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

项目摘要 这个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 大规模平行的细胞生物学过程，促进大脑内功能网络的连接 大脑皮层。这是基础研究的一个重要领域，因为皮质网络内的神经动力学是 思想和行为的直接关联性。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，这定义了 神经发育障碍(NDDS)被认为至少部分是由神经回路受损引起的 发育中的皮质内的连通性。过去十年的一项启示是，NDDS可以由De引起 单个基因中新的遗传功能丧失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层的神经生物学原理，以及 导致与NDDS相关的皮质发育异常的原则。在这个项目中，我们将 探索NDD相关基因在典型发育的皮质中表达促进 通过细胞自主调节固有的膜兴奋性来组装大脑皮层回路。这 假设是重要的，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，目前尚不清楚基因是如何在细胞水平上促进依赖活动的 已知的促进认知功能和行为适应的皮质回路模体的活体发育。目标 1将探索内在膜兴奋性(IME)的遗传控制、活性和基因之间的因果关系。 依赖树突状细胞的形态发生和皮质环路的发育组装。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IME在发育中的皮质神经元中的基因控制来做到这一点，然后观察 这是关于大脑皮层整体和行为适应的。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 在大脑功能的主要水平上-gene&gt；neuron&gt；synapse&gt；circuit&gt；ensemble&gt；behavior.整体而言 这项拟议研究的影响是，它有可能揭示基因表达如何塑造活动- 促进行为适应所需的认知功能的神经回路的依赖组装。 由于我们关注NDD基因的自然功能，这些基本见解也直接与 与儿童大脑障碍相关的皮质连接障碍的病因学。

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.