Cell-type specific transcriptomic signatures of neocortical circuit organization and their relevance to autism.
Cell-type specific transcriptomic signatures of neocortical circuit organization and their relevance to autism.
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DOI：
10.3389/fncir.2022.982721
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发表时间：
2022
影响因子：
3.5
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中科院分区：
文献类型：
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神经科学中的一个普遍挑战是了解不同类型的神经细胞如何选择它们的突触伙伴来形成电路。在新皮质，兴奋性投射神经元和抑制性中间神经元的主要类型在功能上不同的区域是保守的。有证据表明，这些类别形成的典型回路主题主要取决于它们的身份；然而，区域线索可能也会影响它们对突触伙伴的选择。我们挖掘了艾伦研究所的小鼠皮质神经元的单细胞RNA测序数据库，以研究突触连接和生理所需的基因在两个区域的表达：前外侧运动皮质(ALM)和初级视觉皮质(Visp)。我们使用Allen的元数据通过代表ALM和Visp共同的主要兴奋性和抑制性类别的簇来解析细胞。然后，我们进行了两种类型的成对差异基因表达分析：(1)同一脑区(ALM或Visp)内不同神经元类别之间的差异基因表达；(2)ALM和Visp中同一神经元类别之间的差异基因表达。我们筛选了与电路连接相关的差异表达基因的结果，并开发了一种新的生物信息学方法来确定在ALM和/或Visp的每个神经元类别中唯一丰富的集合。这一分析提供了一组有组织的基因，这些基因可能以特定细胞类型的方式调节突触连接和生理。此外，它确定了电路组织的候选机制，这些机制在功能不同的皮质区域中是保守的，或者是区域相关的。最后，我们使用SFARI人类基因模块从这项分析中识别出与自闭症谱系障碍(ASD)风险相关的基因。我们的分析为未来的研究提供了明确的分子靶点，以了解自闭症表型背后的新皮质回路组织和异常。
A prevailing challenge in neuroscience is understanding how diverse neuronal cell types select their synaptic partners to form circuits. In the neocortex, major classes of excitatory projection neurons and inhibitory interneurons are conserved across functionally distinct regions. There is evidence these classes form canonical circuit motifs that depend primarily on their identity; however, regional cues likely also influence their choice of synaptic partners. We mined the Allen Institute’s single-cell RNA-sequencing database of mouse cortical neurons to study the expression of genes necessary for synaptic connectivity and physiology in two regions: the anterior lateral motor cortex (ALM) and the primary visual cortex (VISp). We used the Allen’s metadata to parse cells by clusters representing major excitatory and inhibitory classes that are common to both ALM and VISp. We then performed two types of pairwise differential gene expression analysis: (1) between different neuronal classes within the same brain region (ALM or VISp), and (2) between the same neuronal class in ALM and VISp. We filtered our results for differentially expressed genes related to circuit connectivity and developed a novel bioinformatic approach to determine the sets uniquely enriched in each neuronal class in ALM, VISp, or both. This analysis provides an organized set of genes that may regulate synaptic connectivity and physiology in a cell-type-specific manner. Furthermore, it identifies candidate mechanisms for circuit organization that are conserved across functionally distinct cortical regions or that are region dependent. Finally, we used the SFARI Human Gene Module to identify genes from this analysis that are related to risk for autism spectrum disorder (ASD). Our analysis provides clear molecular targets for future studies to understand neocortical circuit organization and abnormalities that underlie autistic phenotypes.
影响因子：
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作者：
Petros TJ
通讯作者：
Petros TJ