Laminar dissection of cortical human brain gene expression in neuropsychiatric disorders

项目概要/摘要 DLPFC是真正的六层新皮质，不同皮质层的神经元表现出不同的表达 模式、形态学、生理学和连接模式。综合证据表明，损伤 突触的形成或维持可能与精神分裂症和其他神经精神疾病有关 失调。对受试者死后大脑的研究指出了特定的细胞类型并揭示了 位于特定层的神经元和突触结构的差异，表明遗传风险 精神分裂症可能表现为层状特异性。鉴于大脑结构之间的密切关系 和功能，将基因表达精确分配给单个细胞群的空间坐标 这种皮质细胞结构将极大地促进我们对这些区域的失调如何发生的理解 导致神经精神疾病衰弱。在此应用程序中，我们建议生成详细的 精神分裂症 (SCZD)、双相情感障碍 (BPD)、重度抑郁症患者 DLPFC 的空间转录组学图谱 抑郁症（MDD）和自闭症谱系（ASD）障碍，并将这些层状表达模式与 那些来自匹配的神经典型对照（CONT）。我们将使用 10x Genomics Visium 平台， 它将全转录组 RNA 测序与详细的高分辨率组织学相结合， 免疫荧光成像，以生成这些空间转录组学概况。我们将结合这些 地形和细胞类型特异性图，以暗示精神病学中的层和细胞类型特异性群体 将使用补充定量原位验证的疾病遗传风险和疾病状态 杂交技术。这些层特异性和细胞类型特异性的表达谱可以细化 可以针对的衰弱性神经精神疾病的分子原因和后果 预防和治疗。

Project Summary/Abstract The DLPFC is a true six layered neocortex, and neurons in different cortical layers show distinct expression patterns, morphology, physiology and patterns of connectivity. Converging evidence suggests that impairments in the formation or maintenance of synapses may be involved in schizophrenia and other neuropsychiatric disorders. Studies in the postmortem brains of subjects have pointed to specific cell types and revealed differences in neuronal and synaptic structure that are localized to specific layers, suggesting that genetic risk for schizophrenia may manifest with laminar specificity. Given the close relationship between brain structure and function, precisely assigning gene expression to the spatial coordinates of individual cell populations within this cortical cytoarchitecture would significantly advance our understanding of how dysregulation in these areas contributes to debilitating neuropsychiatric disorders. In this application, we propose to generate detailed spatial transcriptomics maps of the human DLPFC in patients with schizophrenia (SCZD), bipolar (BPD), major depressive (MDD) and autism spectrum (ASD) disorders, and contrast these laminar expression patterns to those derived from matched neurotypical controls (CONT). We will use the 10x Genomics Visium platform, which combines transcriptome-wide RNA sequencing with detailed high-resolution histology and immunofluorescence imaging, to generate these spatial transcriptomics profiles. We will combine these topographic and cell type-specific maps to implicate layer- and cell type-specific populations in psychiatric disorder genetic risk and illness state that will be validated using complementary quantitative in situ hybridization techniques. These layer-specific and cell type-specific expression profiles can refine the molecular causes and consequences of debilitating neuropsychiatric disorders that can be targeted for prevention and treatment.