Axonal myelination of interneurons in cortex: functional significance and plasticity

摘要 含小白蛋白(PV+)的快棘篮细胞是大鼠脑内重要的中间神经元亚群。 大脑。皮质PV+篮子细胞调节主要锥体神经元和其他中间神经元的活动，以 影响各种行为。皮质中PV+活性减弱与许多精神疾病有关 精神障碍，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 PV+中间神经元的特性及其对突触后靶点的影响 神经回路的组成部分，两个单一神经元之间的突触连接。我们将多管齐下 通过将来自两个突触连接的神经元的电生理记录与单个 神经元的细胞转录分析和高分辨率阵列断层重建 解剖它们的突触连通性。在这些研究中，突触前神经元将是一个PV+篮子细胞，具有 突触后伙伴是锥体神经元或另一个中间神经元。我们提出了三个具体目标来 研究脑内PV+中间神经元轴突-髓鞘单位的功能和结构。 神经回路。1)我们将通过以下方法阐明成年新皮质中PV+神经元间连接的规律 人与人之间突触联系的生理和解剖学特性比较 神经元(PV+突触前)，包括突触强度、潜伏期和故障率，活动的方向性- 诱导可塑性，以及在两个神经元之间创建的突触的数量， 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)我们会 描述PV+篮子细胞投射到突触后不同隔区的突触的特征 神经元，特别是在远端树突和棘上的PV+突触，包括 它们的轴突路径和突触分子含量，与胞体定向突触进行比较。在.的情况下 脊椎突触我们还将阐明兴奋性突触在同一脊柱上的身份。3)我们会研究 用单细胞RNA-seq检测PV+中间神经元及其突触后靶神经元的基因表达， 并将基因表达模式与突触传递的电生理特性和 突触可塑性，并用3D显示这些突触连接的形态特征 通过阵列断层扫描进行重建，包括但不限于髓鞘形成、轴突路径长度、 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是如何 有助于正常和病理的大脑功能，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。

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.