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

项目摘要 神经发育障碍（NDD），像大多数神经精神疾病，是在一般术语定义 通过认知障碍和行为改变。大型患者基因组测序研究进展 人群的研究已经导致了导致复杂NDD的基因的鉴定。因此， 与NDD相关的基础研究是了解这些高影响力的遗传风险因素如何破坏分子 以及这些细胞变化如何转化为电路的变化 和行为。这一正在进行的R01历来侧重于共识NDD的神经生物学影响 风险基因Syngap 1对小鼠皮层突触连接的组装和功能的影响。在当前 在预算期间，我们在了解触摸介导的行为缺陷的程度方面取得了进展 以及Syngap 1小鼠模型中处理触摸的皮质回路功能障碍。即将到来的 预算期间旨在了解改变的组装，功能， 和可塑性的皮层电路和触摸相关的行为适应不良。基于 安装已发表和未发表的初步数据，我们将测试的总体假设， Syngap1通过塑造促进触觉的皮层回路来调节认知功能和行为 perception.这一假说与NDD病因学有关，因为感觉加工改变是一种普遍存在的 NDD的表现，包括ASD，SCZ和ADHD。一个在该领域获得动力的想法是， 认知功能和行为的改变至少部分是由受损的感觉神经系统引起的。 大脑皮层回路中的信息处理该研究主题与心理健康障碍有关，因为 认知功能是脑功能的主要领域，而感知是定义它的构造。然而， 支持感知的回路，它们如何直接影响与心理健康障碍相关的行为， 以及主要的遗传风险因素如何调节它们，仍然知之甚少。目标1将决定如何 触觉处理皮层神经元中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如何调节中尺度皮层可塑性 在触觉学习中。目的3旨在了解Syngap 1在前脑兴奋性神经元中的表达， 神经元有助于调节支持强化学习的后脑唤醒中心。整体 影响：拟议的研究有可能定义与受损的大脑皮层回路之间的因果联系。 感官处理直接导致NDD相关的认知和行为障碍。此类研究 预计将告知该领域日益增长的想法，即受损的皮层感觉处理直接导致 行为适应不良是神经衰弱症常见的症状

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 Based on mounting published and unpublished preliminary data, we will test the overarching hypothesis that Syngap1 regulates cognitive function and behavior by sculpting cortical circuits that promote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.