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

项目摘要 药物成瘾与精神障碍高度共病，特别是创伤后应激障碍（PTSD） 重度抑郁症（MDD）这些疾病具有潜在的遗传风险，并因以下因素而加剧： 类似的环境因素，包括暴露于压力和创伤事件。背侧前扣带回 大脑皮层（dACC）、杏仁核（NAc）和杏仁核构成了大脑奖赏回路的关键节点， 奖赏信号的紊乱与成瘾、抑郁症和创伤后应激障碍密切相关。人类的dACC， NAc和杏仁核具有独特的神经解剖学特征，对应于不同的生物学功能。 考虑到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大脑中的 细胞结构中单个细胞群的空间坐标可以显著地提高我们的 了解这些区域的失调如何导致成瘾和神经精神共病 紊乱为了实现这一目标，我们建议生成详细的空间转录组图谱， 与单核RNA测序（snRNA-seq）相结合，将分子定义的细胞类型登记到它们的 空间坐标，便于预测内不同神经元类细胞的解剖位置 dACC、NAc和杏仁核。这些分子和空间上定义的细胞群将与 基因表达变化与物质使用和共病神经精神障碍有关。我们 假设这些区域具有精确的分子结构，揭示了1）地形学组织 以及在dACC层内以及跨NAc和杏仁核的子区域的分子定义的细胞类型; 2)与成瘾和共病神经精神疾病相关的基因的空间富集。通过生成 人类dACC，NAc和杏仁核的第一个转录组规模的空间图，关于大脑皮层的关键信息， 将产生人脑结构内这些区域的分子景观。我们的空间 配准方法将有助于人类大脑中细胞类型的精细注释，并有助于 通过识别与成瘾的临床关联来了解成瘾和共病神经精神障碍 分子上和空间上确定的细胞群，可以作为预防和治疗的目标。

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.