Causal probing of slow oscillations in rodent models of Alzheimer´s disease: combining optogenetics with multimodal opto-acousto-magnetic imaging

阿尔茨海默病啮齿动物模型慢振荡的因果探索：光遗传学与多模态光声磁成像相结合

• 批准号: 322164672
• 负责人: Professor Dr. Albrecht Stroh
• 金额: --
• 依托单位: Munich School of BioEngineering
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/322164672?language=en
• 关键词: Causal; probing; slow; oscillations; rodent

Here, the proposed study aims at causally investigating an oscillatory neuronal population activity highly relevant to maintaining cognitive function: the slow oscillation. Slow oscillations of membrane potential in the frequency range below 1 Hz play a major role in memory consolidation. Just recently, a causal link between the dysregulation of slow oscillations in a rodent model of Alzheimer´s disease (AD) to normal network function and behavior could be demonstrated. However, for a truly causal understanding of the therapeutic and diagnostic potential of (dysregulated) slow oscillations in AD, we need to significantly further the available methodological toolbox, as proposed here in this troika collaborative effort. In our preliminary data, we have for the first time identified slow oscillations in brain-wide rodent neuroimaging data (fMRI) using combined Ca2+ recordings as a template, the critical prerequisite for the proposed study. However, we are far from understanding the complex relation of slow wave initiation and dysregulation with respect to disease progression. Importantly, up to now, the temporal sequence of the recruitment of brain circuits such as cortico-thalamic or cortico-hippocampal are not understood, as are the cell-type specificity of the dysregulation of slow oscillations, mainly due to methodological and conceptual roadblocks. Our proposed study, in a pioneering setting, will overcome these limitations and will for the first time causally explore the relation of slow oscillations, recruitment of brain circuits, and disease progression, using highly innovative and complementary imaging methods: 1) applying fast sequences in fMRI to resolve the propagating slow oscillation with a velocity of about 30 mm/s, 2) Developing novel opto-acoustic methods to complement the fMRI approaches, with the potential of an even faster readout, 3) Combining fMRI and optoacoustic approaches with optic-fiber based optogenetics and neuronal Ca2+ recordings, in a closed-loop optogenetic recovery approach, all in a rodent model of AD. The proposed project is driven by the need to address a fundamental question in translational neuroscience, requiring a causal interrogation of neuronal networks and the unique expertise of the PIs and pioneering methodological pedigree.Our common goal is to causally explore an oscillation key to fundamental processes such as memory consolidation; our findings will have true translational value, potentially leading to both, novel diagnostics and novel therapeutic strategies in neurodegenerative disorders such as AD, based on a novel network-centered view.

在这里，拟议的研究旨在因果调查振荡神经元群体活动高度相关的维持认知功能：缓慢振荡。在低于1 Hz的频率范围内，膜电位的缓慢振荡在记忆巩固中起主要作用。就在最近，可以证明阿尔茨海默病（AD）啮齿动物模型中慢振荡失调与正常网络功能和行为之间的因果关系。然而，为了真正了解AD中（失调）慢振荡的治疗和诊断潜力，我们需要显着进一步的可用方法工具箱，如在此提出的三驾马车的合作努力。在我们的初步数据中，我们第一次确定了大脑全啮齿动物神经成像数据（fMRI）中的缓慢振荡，使用组合的Ca 2+记录作为模板，这是拟议研究的关键先决条件。然而，我们还远未了解慢波启动和失调与疾病进展的复杂关系。重要的是，到目前为止，招募的大脑回路，如皮质-丘脑或皮质-海马的时间顺序不了解，是慢振荡失调的细胞类型特异性，主要是由于方法和概念的障碍。我们提出的研究，在一个开创性的设置，将克服这些限制，并将第一次因果地探索慢振荡，招募脑回路和疾病进展的关系，使用高度创新和互补的成像方法：1）在fMRI中应用快速序列以分辨速度约为30 mm/s的传播慢振荡，2）开发新的光声方法来补充fMRI方法，具有更快读出的潜力，3）将fMRI和光声方法与基于光纤的光遗传学和神经元Ca 2+记录结合，在闭环光遗传学恢复方法中，全部在AD的啮齿动物模型中。该项目的提出是为了解决转化神经科学中的一个基本问题，需要对神经元网络进行因果询问，需要PI的独特专业知识和开创性的方法学谱系。我们的共同目标是因果地探索基本过程（如记忆巩固）的关键振荡;我们的发现将具有真正的转化价值，基于新的以网络为中心的观点，可能导致神经退行性疾病如AD的新诊断和新治疗策略。