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.

项目总结/摘要 这个探索性项目是亨廷顿病（HD）研究人员和BRAIN工具之间的合作 开发人员，并将利用新的干预工具，改变神经回路动力学， 在HD的背景下活动到行为。在发现导致这种情况的基因突变近30年后， 使人衰弱的神经变性疾病，治疗仍然局限于控制运动性， 精神和认知缺陷HD患者和小鼠模型的结果表明， 在观察到任何明显症状之前，神经元回路活动的不平衡。该项目将探索 使用在BRAIN倡议下开发的工具来调节HD大脑中的特定微电路。我们的中央 一种假设是，在症状发作之前，通过以下方式操纵选定微电路内的放电活动， 化学发生抑制和/或关键靶群体的激发将减缓HD疾病的进展。一个关键 HD的早期事件是从皮质到纹状体的总体兴奋性输出的病理性增加。底层 机制可能是皮质锥体神经元（PN）的兴奋性增强和/或抑制减少， 皮质小清蛋白中间神经元（PV），其提供对PN的主要抑制驱动。刺激PV提供 这是一种与生理学相关的方法，因为它恢复了这种关键的输入，同时保留了其他调节突触的功能。 输入到PN（目标1）。第二个更直接的修正是减少PN本身的发射 (Aim 2）的情况。最后，第三种方法将在PN末端将兴奋性突触转化为抑制性突触， 将直接减少疾病前驱期特定纹状体神经元的过度活跃 过程（目标3）。我们的主要目标将是确定三个关键切入点中的哪一个提供最多 预防、延缓和减轻R6/2转基因小鼠行为缺陷的有效策略 HD型号为了操纵神经元活动，该项目将利用生物发光光遗传学（BL- OG）平台，其采用发光酶来激活光感测视蛋白，包括最近的 开发了一种“间发光”方法，通过表达光来控制突触传递 发射器和传感器在前和突触后的合作伙伴，分别。为了实现我们的目标， 在电路操作工具开发和HD小鼠模型行为研究方面的专业知识， 对复杂行为背后的大脑机制有了更深入的理解。同时，我们的项目将 推动转化进展，实现潜在的新治疗目的。除了对HD研究的影响外， 我们的结果有望对治疗其他神经退行性疾病产生重大影响， 显示电路不平衡。