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

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.