Direct Visualization of Cell-Type Specific AD Networks for Drug Development

描述(申请人提供)：治疗阿尔茨海默病(AD)以及许多其他神经疾病的药物开发中的一个重要挑战是对该化合物未来临床疗效和副作用的临床前准确预测。神经系统的复杂性使得使用替代体外信息、体外数据或简单的动物行为模型来推断候选化合物的影响变得极其困难。我们的建议旨在通过利用光遗传功能磁共振成像(OfMRI)技术从根本上改变这一过程，方法是利用光遗传功能磁共振成像(OfMRI)技术，在体内全面量化药物给药随时间的纵向影响。OfMRI是一项结合了特定细胞类型、时间精确的光遗传控制和fMRI读数的新技术。PI发表的第一项概念验证研究展示了MRI技术能够准确可视化由其遗传身份、细胞体位置和轴突投射目标指定的细胞类型产生的全脑神经活动。随着ofMRI技术的进一步发展，以实现高通量、高空间分辨率和清醒扫描，PI的实验室拥有初步数据，表明有能力表征特定与基底前脑胆碱能神经元相关的整个大脑网络反应。具有特定时间模式的选择性刺激基底前脑胆碱能神经元可以引起广泛的神经活动，包括海马体和新皮质。这种具有纵向跟踪体内能力的网络活动的直接功能可视化可以用于表征疾病进展，积极识别新的靶点电路，还可以监测不同剂量和疗程如何随着时间的推移影响每一只动物的疾病进展。这与传统的体外技术不同，传统的体外技术依赖于在不同的时间点牺牲大量动物，这增加了方差、成本和时间，而只获得被动的、替代的功能标记或难以重现行为测试。在这项提议中，我们将量化正常和突变APP小鼠的网络功能，以量化与基底前脑胆碱能神经元相关的网络功能变化。通过这些量化，我们的目标是建立这种方法作为定量药物设计和评估的新平台。通过观察与AD相关的关键神经电路元件的网络参与，我们将确定AD的电路机制，并测试已显示出良好电生理、行为和解剖学效果的候选药物。我们的目的是展示基于MRI的疗效观察。预防和/或逆转AD相关的回路损害可能是完全或部分有效的，我们将能够在疾病进展和药物治疗期间直接观察与特定神经元群体相关的变化在活体动物脑中的位置。静息状态的功能磁共振研究也将并行进行，以增加临床环境中的翻译潜力。

DESCRIPTION (provided by applicant): An important challenge in drug development for Alzheimer's Disease (AD), as well as many other neurological diseases, is the accurate pre-clinical predictability of the future clinical efficacy and side effects of the compound. The complexity of the neurological system makes it extremely difficult to infer impact of the candidate compound using surrogate in vitro information, ex vivo data, or simple animal behavior models. Our proposal aims to fundamentally transform this process through accurate disease circuit characterization along with in vivo full brain quantification of the drug administration impact longitudinally over time in the same animals utilizing the optogenetic functional magnetic resonance imaging (ofMRI) technology. ofMRI is a novel technology combining cell type specific, temporally precise optogenetic control with fMRI readouts. The first proof of concept study published by the PI demonstrated ofMRI technology's ability to accurately visualize brain-wide neural activity resulting from cell types specified by its genetic identity, cell body location, and axonal projection target. With further developments in ofMRI technology to achieve high-throughput, high spatial resolution, and awake scanning, the PI's lab has preliminary data showing the ability to characterize whole brain network response specifically associated with basal forebrain cholinergic neurons. Selective stimulation of cholinergic neurons in the basal forebrain with defined temporal patterns was shown to elicit widespread neural activity including the hippocampus and neocortex. Such direct functional visualization of the network activity with the ability to longitudinally track in vivo can be used o characterize the disease progress, actively identify novel target circuits, and also monitor how different doses and course of treatment impacts each individual animal over time with disease progress. This is in contrast with conventional ex vivo technology that relies on sacrificing a large number of animals at different time points, which increases variance, cost, and time while only obtaining passive, surrogate markers of function or difficult to reproduce behavioral tests. I this proposal, we will quantify network function across normal, and mutant APP mice to quantify network function changes associated with cholinergic neurons of the basal forebrain. With these quantifications, we aim to establish this approach as a new platform for quantitative drug design and evaluation. With the ability to observe network engagement associated with key neural circuit elements implicated in AD, we will identify the AD circuit mechanism and also test a candidate drug that has already shown good electrophysiological, behavioral, and anatomical efficacy. We aim to demonstrate ofMRI-based observation of therapeutic effects. The prevention and/or reversal of AD-related circuit impairment could be fully or partially effective and we will e able to directly observe locations of the changes associated with specific neuronal populations in live animal brains during disease progression and drug therapy. Resting state fMRI studies will also be conducted in parallel to increase translational potential into clinical settings.