Nanosensors for sensitive brain-wide neurochemical imaging

用于敏感全脑神经化学成像的纳米传感器

• 批准号: 10154138
• 负责人: Alan Jasanoff
• 金额: $ 142.82万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10154138
• 关键词: Address; Animals; Architecture; Behavioral; Biochemical; Brain; Brain Diseases; Buffers; Caliber; Cell membrane; Cerebrospinal Fluid; Characteristics; Chemicals; Contrast Media; Data; Detection; Directed Molecular Evolution; Dopamine; Engineering; Exhibits; Functional Magnetic Resonance Imaging; Goals; Ice; Image; Infusion procedures; Injections; Knowledge; Label; Laboratories; Ligands; Light; Lipids; Liposomes; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Mediating; Membrane; Methods; Microscopic; Modeling; Molecular; Molecular Probes; Neurotransmitters; Paper; Peptides; Permeability; Physiological; Play; Procedures; Process; Publishing; Rattus; Regulation; Relaxation; Rodent; Role; Sampling; Series; Serotonin; Signal Transduction; Stimulus; Technology; Tertiary Protein Structure; Water; Work; Yeasts; base; blood-brain barrier disruption; brain parenchyma; brain tissue; cell type; design; experimental study; hemodynamics; imaging agent; imaging platform; in vivo; interstitial; median forebrain bundle; minimally invasive; monoamine; nanosensors; neural circuit; neurochemistry; novel; polypeptide; response; sensor; spatiotemporal; subcellular targeting

The large-scale dynamics of neural circuitry depend on interactions among numerous neurochemical spe- cies that play functionally distinct roles throughout the brain. Understanding the spatial and temporal character- istics of chemical signaling is thus crucial for building mechanistic models of brain function. Our laboratory has introduced paramagnetic neurotransmitter sensors that enable functional analysis of neurochemical phenomena over large fields of view by molecular-level functional magnetic resonance imaging (molecular fMRI). We have published applications of these sensors to spatiotemporal mapping of neurochemical phenomena in a series of substantial papers. The scope of such experiments has however been limited by the modest sensitivity provided by the existing probes, which must be applied at concentrations that substantially exceed physiological neuro- transmitter levels. The goal of this proposal is to establish a platform technology for noninvasive neurochemical imaging with substantially higher sensitivity, focusing initially on monoamine transmitters. Our approach is based on a novel principle for biochemical sensing in MRI that uses paramagnetic liposomes as responsive contrast agents. In this mechanism, the presence of neurotransmitter targets gates large contrast effects afforded by the liposomes, giving rise to a formidable amplification factor with respect to previous probes. Using this design, we predict that sensitivity to behaviorally relevant low-micromolar or submicromolar neurotransmitter concentrations will be achieved, with minimal potential for buffering effects. In addition, our preliminary studies suggest that wide-field brain delivery with these probes is achievable, and we also predict that perisynaptic cell type-specific readouts can be obtained by targeting the liposomes. Our work will address three Aims: In Aim 1, we will establish our liposome-based nanosensor (LBN) plat- form by combining lipid, polypeptide, and small molecular components to establish the new sensing mechanism we seek to exploit. We will use a variety of synthetic and molecular engineering methods to optimize this mech- anism for detection of behaviorally relevant interstitial dopamine and serotonin concentrations, with the goal of achieving sensitivity in the 0.1-1 µM range. In Aim 2, we will optimize strategies for brain-wide delivery of these probes, exploiting chemically-mediated blood-brain barrier disruption and infusion into cerebrospinal fluid. We will also implement a perisynaptic targeting approach. In Aim 3, we will validate liposome-based dopamine and serotonin LBNs by molecular fMRI in live rat brains, with reference to parallel neurochemical and hemodynamic fMRI measurements. In addition to establishing the novel neurochemical imaging platform we propose, these experiments will yield first-of-their-kind data about the wide-field distribution of dopamine and serotonin signaling in response to stimuli, as well as the relationship of these neurochemicals to conventional brain activity readouts. Although the technology we will develop will initially be applied in sedated rodents, we expect it to be applicable to many additional species and behavioral contexts.

神经记录的大规模动力学取决于众多神经化学的相互作用 在整个大脑中扮演功能不同的角色的电源。了解空间和临时特征 - 因此，化学信号传导的istics对于构建大脑功能的机械模型至关重要。我们的实验室有 引入了顺磁性神经递质传感器，该传感器能够对神经化学现象的功能分析 通过分子级功能磁共振成像（分子fMRI）的大量视野。我们有 这些传感器在一系列神经化学现象的空间时间映射中发布的应用 大量论文。但是，此类实验的范围受到所提供的适度灵敏度的限制 通过现有问题，必须以大大超过物理神经的浓度应用 发射机水平。该建议的目的是为无创神经化学建立平台技术 具有较高灵敏度的成像，最初集中在单胺发送器上。我们的方法是基于 在MRI中使用顺磁性脂质体作为反应性对比度的新型生化感测的新原理 代理商。在这种机制中，神经递质的存在靶向门，大门具有很大的对比效应 脂质体，就以前的问题引起了强大的扩增因子。使用此设计，我们 预测对行为相关的低微摩尔或亚微摩尔神经递质浓度的敏感性 将实现，具有缓冲效应的潜力最小。此外，我们的初步研究表明 使用这些探针的宽场大脑递送是可以实现的，我们还预测，周突触细胞类型特异性 可以通过靶向脂质体获得读数。 我们的工作将解决三个目标：在AIM 1中，我们将建立基于脂质体的纳米传感器（LBN）平台 通过结合脂质，多肽和小分子成分形成形式，以建立新的感应机制 我们将使用各种合成和分子工程方法来优化这种机械 用于检测行为相关的间质多巴胺和5-羟色胺浓度的anism，目的是 在0.1-1 µm范围内达到灵敏度。在AIM 2中，我们将优化这些策略，以全面交付这些策略 探针，利用化学介导的血脑屏障破坏并输注脑脊液。我们 还将实施一种无针对性靶向方法。在AIM 3中，我们将验证基于脂质体的多巴胺和 血清素LBN通过分子fMRI在活大鼠大脑中，参考平行神经化学和血液动力学 fMRI测量。除了建立我们建议的新型神经化学成像平台外， 实验将产生有关多巴胺和5-羟色胺信号传导的宽视野分布的第一届数据 响应刺激以及这些神经化学物质与常规大脑活动读数的关系。 尽管我们将开发的技术最初将用于镇静的啮齿动物，但我们希望它适用 对于许多其他物种和行为环境。