sensor in pre- and post-synaptic partners, respectively. To achieve our goals, we are combining expertise in circuit manipulation tool development and HD mouse model behavioral research towards a more refined understanding of the brain mechanisms underlying complex behaviors. At the same time our project will drive translational progress toward potential novel therapeutic purposes. In addition to the impact on HD research our results are expected to have a significant impact on approaching other neurodegenerative diseases that show circuit imbalances.

项目摘要/摘要 这个探索性项目是亨廷顿氏病（HD）研究人员与大脑工具之间的合作 开发人员并将利用新颖的介入工具来改变神经电路动力学以可获得大脑 在高清背景下进行行为的活动。在识别遗传突变后将近30年 使神经退行性疾病衰弱，治疗仍然仅限于管理室内后期症状， 精神病和认知缺陷。来自患者的发现和HD点的小鼠模型到症状前的发现 在观察到任何明显症状之前，神经元电路活性的失衡。这个项目将探索 使用大脑倡议下开发的工具来调节HD脑中的特定微电路。我们的中心 假设是在通过 关键目标种群的化学发生抑制和/或兴奋将减缓HD疾病的进展。关键 HD中的早期事件是从皮质到纹状体的总体兴奋输出的病理增加。潜在的 机制可以增强皮质锥体神经元（PNS）的刺激性和/或通过抑制作用减少 皮质性白蛋白中间神经元（PVS）可为PNS提供主要抑制作用。刺激PVS提供 一种与物理相关的方法，因为它可以恢复此关键输入，同时保留其他调节突触 输入PNS（AIM 1）。一秒钟，更直接的更正是减少PN本身的触发 （目标2）。最后，第三种方法会将兴奋性突触转换为PN终端的抑制性突触 将直接减少疾病前驱期特异性纹状体神经元的多动症 过程（目标3）。我们的主要目标是确定三个关键入口点中的哪个提供了最多 防止或延迟和缓解行为的有效策略在R6/2转基因小鼠中定义 高清模型。为了操纵神经元活动，该项目将利用生物发光光学遗传学（bl- OG）平台，员工照明发射荧光素酶以激活光启动的OPSIN，包括最近的 开发的“发光”方法可以通过表达光线来控制突触传播 前后突触伴侣的发射器和传感器。为了实现我们的目标，我们正在结合 电路操纵工具开发和高清鼠标模型的行为研究的专业知识对更多的行为研究 对复杂行为背后的大脑机制的完善理解。同时我们的项目将 驱动器转化为潜在的新疗法目的。除了对高清研究的影响 我们的结果预计将对处理其他神经退行性疾病产生重大影响 显示电路不平衡。