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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：
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
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/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

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皮层区域，表现出选择性参与高级感觉或行为