Neurodevelopmental Disorder Risk Gene Regulation of Intrinsic Membrane Excitability: A Rheostat that Tunes Dendritic Morphogenesis to Regulate Circuit Assembly During Development

内在膜兴奋性的神经发育障碍风险基因调节：调节树突形态发生以调节发育过程中电路组装的变阻器

• 批准号: 10571558
• 负责人: GAVIN R RUMBAUGH
• 金额: $ 67.84万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571558
• 关键词: Area; Basic Science; Behavior; Behavioral; Biological Process; Brain; Brain Diseases; Candidate Disease Gene; Cells; Cerebral cortex; Childhood; Data; Decision Making; Development; Disease; Etiology; Gene Expression; Gene Expression Regulation; Genes; Genetic; Glutamates; Goals; Human; Image; Impaired cognition; Impairment; Ion Channel; Kv4 channel; Learning; Link; Mediating; Membrane; Molecular; Morphogenesis; Mus; Neurobiology; Neurodevelopmental Disorder; Neurons; Organ; Pathway interactions; Perception; Perceptual learning; Perinatal; Peripheral; Potassium Channel; Process; Protein Isoforms; Proteins; RNA Splicing; Regulation; Research; Research Design; Role; SYNGAP1; Sensory; Shapes; Signal Transduction; Somatosensory Cortex; Structure; Surface; Synapses; Testing; Thinking; Touch sensation; Vibrissae; Work; autistic; behavioral impairment; cognitive ability; cognitive function; cognitive process; course development; excitatory neuron; gene function; in vivo; insight; loss of function; maladaptive behavior; neural circuit; neurophysiology; novel; relating to nervous system; response; risk variant; sensory cortex; tool; two-photon

Project Summary The goal of this project is to understand how gene expression during development shapes the delicate and massively parallel cell biological processes that promote wiring of functional networks within the cerebral cortex. This is an important area of basic research because neural dynamics within cortical networks are the direct correlates of thought and behavior. These cognitive processes emerge as neural circuits form through expression of genes over the course of development. Moreover, cognitive impairment, which defines neurodevelopmental disorders (NDDs), is thought to arise, at least in part, from impaired neural circuit connectivity within the developing cortex. A revelation over the past decade is that NDDs can be caused by de novo genetic loss-of-function SNVs within a single gene. Thus, in-depth study of natural functions of these genes can reveal the neurobiological principles underlying the typically developing cortex and as well as principles that contribute to abnormal cortical development associated with NDDs. In this project, we will explore the hypothesis that expression of NDD-associated genes in the typically developing cortex promotes the assembly of cortical circuits through cell-autonomous regulation of intrinsic membrane excitability. This hypothesis is significant because it is known that neural activity shapes the assembly of developing cortical circuits. However, it remains unknown how genes function at the cellular level to promote activity-dependent in vivo development of cortical circuit motifs known to promote cognitive function and behavioral adaptations. Aim 1 will explore the causal relationships between genetic control of intrinsic membrane excitability (IME), activity- dependent dendritic morphogenesis, and developmental assembly of cortical circuits. Aim 2 will explore causal links between genetic control of IME, neuronal ensemble structure/function, and behavioral adaptations. We will do this by regulating genetic control of IME in developing cortical neurons and then observing the effect of this on cortical ensembles and behavioral adaptions. This research design is important because the brain functions across multiple temporal and spatial scales – indeed, this project attempts to link gene function across the major levels of brain function – gene>neuron>synapse>circuit>ensemble>behavior. The overall impact of this proposed research is that it has the potential to reveal how gene expression shapes the activity- dependent assembly of neural circuits that promote cognitive functions required for behavioral adaptations. Because we focus on natural functions of an NDD gene, these basic insights are also directly relatable to the etiology of cortical wiring impairments associated with childhood brain disorders.

项目概要 该项目的目标是了解发育过程中的基因表达如何塑造精致和 大规模并行细胞生物过程，促进大脑内功能网络的连接 皮质。这是基础研究的一个重要领域，因为皮质网络中的神经动力学是 思想和行为的直接关联。这些认知过程随着神经回路的形成而出现 基因在发育过程中的表达。此外，认知障碍定义 神经发育障碍（NDD）被认为至少部分是由神经回路受损引起的 发育中皮层内的连通性。过去十年的一个启示是，NDD 可能是由 de 单基因内的 novo 遗传性功能丧失 SNV。因此，深入研究这些物质的自然功能 基因可以揭示典型发育皮质的神经生物学原理，以及 导致与 NDD 相关的异常皮质发育的原则。在这个项目中，我们将 探索以下假设：典型发育皮质中 NDD 相关基因的表达促进 通过细胞自主调节内在膜兴奋性来组装皮质回路。这 假设很重要，因为众所周知，神经活动塑造了发育中的皮质的组装 电路。然而，目前尚不清楚基因如何在细胞水平上发挥作用以促进活性依赖性 已知可促进认知功能和行为适应的皮质回路基序的体内发育。目的 1 将探讨内在膜兴奋性 (IME) 的遗传控制、活性之间的因果关系 依赖的树突形态发生和皮质回路的发育组装。目标 2 将探索因果关系 IME 的遗传控制、神经元整体结构/功能和行为适应之间的联系。我们 将通过调节发育皮质神经元中 IME 的遗传控制来实现这一点，然后观察 这是关于皮质整体和行为适应的。这项研究设计很重要，因为大脑 跨越多个时间和空间尺度的功能——事实上，这个项目试图将基因功能联系起来 跨越大脑功能的主要层面——基因>神经元>突触>电路>整体>行为。整体 这项拟议研究的影响在于，它有可能揭示基因表达如何塑造活动—— 神经回路的依赖性组装，促进行为适应所需的认知功能。 因为我们关注 NDD 基因的自然功能，所以这些基本见解也与 与儿童脑部疾病相关的皮质线路损伤的病因学。