Registration of spatial gene expression in key nodes of reward-related circuitry in the human brain

人脑奖励相关回路关键节点的空间基因表达登记

• 批准号: 10199451
• 负责人: Keri Martinowich
• 金额: $ 82.17万
• 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: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10199451
• 关键词: Address; Adult; Amygdaloid structure; Anatomy; Anterior; Anxiety; Architecture; Area; Autopsy; Behavior; Biological Process; Brain; Brain region; Cell Nucleus; Cells; Chromium; Clinical; Data; Data Set; Disease; Dorsal; Drug Addiction; Environmental Risk Factor; Exposure to; Female; Fluorescent in Situ Hybridization; Fright; Gene Expression; Gene Expression Profile; Genes; Genetic Risk; Genomics; Goals; Human; Individual; Link; Location; Major Depressive Disorder; Manuals; Maps; Measurement; Mediating; Mental disorders; Molecular; Neurons; Nucleus Accumbens; Pattern; Play; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Prevention; Process; Rewards; Rodent; Role; Sampling; Signal Transduction; Small Nuclear RNA; Spottings; Stress; Structure; Substance abuse problem; Supervision; Tissue-Specific Gene Expression; addiction; brain tissue; cell type; cingulate cortex; comorbidity; differential expression; male; neural circuit; neuropsychiatric disorder; novel; reward circuitry; sequencing platform; single molecule; substance use; tool; transcriptome; transcriptome sequencing; transcriptomics; traumatic event

PROJECT SUMMARY Drug addiction is highly comorbid with psychiatric disorders, particularly post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). These conditions share underlying genetic risk and are exacerbated by similar environmental factors, including exposure to stress and traumatic events. The dorsal anterior cingulate cortex (dACC), nucleus accumbens (NAc) and amygdala constitute key nodes of the brain’s reward circuitry, and perturbations in reward signaling are highly implicated in addiction, MDD and PTSD. The human dACC, NAc and amygdala have unique neuroanatomical features, which correspond to distinct biological functions. Given the close relationship between brain structure and function, precisely assigning gene expression to the spatial coordinates of individual cell populations within the cytoarchitecture can significantly advance our understanding of how dysregulation in these areas contributes to addiction and comorbid neuropsychiatric disorders. Towards this goal, we propose to generate detailed spatial transcriptomic maps, which will be combined with single-nucleus RNA sequencing (snRNA-seq) to register molecularly-defined cell types to their spatial coordinates, facilitating prediction of the anatomical locations of distinct neuronal classes of cells within the dACC, NAc and amygdala. These molecularly- and spatially-defined populations of cells will be associated with gene expression changes linked to substance use and comorbid neuropsychiatric disorders. We hypothesize that these regions have a precise molecular architecture that reveals 1) topographically organized and molecularly-defined cell types within layers of the dACC, and across sub-regions of the NAc and amygdala; 2) spatial-enrichment of genes associated with addiction and comorbid neuropsychiatric disorders. By generating the first transcriptome-scale spatial maps of the human dACC, NAc and amygdala, critical information about the molecular landscape of these regions within the architecture of the human brain will be generated. Our spatial registration approach will facilitate refined annotation of cell types in the human brain, and contribute to understanding addiction and comorbid neuropsychiatric disorders by identifying clinical associations with molecularly- and spatially-defined cell populations that can be targeted for prevention and treatment.

项目总结 药物成瘾与精神障碍，特别是创伤后应激障碍(PTSD)高度并存。 和严重抑郁障碍(MDD)。这些疾病都有潜在的遗传风险，并因 类似的环境因素，包括暴露在压力和创伤事件中。背侧前扣带核 大脑皮质(DACC)、伏隔核(NAC)和杏仁核构成大脑奖励回路的关键节点， 奖赏信号的干扰与成瘾、多动症和创伤后应激障碍高度相关。人类的DACC， NAC和杏仁核具有独特的神经解剖学特征，与不同的生物学功能相对应。 鉴于大脑结构和功能之间的密切关系，精确地将基因表达分配给 细胞结构内单个细胞群体的空间坐标可以显著推进我们的 了解这些区域的调节失调如何导致成瘾和共病的神经精神疾病 精神错乱。为了实现这一目标，我们建议生成详细的空间转录地图，这将是 结合单核RNA测序(SnRNA-seq)将分子定义的细胞类型注册到其 空间坐标，便于预测不同神经元类别细胞的解剖位置 DACC、NAC和杏仁核。这些分子上和空间上定义的细胞群体将相互关联 基因表达的变化与药物使用和共病的神经精神障碍有关。我们 假设这些区域有一个精确的分子结构，揭示了地形上的组织 以及dACC各层内以及NAC和杏仁核亚区之间的分子定义的细胞类型； 2)与成瘾和共病神经精神障碍相关的基因的空间丰富。通过生成 人类dACC、NAC和杏仁核的第一个转录组比例空间图，关于 人类大脑结构内这些区域的分子景观将被生成。我们的空间 配准方法将有助于对人脑中的细胞类型进行精细的注释，并有助于 通过确定与成瘾和共病神经精神障碍的临床联系来了解成瘾和共病的神经精神障碍 分子和空间上定义的细胞群体，可以作为预防和治疗的目标。