Selective dissection of local and distributed neocortical inhibitory circuits underlying sensory representation

感觉表征基础上的局部和分布式新皮质抑制电路的选择性解剖

• 批准号: 10541697
• 负责人: Emmanuel Luis Crespo
• 金额: $ 3.95万
• 依托单位: CENTRAL MICHIGAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541697
• 关键词: Address; Adult; Area; Automobile Driving; Behavior; Behavioral; Biological; Brain; Cells; Childhood; Cognitive; Communication; Complement; Complex; Data; Detection; Development; Developmental Process; Disease; Dissection; Doctor of Philosophy; Early Intervention; Electrophysiology (science); Engineering; Environmental Risk Factor; Equilibrium; Esthesia; Etiology; Gene Proteins; Genetic; Goals; Hyperactivity; Hypersensitivity; Image; Immunologic Factors; Interneurons; Intervention; Lead; Learning; Life; Link; Mediating; Mental disorders; Mentors; Molecular; Motion; Mus; Neocortex; Neurodevelopmental Disorder; Neurologic; Phase; Population; Predisposition; Prefrontal Cortex; Principal Investigator; Process; Property; Reporting; Research; Research Personnel; Research Project Grants; Rewards; Role; Sensory; Sensory Process; Social Behavior; Social Interaction; Specificity; Syndrome; Task Performances; Technology; Testing; Time; Training; Vibrissae; Water; Work; autism spectrum disorder; autistic children; behavioral phenotyping; brain shape; cell type; clinical diagnostics; density; diagnostic criteria; extracellular; hippocampal pyramidal neuron; in vivo; information processing; inhibitory neuron; insight; neocortical; nervous system disorder; neural circuit; neurophysiology; next generation; novel; optogenetics; postnatal development; recruit; relating to nervous system; sensor; sensory cortex; sensory integration; social attachment; social deficits; therapeutic target; tool; tool development; two-photon; voltage

PROJECT SUMMARY/ABSTRACT The research proposed here is aimed at furthering our understanding of causal relationships between early neural circuit formation and adult behavior, and specifically how healthy brain development can go awry to result in deficits in sensory processing across a lifetime. Towards a deeper understanding of normal and aberrant neurodevelopmental processes, there is a critical need to deconstruct the driving pathophysiological mechanisms between developmental cortical hyperactivity and emergence of persistent maladaptive cognitive, sensory and social behaviors. Without such information, the promise of novel targets for early intervention in neurodevelopmental diseases will likely remain limited. During the F99 Phase, I will test if developmental hyperexcitation of pyramidal neurons leads to persistent adult hypersensitivity (Aim IA) and deficits in fast-spiking inhibitory neuron recruitment (Aim IB)—key neurophysiological and behavioral signatures seen in autism spectrum disorders and neurodevelopmental syndromes. In Aim II, I will complement my neurophysiological training in high density electrophysiological recordings and perform two-photon imaging of prefrontal cortex projections into sensory areas to test how they influence encoding and circuit dynamics regulated by local inhibitory neuron subtypes. This work will contribute to understanding the neurodevelopmental origins of hypersensitivity and will help to broaden our understanding of disturbances in spontaneous activity beyond genetic, immune and environmental factors by providing mechanistic insight into causal cell-type specific roles of pyramidal neuron and inhibitory neuron subtypes. The training for the F99/K00 Phases will complement my deep background in developing molecular technologies to dissect neocortical local and long-range projections driving complex behavior. In my own lab I will readily develop next-generation molecular technologies for dissecting neocortical computations across temporal and spatial scales with increasing biological complexity (genes, proteins, cells, circuits) underlying sensory processing.

项目概要/摘要 这里提出的研究旨在进一步了解早期之间的因果关系 神经回路的形成和成人行为，特别是健康的大脑发育如何出错 一生中感觉处理的缺陷，以更深入地了解正常和异常。 神经发育过程中，迫切需要解构驱动病理生理学 发育性皮质过度活跃与持续适应不良的出现之间的机制， 如果没有这些信息，早期干预的新目标就不可能实现。 在 F99 阶段，我将测试是否存在发育疾病。 锥体神经元的过度兴奋导致持续的成人超敏反应（Aim IA）和快速放电缺陷 抑制性神经元募集 (Aim IB)——自闭症中的关键神经生理学和行为特征 在目标 II 中，我将补充我的神经生理学知识。 高密度电生理记录训练并进行前额皮质双光子成像 投射到感觉区域，以测试它们如何影响局部调节的编码和电路动态 这项工作将有助于理解抑制性神经元亚型的神经发育起源。 超敏反应，并将有助于扩大我们对自发活动干扰的理解 通过提供对因果细胞类型特定作用的机制洞察来研究遗传、免疫和环境因素 F99/K00 阶段的锥体神经元和抑制​​性神经元亚型的培训将补充我的知识。 分子技术发展的深厚背景来剖析新皮质局部和远程预测 在我自己的实验室中，我将轻松开发下一代分子技术。 随着生物复杂性的增加，在时间和空间尺度上剖析新皮质计算 （基因、蛋白质、细胞、电路）是感觉处理的基础。