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.

抽象的 含有小白蛋白（PV+）的快速尖峰篮细胞是神经元中重要的中间神经元亚群。 脑。皮质 PV+ 篮细胞调节主要锥体神经元和其他中间神经元的活动 影响多种行为。皮层 PV+ 活动减少与许多精神疾病有关 疾病，包括精神分裂症和其他分离性障碍以及自闭症。我们建议调查 通过关注最小的PV+中间神经元的特性及其对其突触后目标的影响 神经回路的元件，两个单个神经元之间的突触连接。我们将多管齐下 方法通过结合两个突触连接的神经元的电生理记录，与单个 神经元的细胞转录组分析和高分辨率阵列断层扫描重建 他们的突触连接的解剖。在这些研究中，突触前神经元将是 PV+ 篮状细胞， 突触后伙伴是锥体神经元或另一个中间神经元。我们提出三个具体目标 研究PV+中间神经元的轴突髓磷脂单元在该量子元件内的功能和结构 神经回路。 1）我们将通过以下方式阐明成人新皮质中PV+中间神经元连接的规则 比较个体之间突触连接的生理学和解剖学特性 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产生的突触数量， 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范围。 2）我们会 表征 PV+ 篮状细胞投射到突触后不同区室的突触 神经元，特别是远端树突和棘上的 PV+ 突触，尤其是鲜为人知的神经元，包括 它们的轴突路径和突触分子含量，并将其与体细胞定向的突触进行比较。如果是 脊柱突触 我们还将阐明同一脊柱上兴奋性突触的身份。 3）我们将学习 使用单细胞 RNA-seq 检测 PV+ 中间神经元及其突触后目标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，以及 3D 揭示的这些突触连接的形态特征 通过阵列断层扫描重建，包括但不限于髓鞘形成、轴突路径长度、 突触及其分子特征。通过阐明 PV+ 细胞及其有髓轴突的功能 最小的神经回路相互作用，我们的目标是深入了解大脑回路的这些关键元素如何 有助于正常和病理性的大脑功能，从而提供改善所需的知识基础 PV+ 中间神经元相关疾病的治疗设计。