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

• 批准号: 10652546
• 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
• 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/10652546
• 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; 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; Visualization; Work; bioluminescence imaging; cell type; delivery vehicle; design; experimental study; hemodynamics; imaging probe; improved; in vivo; neural; neural circuit; neurotoxicity; nonhuman primate; operation; response; retrograde transport; side effect; technology development; tool; validation studies; vector; visual processing; visual stimulus

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皮质区域，这些区域在高级感觉或行为方面表现出选择性参与 运营。这些区域的功能专业化被认为是灵长类特异性认知的核心 学院和相关疾病。解密灵长类动物大脑区域功能专业的起源 但是，由于没有合适的实验性，这很大程度上是一项艰巨的任务 工具。为了解决这个问题，我们将开发一种测量投入到专业领域的活动的方法 从整个大脑中，可以对多区域神经回路的信息流进行系统分析 这引起了高级功能。我们的方法将在概念上采用一个新的基因编码家庭 成像探针称为Nostics，将表达神经元的钙信号转导为 局部血液动力学信号，可以使用脑范围的测量技术动态监测 像功能性磁共振成像（fMRI）。当使用逆转运输的病毒向量交付时， Nostics可以允许针对性fMRI的分布式细胞种群中的神经活动记录 对大脑中任何注射靶的单突触输入。在我们的初步工作中，我们创建了第一代 怀旧的探针并用它们证明了啮齿动物中遗传靶向的功能成像。在目标1中 这个项目，我们将采取两个步骤，以适应此工具以用于非人类灵长类动物。我们将创建第二 在电路特异性功能成像中显示出改善性能的一代怀旧，同时也可以开发 对允许在灵长类动物大脑中纵向跟踪这些探针表达的病毒载体。我们将 还适应了掺入腺相关病毒中的怀旧探针，这些病毒提供了扩展的capa- 与我们目前使用的疱疹病毒相比，可使用。在AIM 2中，我们将执行试点实验以调查 NOSTICS是否可以在非人类灵长类动物中提供特定电路的读数。这些测试已经是 使用我们当前可用的探针和向量的Sible，以及AIM 1的新变体也将在 可用的。成功演示了Marmoset中电路成像的怀旧功能构成我们的 建议进入该项目的UH3阶段的GO/NO-GO标准。然后在AIM 3（UH3阶段）中，我们将 在两个范式中验证探索其在大脑区域的性能的两个范式中的怀旧探针，实验性 上下文和灵长类动物。在第一个范式中，我们将使用Nostics检查功能的起源 在Marmoset大脑的面部选择区域进行专业化。在第二个范式中，我们将适用于Nostics 调查猕猴视觉腹腹流中对象选择性响应的大脑贡献 皮质。这些实验将作为多实验室合作进行，既可以利用和分散 怀旧技术；因此，这项工作将建立一种广泛适用的变革性方法 灵长类动物脑功能的机械分析。