Regional specificity of neuronal cell types, functional connectivity, and cell type-specific correlation to brain disorders in the human ventral tegmental area

Abstract

The ventral tegmental area (VTA) in the midbrain is a key reward system hub associated with multiple brain disorders. While rodent studies reveal a diverse neuronal population and distinct connectivity patterns, the architecture of the human VTA remains poorly understood. Here, we generated a transcriptomic reference atlas of the adult human VTA with subregional resolution. We identify multiple neuronal cell types defined by differential transcription factor expression, as well as regionally enriched GABAergic cell types. Functional connectivity analysis with fMRI suggests that this spatial organization corresponds to distinct connectivity profiles. Integration with other human midbrain single-nucleus RNA-seq datasets reveals a VTA-specific combinatorial GABA-dopaminergic cell type and regional differences among dopaminergic neurons. Finally, we find multiple associations between neuronal cell types and genetic risk for psychiatric disorders and body mass index. Altogether, this study provides a foundation for mechanistic and therapeutic studies into VTA-related diseases.