Circuit-Specific Interrogation of the Primate Claustrum

灵长类动物闭状体的电路特异性询问

• 批准号: 10604913
• 负责人: Hala Galal El-Nahal
• 金额: $ 3.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-09-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604913
• 关键词: Address; Animal Model; Animals; Appearance; Area; Back; Behavior; Behavioral; Brain; Brain Diseases; Cells; Cerebral cortex; Claustral structure; Cognition; Disease; Esthesia; Esthetics; Exhibits; Eye Movements; Functional Magnetic Resonance Imaging; Genes; Genetic Techniques; Geometry; Goals; Health; Histology; Human; Injections; Jaw; Label; Location; Macaca; Maps; Mediating; Methods; Monkeys; Movement; Neurons; Operative Surgical Procedures; Opsin; Optics; Outcome; Pathologic; Performance; Physiological; Primates; Proteins; Psychophysics; Rattus; Research Design; Rodent; Role; Saccades; Sensorimotor functions; Shapes; Signal Transduction; Specificity; Stimulus; Structure; System; Techniques; Technology; Testing; Thinness; Training; Translating; Viral; Viral Vector; Virus; Vision; Visual; Work; anatomical tracing; base; career; clinically relevant; cognitive function; experimental study; extracellular; fluorophore; frontal eye fields; genetic approach; genetic technology; gray matter; nervous system disorder; neurophysiology; neuropsychiatric disorder; nonhuman primate; novel strategies; optogenetics; relating to nervous system; resilience; visual motor

PROJECT SUMMARY The claustrum is a narrow, subcortical sheet of gray matter with interconnections across the cerebral cortex. Its irregular shape and deep location make it difficult to study with classical neurophysiological techniques. Recent genetic technologies such as optogenetics provide new hope for understanding the claustrum. They have advanced its study in rodents, implicating the claustrum in an array of sensorimotor and cognitive functions. Circuit-specific studies are needed to resolve how these functions map to the claustrum’s widespread connections. Such studies would be especially valuable in macaque monkeys, the animal model most homologous to humans. My overall goal is to translate viral technologies to monkeys and use them to study the role of a specific claustrum-prefrontal cortical circuit in visuo-saccadic behavior. During systematic testing of viral vectors in macaques, I identified a promising candidate for delivering opsin genes to the claustrum: the retrograde virus rAAV2-retro. When injected into the frontal eye field (FEF), a prefrontal cortical area involved in vision, movement, and cognition, rAAV2-retro constructs yielded strong labeling of FEF-projecting claustrum neurons. This finding provides a long-sought, unique opportunity to study claustrum neurons with circuit-level specificity in the primate brain. I propose to validate viral techniques in the claustro-FEF circuit and use them to test my overall hypothesis that the claustrum mediates competitive selection of the most behaviorally relevant stimulus via suppression of all other stimuli. To test my hypothesis, I have three integrated aims. In Aim 1, I will conduct anatomical tracing studies to elucidate the motif of connectivity between the claustrum and FEF. In Aim 2, I will use rAAV2-retro to express an inhibitory opsin in FEF-projecting claustrum neurons. Then I will use phototagging to identify those neurons and extracellularly record from them to characterize the signals sent from the claustrum to the FEF during a battery of saccade tasks. In Aim 3, I will use the same inhibitory opsins to selectively silence FEF-projecting claustrum neurons, allowing me to determine whether they are required for competitive selection of saccade targets. The claustrum is implicated in a wide range of neurological diseases and neuropsychiatric disorders. Thus, the results of the proposed work will help reveal how pathological changes to neural activity in the claustrum may contribute to brain disorders. In addition to its clinical relevance, the proposed work will significantly expand my doctoral training to include neural recording and optogenetic methods in non-human primates.

项目摘要 Claustrum是一片狭窄的灰质皮层皮层片，在大脑皮层上有互连。 不规则的形状和深层位置使得使用经典的神经生理技术很难研究。最近的 诸如光遗传学之类的遗传技术为理解Claustlum提供了新的希望。他们有 在啮齿动物中进行了研究，暗示了一系列感觉运动和认知功能中的claustrum。 需要特定于电路的研究来解决这些功能如何映射到Claustrum的宽度 连接。这样的研究在猕猴中特别有价值，这是动物模型的大多数 与人类同源。我的总体目标是将病毒技术转化为猴子，并使用它们来研究 特定的claustrum-prefrontal皮质回路在视觉 - 神经行为中的作用。在系统测试的病毒期间 猕猴中的向量，我确定了将Opsin基因传递到Claustrum的承诺候选者： 逆行病毒RAAV2-RETRO。当注入额叶眼场（FEF）时，涉及的前额叶皮质区域 视觉，运动和认知，RAAV2-RETRO构建体产生了FEF预测claustrum的强烈标记 神经元。这一发现提供了一个长期以来的独特机会，可以使用电路级学习神经元 主要大脑的特异性。我建议在Claustro-fef电路中验证病毒技术，然后使用它们 检验我的总体假设，即clustrum介导了最相关的最相关的竞争选择 通过抑制所有其他刺激。为了检验我的假设，我有三个综合目的。在AIM 1中，我会 进行解剖示踪研究，以阐明clustustrum和FEF之间连通性的基序。目标 2，我将使用raav2-retro来表达FEF投射神经元中的抑制作用。那我会使用 光吸收以识别那些神经元并从它们的细胞外记录以表征从中发送的信号 在一系列扫视任务期间，Claustrum到FEF。在AIM 3中，我将使用相同的抑制作用来 有选择地沉默的FEF投射神经元，使我能够确定它们是否需要 扫视目标的竞争选择。 claustrum暗示着多种神经系统疾病 和神经精神疾病。这是拟议工作的结果将有助于揭示病理的变化 在神经的神经元活动中可能导致脑部疾病。除了其临床相关性， 拟议的工作将大大扩大我的博士培训，包括神经元记录和光遗传学方法 在非人类隐私中。