Axonal myelination of interneurons in cortex: functional significance and plasticity

皮质中间神经元的轴突髓鞘形成：功能意义和可塑性

• 批准号: 10626677
• 负责人: Vernon Daniel MADISON
• 金额: $ 55.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626677
• 关键词: 3-Dimensional; Acute; Adult; Anatomy; Architecture; Array tomography; Axon; Behavior; Biology; Brain; Cell Nucleus; Cells; Characteristics; Chemosensitization; Cognitive; Complex; Cytoplasm; Data; Defect; Dendrites; Dendritic Spines; Development; Disease; Dissociative disorder; Distal; Electron Microscopy; Electrophysiology (science); Elements; Ensure; Excitatory Synapse; Failure; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Health; Immunofluorescence Immunologic; Individual; Influentials; Interneurons; Knowledge; Length; Location; Maps; Measures; Mechanics; Mental Depression; Mental disorders; Microscopic; Molecular; Morphology; Mus; Myelin; Myelin Sheath; Myoepithelial cell; Neocortex; Neurons; Output; Parvalbumins; Pathologic; Physiological; Physiology; Play; Positioning Attribute; Property; Resolution; Role; Schizophrenia; Signal Transduction; Slice; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Thick; Vertebral column; Wild Type Mouse; Work; autism spectrum disorder; brain tissue; differential expression; hippocampal pyramidal neuron; improved; insight; knowledge base; molecular subtypes; myelination; neocortical; nervous system disorder; neural circuit; neuronal cell body; neuronal circuitry; novel; oligodendrocyte myelination; postsynaptic; postsynaptic neurons; presynaptic; presynaptic neurons; quantum; receptor; reconstruction; relating to nervous system; single-cell RNA sequencing; therapy design; transcriptomics; transmission process

ABSTRACT Parvalbumin-containing (PV+) fast spiking basket cells comprise an important subset of interneurons in the brain. Cortical PV+ basket cells regulate the activity of principal pyramidal neurons and other interneurons to influence a variety of behaviors. Diminished PV+ activity in cortex is associated with numerous psychiatric disorders, including schizophrenia and other dissociative disorders, and autism. We propose to investigate the properties of PV+ interneurons and their influence on their postsynaptic targets by focusing on the smallest element of a neural circuit, the synaptic connection between two single neurons. We will apply a multipronged approach by combining electrophysiological recordings from two synaptically connected neurons, with single cell transcriptomic analysis of both neurons and high-resolution array tomographic reconstruction of the anatomy of their synaptic connectivity. In these studies, the presynaptic neuron will be a PV+ basket cell, with the postsynaptic partner being a pyramidal neuron or another interneuron. We propose three specific aims to study the function and structure of the axon-myelin unit of PV+ interneurons within this quantal element of the neural circuitry. 1) We will elucidate the rules of PV+ interneuron connectivity in the adult neocortex by comparing the physiological and anatomical properties of the synaptic connections between individual neurons (PV+ presynaptic), including synaptic strength, latency, and failure rate, the directionality of activity- induced plasticity, as well as the number of synapses created between the two neurons, the number of connecting axon paths, length and thickness of axon paths and the extent of axon myelination. 2) We will characterize the synapses that PV+ basket cells project onto different compartments of the postsynaptic neuron, and specifically the much less understood PV+ synapses onto distal dendrites and spines, including their axonal paths and synaptic molecular content, comparing those to soma-directed synapses. In the case of spine synapses we will also clarify the identity of the excitatory synapse onto the same spine. 3) We will study the gene expression in PV+ interneurons and in their postsynaptic target neurons with single cell RNA-seq, and correlate gene expression patterns with the electrophysiological properties of synaptic transmission and synaptic plasticity, and with the morphological characteristics of these synaptic connections revealed by 3D reconstruction by array tomography, including, but not limited to myelination, axonal path length, number of synapses, and their molecular character. By elucidating the function of PV+ cells and their myelinated axon in the smallest neural circuit interaction, we aim to gain insight into how these crucial elements of brain circuits contribute to normal and pathological brain function, thus providing the knowledge base needed for improved treatment design for PV+ interneuron-related disorders.

摘要 含有小清蛋白（PV+）的快速尖峰篮细胞包含在神经元中的重要的中间神经元子集。 个脑袋皮质PV+篮状细胞调节主锥体神经元和其他中间神经元的活性， 影响各种行为。皮质中PV+活性降低与许多精神疾病相关。 包括精神分裂症和其他解离性障碍以及自闭症在内的精神障碍。我们建议调查 PV+中间神经元的特性及其对突触后靶点的影响， 神经回路的一个组成部分，两个单个神经元之间的突触连接。我们将采取多管齐下的 方法通过结合来自两个突触连接的神经元的电生理记录， 神经元的细胞转录组学分析和神经元的高分辨率阵列断层扫描重建， 突触连接的解剖学在这些研究中，突触前神经元将是PV+篮状细胞， 突触后配对体是锥体神经元或另一中间神经元。我们提出三个具体目标， 研究PV+中间神经元的轴突-髓鞘单位的功能和结构， 神经回路1)我们将阐明成年新皮层PV+中间神经元连接的规则， 比较个体之间突触连接的生理和解剖特性， 神经元（PV+突触前），包括突触强度，潜伏期和失败率，活动的方向性- 诱导的可塑性，以及两个神经元之间创建的突触数量， 连接轴突路径、轴突路径的长度和厚度以及轴突髓鞘形成的程度。2)我们将 表征PV+篮状细胞投射到突触后神经元的不同隔室的突触。 神经元，特别是远侧树突和棘上的PV+突触，包括 它们的轴突路径和突触分子的内容，比较那些胞体导向的突触。的情况下 棘突触我们也将阐明同一棘上的兴奋性突触的身份。3)我们将研究 用单细胞RNA-seq在PV+中间神经元及其突触后靶神经元中的基因表达， 并将基因表达模式与突触传递的电生理特性相关联， 突触可塑性，并与这些突触连接的形态学特征揭示了3D 通过阵列断层扫描进行的重建，包括但不限于髓鞘形成、轴突路径长度、轴突的数量、轴突的长度 突触和它们的分子特征。通过阐明PV+细胞及其有髓轴突在 最小的神经回路相互作用，我们的目标是深入了解这些大脑回路的关键元素是如何 有助于正常和病理的大脑功能，从而提供所需的知识基础， PV+神经元间相关疾病的治疗设计。