Department of Neuroscience, The Ohio State University College of Medicine, Columbus, OH, United States.
Front Neural Circuits. 2022 Sep 23;16:982721. doi: 10.3389/fncir.2022.982721. eCollection 2022.
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.
神经科学面临的一个主要挑战是了解不同类型的神经元如何选择其突触伙伴来形成回路。在大脑皮层中，功能不同的区域中存在多种兴奋性投射神经元和抑制性中间神经元。有证据表明，这些神经元类型形成了依赖于其身份的典型回路基元；然而，区域线索也可能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层神经元单细胞 RNA 测序数据库，以研究两个区域（前外侧运动皮层 (ALM) 和初级视觉皮层 (VISp))中突触连接和生理学所需基因的表达。我们使用艾伦研究所的元数据通过代表两种常见于 ALM 和 VISp 的主要兴奋性和抑制性神经元类型的聚类来解析细胞。然后，我们进行了两种类型的成对差异基因表达分析：(1) 在同一脑区（ALM 或 VISp）内的不同神经元类型之间，以及 (2) 在 ALM 和 VISp 中相同的神经元类型之间。我们对与回路连接相关的差异表达基因进行了过滤，并开发了一种新的生物信息学方法来确定在 ALM、VISp 或两者中每个神经元类型唯一富集的基因集。该分析提供了一组有组织的基因，这些基因可能以细胞类型特异性的方式调节突触连接和生理学。此外，它确定了跨功能不同的皮层区域保守或依赖区域的回路组织的候选机制。最后，我们使用 SFARI 人类基因模块来确定该分析中与自闭症谱系障碍 (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标，以了解新皮层回路的组织和自闭症表型的异常。
