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

项目摘要/摘要 药物成瘾与神经精神障碍，特别是严重抑郁障碍(MDD)高度并存。 这两种情况都是适度可遗传的，并因环境因素，特别是紧张的生活而加剧。 事件，表明遗传和表观遗传的共同责任。此外，这两种疾病的特点都是调节失调。 多巴胺(DA)和5-羟色胺(5-羟色胺)能系统调节动机和认知功能。这个 缰核(Hb)是同时控制DA和5HT系统的为数不多的大脑区域之一，是一个高度有组织的 管理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，但遗传和表观遗传学 调节这种功能障碍的机制尚不清楚。鉴于大脑结构之间的密切关系 和功能，将基因表达分配给功能上不同的解剖亚群和细胞群体 将极大地促进我们对血红蛋白失调是如何导致 神经精神障碍和自闭症。为此，我们建议使用10倍基因组学多基因组和 Viem技术生成相应的人类Hb单细胞和空间分子参考图 在内侧和外侧亚区识别遗传定义和拓扑结构组织的细胞类型 大脑的这一区域。我们还将从患者的匀浆中产生人类Hb的转录数据 MDD和共病MDD/阿片使用障碍(OUD)，并将这些基因表达模式与 来自匹配的神经典型对照。我们将整合免费的地形和单元格类型- 从抑郁症和成瘾患者的匀浆数据中提取特定的参考图 处于疾病状态的特定Hb细胞群体和亚区及其高度共存的遗传风险 条件。通过制作第一个人类缰核的分子神经解剖学图谱，我们将促进 在大脑奖励电路的关键集成中枢中，使用大脑架构改进了细胞类型的注释，该中枢可以 以预防和治疗衰弱的神经精神障碍和药物使用障碍为目标。

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.