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: 10867859
• 负责人: Emmanuel Luis Crespo
• 金额: $ 4.06万
• 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/10867859
• 关键词: Address; Adult; Anesthesia procedures; Area; Automobile Driving; Behavior; Behavioral; Biological; Brain; Cells; Childhood; Cognitive; Communication; Complement; Complex; Data; Detection; Development; Developmental Process; Dissection; Doctor of Philosophy; Early Intervention; Electrophysiology (science); Engineering; Environmental Risk Factor; Equilibrium; Esthesia; Etiology; Genes; Genetic; Goals; Hyperactivity; Hypersensitivity; Image; Immunologic Factors; Interneurons; Intervention; Learning; Life; Link; Maps; Mediating; Mental disorders; Mentors; Molecular; Motion; Mus; Neocortex; Neurodevelopmental Disorder; Neurologic; Phase; Population; Postdoctoral Fellow; Predisposition; Prefrontal Cortex; Principal Investigator; Process; Property; Proteins; Reporting; Research; Research Personnel; Research Project Grants; Rewards; Role; Sensory; Sensory Process; Social Behavior; Social Interaction; Specificity; Syndrome; Task Performances; Technology; Testing; 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; inhibitory neuron; insight; neocortical; nervous system disorder; neural; neural circuit; neurophysiology; next generation; novel; optogenetics; postnatal development; recruit; 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.

项目摘要/摘要 这里提出的研究旨在进一步了解我们对早期因果关系的理解 神经电路的形成和成人行为，特别是健康的大脑发育如何出现问题 在一生中的感觉处理中定义。深入了解正常和异常 神经发育过程，迫切需要解构驾驶病理生理学 发育性皮质多动症与持续不良适应性认知的出现之间的机制， 感官和社会行为。没有这样的信息，新的目标是提早干预的新目标 神经发育疾病可能会保持有限。在F99阶段，我将测试是否发展 锥体神经元的过度兴奋会导致持续的成人超敏反应（AIM IA），并在快速加速器中定义 抑制性神经元募集（AIM IB） - 自闭症中可见的键神经生理和行为特征 频谱障碍和神经发育综合征。在AIM II中，我将完成我的神经生理学 在高密度电生理记录中训练并进行前额叶皮层的两光子成像 项目进入感官区域，以测试它们如何影响当地调节的编码和电路动态 抑制性神经元亚型。这项工作将有助于理解 超敏反应，将有助于扩大我们对赞助活动灾难的理解 遗传，免疫和环境因素通过提供有关因果细胞类型角色的机械洞察力 锥体神经元和抑制​​性神经元亚型的。 F99/K00阶段的培训将完成我的 开发分子技术的深层背景，以剖析新皮质局部和远程投影 驱动复杂行为。在我自己的实验室中，我很容易开发用于下一代分子技术 随着生物学复杂性的增加，跨临时和空间尺度上解剖新皮质计算 （基因，蛋白质，细胞，电路）基础感觉处理。