Targeted Circuit Manipulation for Ameliorating Huntington's Disease Pathogenesis

项目摘要/摘要 这个探索性项目是亨廷顿病(HD)研究人员和Brain Tool之间的合作 开发人员将利用新的介入工具改变神经回路动力学，从而将大脑因果联系起来 HD背景下的活动与行为。在发现导致这种情况的基因突变近30年后 对于衰弱的神经退行性疾病，治疗仍然局限于治疗运动性痴呆的晚期症状， 精神和认知缺陷。HD患者和小鼠模型的研究结果指向症状前期 神经回路活动失衡，远在观察到任何明显症状之前。该项目将探索 使用在大脑倡议下开发的工具来调制HD大脑中的特定微电路。我们的中央 假说是，在症状出现之前，通过控制选定的微电路中的放电活动 关键目标人群的化学生成抑制和/或激发将减缓HD疾病的进展。一个至关重要的 HD的早期事件是从皮质到纹状体的整体兴奋性输出病理性增加。潜在的 其机制可能是增强皮质锥体神经元(PNS)的兴奋性和/或减少抑制 皮质小白蛋白中间神经元(PV)是PNS的主要抑制驱动力。激励VS提供优惠 一种与生理相关的方法，因为它恢复了这一关键输入，同时保留了其他调制突触 对PNS的投入(目标1)。第二个也是更直接的修正是减少对PNS本身的解雇 (目标2)。最后，第三种方法将在PN终末将兴奋性突触转化为抑制性突触， 会直接减少疾病前驱期特定纹状体神经元的过度活动 进程(目标3)。我们的主要目标将是确定三个关键入口点中的哪一个提供最多 预防或延缓和减轻R6/2转基因小鼠行为缺陷的有效策略 高清模型。为了操控神经元的活动，该项目将利用生物发光光遗传(BL- Og)平台，使用发光荧光素酶来激活感光视蛋白，包括最近的 开发了一种能够通过表达光来控制突触传递的“间光”方法 突触前和突触后伙伴中的发射器和感受器。为了实现我们的目标，我们正在联合起来 在电路操作工具开发和HD鼠标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更深入的了解。同时，我们的项目将 推动潜在的新治疗目的的翻译进展。除了对HD研究的影响 我们的结果有望对研究其他神经退行性疾病产生重大影响 显示电路不平衡。

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.