Cellular resolution spatio-molecular expression across the anterior-posterior axis of the nucleus accumbens in the human brain

About This Grant

PROJECT SUMMARY The nucleus accumbens (NAc) is a key node of the brain’s reward circuitry, and perturbations in NAc-mediated reward signaling are highly implicated in substance use disorders. The human NAc has unique neuroanatomical features, which correspond to distinct biological functions. Given the close relationship between brain structure and function, precisely assigning spatial coordinates to transcriptionally-distinct cell populations within the intact cytoarchitectural structure is important to advance our understanding of how NAc cell types mediate reward signaling and control motivated behavior. Towards this goal, we recently generated spatial transcriptomic maps combined with paired single-nucleus RNA sequencing (snRNA-seq) to register molecularly-defined cell types to precise spatial coordinates across the dorsal-ventral and medial-lateral axes of the human NAc. Results from those data suggest existence of topographically organized and molecularly-defined cell types across NAc sub- regions in two-dimensional space. In addition to topographical expression in two-dimensional space, the data also suggest potential changes in the density and localization of these transcriptionally-distinct subtypes across the anterior-posterior axis. This application extends our ongoing studies to generate a three-dimensional cellular resolution spatio-molecular map across the neuroanatomical extent of the human NAc, which will be used to computationally assign molecular identities to NAc cell types across dorsal-ventral, medial-lateral and anterior- posterior axes. These refined annotations will be used to register gene expression changes linked to behavioral phenotypes and genetic risk associated with substance use to spatially-defined NAc cell populations. These data are critical for understanding NAc function and identifying clinical associations with molecularly- and spatially- defined cell populations that can be targeted for prevention and treatment.