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.

项目总结/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年人的行为，特别是健康的大脑发育如何出错， 在感觉处理上的缺陷。为了更深入地理解正常和异常 神经发育过程中，有一个关键需要解构驱动病理生理学 发展性皮质机能亢进和持续性适应不良认知的出现之间的机制， 感官和社会行为。如果没有这些信息，早期干预的新靶点的前景将是渺茫的。 神经发育疾病可能仍然有限。在F99阶段，我将测试开发 锥体神经元的过度兴奋导致持续的成人超敏反应（Aim IA）和快速发放的缺陷 抑制性神经元募集（Aim IB）--在自闭症中观察到的关键神经生理学和行为特征 谱系障碍和神经发育综合征。在目标II中，我将补充我的神经生理学 进行高密度电生理记录的训练，并对前额叶皮层进行双光子成像 投射到感觉区域，以测试它们如何影响编码和由局部神经元调节的回路动力学。 抑制性神经元亚型这项工作将有助于了解神经发育的起源， 这将有助于扩大我们对自发活动障碍的理解， 遗传、免疫和环境因素，通过提供对因果细胞类型特异性作用的机械见解 锥体神经元和抑制性神经元亚型。F99/K 00阶段的培训将补充我的 在开发分子技术以剖析新皮层局部和远程投射方面有着深厚的背景 驱动复杂的行为在我自己的实验室里，我将随时开发下一代分子技术， 随着生物学复杂性的增加，在时间和空间尺度上剖析新皮层计算 （基因、蛋白质、细胞、电路）的感觉处理。