Intersection of causal neurodevelopmental disorder risk genes, cortical circuit function, and cognitive processing required for behavioral adaptions

项目总结 神经发育障碍(NDDS)，就像大多数神经精神障碍一样，是用一般术语来定义的 通过认知障碍和行为改变。大病人基因组测序研究进展 种群导致了导致复杂NDD的基因的识别。因此，一个主要的领域 与NDDS相关的基础研究是了解这些高影响的遗传风险因素如何扰乱分子 和脑细胞的细胞机制，以及这些细胞变化如何转化为电路的变化 和行为。正在进行的R01历来专注于共识NDD的神经生物学影响 风险基因Syngap1对小鼠皮质突触连接的组装和功能的影响。在当前 在预算期间，我们在了解触摸中介行为缺陷的程度方面取得了进展 在Syngap1小鼠模型中，处理触摸的皮质回路内的功能障碍。即将到来的 预算期旨在了解改变的装配、功能、 在这个模型中，大脑皮质回路和与触摸相关的行为适应不良的可塑性。基于 收集已公布和未公布的初步数据，我们将检验总体假设 Syngap1通过塑造促进触觉的大脑皮层回路来调节认知功能和行为 感知力。这一假说与NDD病因学相关，因为感觉加工的改变是无处不在的 NDDS的表现，包括ASD、SCZ和ADHD。在该领域获得声势的一个想法是 认知功能和行为的改变至少部分是由感官受损引起的 在大脑皮层回路内进行处理。这一研究主题与精神健康障碍相关，因为 认知功能是大脑功能的一个主要领域，而知觉是定义它的一个概念。然而， 支持感知的回路，它们如何直接影响与精神健康障碍相关的行为， 以及主要的遗传风险因素是如何调控它们的，目前还知之甚少。目标1将决定如何 触觉加工皮质神经元中Syngap1的表达有助于触觉学习和行为 Syngap1小鼠的表型。目的2研究将确定Syngap1如何调节中尺度皮质可塑性 在触觉学习过程中。AIM 3旨在深入了解Syngap1在前脑兴奋性反应中的表达 神经元对支持强化学习的后脑唤醒中枢的调制起作用。总括 影响：拟议中的研究有可能定义与受损的大脑皮质回路之间的因果联系 感觉处理直接导致新城疫相关的认知和行为障碍。这类研究是 预计将向该领域日益增长的观点提供信息，即皮质感觉处理受损直接导致 NDD常见的行为适应不良。

PROJECT SUMMARY Neurodevelopmental disorders (NDDs), like most neuropsychiatric disorders, are defined in general terms through cognitive impairment and behavioral alterations. Advances in genome sequencing from large patient populations has led to the identification of genes that cause complex NDDs. As a result, a major area of basic research related to NDDs is to understand how these high-impact genetic risk factors disrupt molecular and cellular mechanisms in brain cells and how these cellular alterations translate to changes in circuitry and behavior. This ongoing R01 has historically focused on the neurobiological impact of a consensus NDD risk gene, Syngap1, on the assembly and function of cortical synaptic connectivity in mice. In the current budget period, we have made progress toward understanding the extent of touch-mediated behavioral deficits and dysfunction within cortical circuitry that processes touch in the Syngap1 mouse model. The upcoming budget period seeks to understand the cause-and-effect relationships between altered assembly, function, and plasticity of cortical circuits and touch-associated behavioral maladaptations in this model. Based on mounting published and unpublished preliminary data, we will test the overarching hypothesis that Syngap1 regulates cognitive function and behavior by sculpting cortical circuits that promote tactile perception. This hypothesis is relevant to NDD etiology because altered sensory processing is a ubiquitous manifestation of NDDs, including ASD, SCZ, and ADHD. An idea gaining momentum in the field is that alterations to cognitive function and behavior are caused, at least in part, through impaired sensory processing within cortical circuits. This research topic is relevant to mental health disorders because cognitive function is a major domain of brain function and perception is a construct that defines it. However, the circuits that support perception, how they directly impact behaviors relevant to mental health disorders, and how major genetic risk factors regulate them, remains poorly understood. Aim 1 will determine how Syngap1 expression within tactile processing cortical neurons contributes to tactile learning and behavioral phenotypes in Syngap1 mice. Aim 2 studies will determine how Syngap1 regulates mesoscale cortical plasticity during tactile learning. Aim 3 is designed to provide insight into how Syngap1 expression in forebrain excitatory neurons contributes to modulation of hindbrain arousal centers that support reinforcement learning. Overall Impact: The proposed research has the potential to define cortical circuits that causally link impaired sensory processing directly to NDD-associated cognitive and behavioral impairments. Such studies are expected to inform the growing idea in the field that impaired cortical sensory processing directly leads to behavioral maladaptations common to NDDs.