Laminar dissection of cortical human brain gene expression in neuropsychiatric disorders

神经精神疾病中皮质人脑基因表达的层状解剖

• 批准号: 10600034
• 负责人: Keri Martinowich
• 金额: $ 77.03万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-23 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600034
• 关键词: Aging; Area; Autopsy; Biological Assay; Brain; Brain Diseases; Brain region; Cell Count; Cell Nucleus; Cells; Data; Data Analyses; Development; Dissection; Freezing; Gene Expression; Genes; Genetic Risk; Genetic Transcription; Genetic Variation; Genome Mappings; Genomics; Histologic; Histology; Human; Image; Immunofluorescence Immunologic; Impairment; In Situ Hybridization; Individual; Maintenance; Maps; Measurement; Measures; Mental disorders; Molecular; Molecular Profiling; Morphology; Neocortex; Neurons; Neuropil; Patients; Pattern; Physiology; Play; Population; Prefrontal Cortex; Prevention; Process; Quantitative Trait Loci; RNA; Resolution; Risk; Role; Sampling; Schizophrenia; Signal Transduction; Specificity; Spottings; Structure; Synapses; Techniques; Tissues; Work; autism spectrum disorder; brain tissue; cell type; depressive symptoms; differential expression; genome wide association study; imaging Segmentation; neocortical; neuropsychiatric disorder; risk variant; schizophrenia risk; single nucleus RNA-sequencing; transcriptome; transcriptome sequencing; transcriptomics; white matter

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.

项目总结/摘要 DLPFC是一个真正的六层新皮质，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。越来越多的证据表明 在突触的形成或维持可能涉及精神分裂症和其他神经精神疾病 紊乱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 神经元和突触结构的差异定位于特定层，这表明遗传风险 精神分裂症可能表现为层状特异性。考虑到大脑结构与 和功能，精确地将基因表达分配到单个细胞群的空间坐标中， 这一皮层细胞结构将极大地促进我们对这些区域调节异常的理解， 会导致神经精神紊乱在这个应用程序中，我们建议生成详细的 精神分裂症（SCZD）、双相型（BPD）、重度精神分裂症（PD）患者中人类DLPFC的空间转录组学图谱 抑郁症（MDD）和自闭症谱系障碍（ASD），并将这些层状表达模式与 来自匹配的神经型对照（CONT）的那些。我们将使用10 x 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，以产生这些空间转录组学谱。我们将把这些联合收割机结合起来 地形图和细胞类型特异性图，以暗示精神病患者中的层和细胞类型特异性群体 疾病遗传风险和疾病状态，将使用补充定量原位验证 杂交技术这些层特异性和细胞类型特异性表达谱可以细化 分子原因和后果的衰弱性神经精神疾病，可以针对 预防和治疗。