Regulation of Gene Expression in the Human Habenula in Comorbid Opioid Addiction and Depression

项目总结/摘要 药物成瘾与神经精神障碍，特别是重度抑郁症（MDD）高度共病。 这两种情况都是适度遗传的，并因环境因素而加剧，特别是压力生活 事件，表明遗传和表观遗传的综合责任。此外，这两种疾病的特点失调 多巴胺能（DA）和多巴胺能（5 HT）系统调节动机和认知功能。的 缰核（Hb）是少数几个同时控制DA和5-HT系统的脑区之一，是一个高度组织化的 控制动机行为和情感状态的奖励回路的中心节点。Hb功能障碍是 与情绪调节受损和物质使用障碍（SUD）有关，但遗传和表观遗传 介导这种功能障碍的机制是未知的。考虑到大脑结构与 和功能，将基因表达分配给功能上不同的解剖学细分和细胞群体 在人类血红蛋白将显着推进我们的理解如何血红蛋白失调有助于 神经精神疾病和SUD。为此，我们建议采用10倍基因组学多组， Visium技术生成相应的人血红蛋白单细胞和空间分子参考图谱 以鉴定内侧和外侧亚部中遗传定义和地形学组织的细胞类型 大脑的这个区域。我们还将从患有以下疾病的患者的匀浆人Hb中生成转录组学数据： MDD和共病MDD/阿片类药物使用障碍（OUD），并将这些基因表达模式与那些 来自匹配的神经典型对照。我们会整合互补的地形和细胞类型- 抑郁症和成瘾患者匀浆数据的特异性参考图谱 特定的Hb细胞群体和亚区的疾病状态和遗传风险，这些高度共病 条件通过生成人类缰核的第一个分子神经解剖图谱，我们将促进 在大脑奖励回路的关键整合中心，用大脑结构对细胞类型进行精细注释， 目标是预防和治疗衰弱性神经精神和物质使用障碍。

PROJECT SUMMARY/ABSTRACT Drug addiction is highly comorbid with neuropsychiatric disorders, especially major depressive disorder (MDD). Both conditions are moderately heritable and exacerbated by environmental factors, particularly stressful life events, suggesting combined genetic and epigenetic liability. Furthermore, both illnesses feature dysregulation of dopaminergic (DA) and serotonergic (5HT) systems modulating motivation and cognitive function. The habenula (Hb) is one of the few brain regions controlling both DA and 5HT systems and is a highly organized central node for reward circuits governing motivated behavior and affective states. Hb dysfunction is associated with impaired mood regulation and substance use disorder (SUD), but the genetic and epigenetic mechanisms mediating this dysfunction are unknown. Given the close relationship between brain structure and function, assigning gene expression to functionally distinct anatomical subdivisions and cell populations within the human Hb would significantly advance our understanding of how Hb dysregulation contributes to neuropsychiatric disorders and SUD. Towards this end, we propose to employ 10x Genomics Multi-ome and Visium technologies to generate corresponding single cell and spatial molecular reference maps of human Hb to identify genetically-defined and topographically-organized cell types across medial and lateral subdivisions of this brain region. We will also generate transcriptomic data from homogenate human Hb in patients with MDD and comorbid MDD/opioid use disorder (OUD), and contrast these gene expression patterns to those derived from matched neurotypical controls. We will integrate complimentary topographic and cell type- specific reference maps with homogenate data from patients with depression and addiction to implicate specific Hb cell populations and subregions in illness state and genetic risk for these highly comorbid conditions. By generating the first molecular neuroanatomical atlas of the human habenula, we will facilitate refined annotation of cell types with brain architecture in a key integration hub of brain reward circuitry that can be targeted for prevention and treatment of debilitating neuropsychiatric and substance use disorders.