Hemogenetic imaging technology for circuit-specific analysis of primate brain function

用于灵长类大脑功能电路特异性分析的血遗传学成像技术

基本信息

批准号：
10271639
负责人：
Alan Jasanoff
金额：
$ 60.31万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10271639
关键词：
Address Animals Area Autopsy Behavioral Brain Brain region Calcium Signaling Callithrix Categories Cells Cognitive Collaborations Complement Computer Models Data Dependence Dependovirus Disease Electrophysiology (science)Elements Exhibits Face Faculty Family Functional Imaging Functional Magnetic Resonance Imaging Generations Goals Grain Herpesviridae Human Image Imaging technology Individual Injections Investigation Laboratories Literature Longitudinal Studies Luciferases Macaca Magnetic Resonance Imaging Measurement Measures Methodology Methods Monitor Monkeys Neurobiology Neurons Neurosciences Research Output Pattern Performance Pharmaceutical Preparations Population Primates Property Protein Engineering Proteins Reporter Reproducibility Resolution Rodent Sensory Signal Transduction Source Stimulus Stream Surveys Techniques Technology Testing Training Validation Variant Viral Viral Packaging Viral Vector Virus Visual Visual Cortex Visual Pathways Visual system structure Visualization Work base bioluminescence imaging cell type design experimental study hemodynamics imaging probe improved in vivo neural circuit neurotoxicity nonhuman primate operation relating to nervous system response retrograde transport side effect technology development tool validation studies vector visual processing visual stimulus

项目摘要

Primate brains contain cortical areas that exhibit selective engagement in high-level sensory or behavioral operations. The functional specialization of these regions is thought to be central to primate-specific cognitive faculties and to associated disorders. Deciphering the origins of functional specialization in primate brain regions has been an enormously challenging task, however, due in large part to the absence of suitable experimental tools. To address this problem, we will develop a method for measuring the activity of inputs to specialized areas from throughout the brain, permitting systematic analyses of information flow in the multiregional neural circuitry that gives rise to high-level functions. Our method will employ a conceptually new family of genetically encoded imaging probes called NOSTICs, which transduce the calcium signaling of NOSTIC-expressing neurons into localized hemodynamic signals that can be dynamically monitored using brain-wide measurement techniques like functional magnetic resonance imaging (fMRI). When delivered using retrogradely transported viral vectors, NOSTICs can permit targeted fMRI-based recording of neural activity in distributed cell populations that provide monosynaptic input to any injection target in the brain. In our preliminary work, we have created first-generation NOSTIC probes and used them to demonstrate genetically targeted functional imaging in rodents. In Aim 1 of this project, we will take two steps that adapt this tool for use in nonhuman primates. We will create second- generation NOSTICs that display improved performance for circuit-specific functional imaging, while also devel- oping viral vectors that allow expression of these probes to be tracked longitudinally in primate brains. We will also adapt the NOSTIC probes for incorporating into adeno-associated viruses, which provide extended capa- bility compared with the herpes viruses we currently use. In Aim 2, we will perform pilot experiments to investigate whether NOSTICs can provide circuit-specific readouts in nonhuman primates. These tests will already be pos- sible using our currently available probes and vectors, and new variants from Aim 1 will also be tested when available. Successful demonstration of NOSTIC functionality for circuit imaging in marmosets constitutes our proposed go/no-go criterion for entry into the UH3 stage of this project. Then in Aim 3 (UH3 stage), we will validate NOSTIC probes in two paradigms that explore their performance across brain regions, experimental contexts, and primate species. In the first paradigm, we will apply NOSTICs to examine origins of functional specialization in face-selective regions of the marmoset brain. In the second paradigm, we will apply NOSTICs to investigate brain-wide contributions to object selective responses in the ventral stream of the macaque visual cortex. These experiments will be performed as multi-laboratory collaborations that both harness and dissemi- nate the NOSTIC technology; this work will therefore establish a broadly applicable transformative approach for mechanistic analysis of primate brain function.

灵长类动物的大脑包含选择性参与高级感觉或行为的皮质区域运营。这些区域的功能专门化被认为是灵长类动物特异性认知的核心能力和相关疾病。破译灵长类大脑区域功能专业化的起源然而，这一直是一项极具挑战性的任务，很大程度上是由于缺乏合适的实验工具。为了解决这个问题，我们将开发一种测量专门领域投入活动的方法来自整个大脑，允许对多区域神经回路中的信息流进行系统分析这产生了高级功能。我们的方法将采用一个概念上新的基因编码家族称为 NOSTIC 的成像探针，可将表达 NOSTIC 的神经元的钙信号转导为可以使用全脑测量技术动态监测局部血流动力学信号例如功能性磁共振成像（fMRI）。当使用逆行运输的病毒载体递送时， NOSTIC 可以基于功能磁共振成像（fMRI）对分布式细胞群中的神经活动进行有针对性的记录，从而提供单突触输入到大脑中的任何注射目标。在我们的前期工作中，我们创建了第一代 NOSTIC 探针并用它们来演示啮齿动物的基因靶向功能成像。目标 1 在这个项目中，我们将采取两个步骤将该工具应用于非人类灵长类动物。我们将创造第二个—— 一代NOSTIC显示出改进的电路特定功能成像性能，同时还开发了打开病毒载体，允许在灵长类动物大脑中纵向追踪这些探针的表达。我们将还调整 NOSTIC 探针以整合到腺相关病毒中，从而提供扩展的能力与我们目前使用的疱疹病毒相比。在目标 2 中，我们将进行试点实验来调查 NOSTIC 是否可以在非人类灵长类动物中提供特定于电路的读数。这些测试已经是 pos- 可以使用我们当前可用的探针和载体，并且 Aim 1 的新变体也将在以下情况下进行测试：可用的。狨猴电路成像 NOSTIC 功能的成功演示构成了我们的目标提议进入该项目 UH3 阶段的通过/不通过标准。然后在目标 3（UH3 阶段）中，我们将在两种范式中验证 NOSTIC 探针，探索其跨大脑区域的性能，实验环境和灵长类物种。在第一个范式中，我们将应用 NOSTIC 来检查功能的起源专门研究狨猴大脑的面部选择性区域。在第二个范式中，我们将应用 NOSTIC 研究全脑对猕猴视觉腹侧流中物体选择性反应的贡献皮质。这些实验将作为多实验室合作进行，既利用又传播推出NOSTIC技术；因此，这项工作将为以下领域建立一个广泛适用的变革方法：灵长类动物脑功能的机制分析。