EXPLORING BRAIN ASYMMETRY IN DEPRESSION: MOLECULAR INSIGHTS FROM A SINGLE-CELL STUDY

Major depressive disorder (MDD) is a common and debilitating psychiatric disorder associated with heightened suicide risk, yet the underlying biological mechanisms remain poorly understood. Atypical brain asymmetries relative to population-level have been implicated in MDD, particularly in functional and structural studies; however, molecular-level hemispheric differences have been less explored. To address this gap, we examined cell-type specific transcriptomics in the subgenual anterior cingulate cortex (sgACC), a region involved in emotion and cognition and strongly implicated in MDD.
We performed single-nucleus RNA sequencing (snRNA-seq) on mirrored post-mortem sgACC tissue dissections from both hemispheres of 31 individuals without MDD and 33 with MDD that died by suicide. Nuclei were isolated from the tissues and processed using the 10x Genomics Chromium 3′ workflow, enabling high-throughput profiling of mRNA transcripts and assignment to their cell of origin.
We generated high-quality, large-scale snRNA-seq data comprising approximately 50 billion transcripts from over 500,000 nuclei across both hemispheres from 64 donors. Preliminary quality control metrics and unfiltered cell clustering demonstrate high technical quality, suitability for desired analysis, and expected cellular composition of the sgACC with clear cell type marker genes. Ongoing analyses will assess hemispheric cell-type specific gene expression differences in psychiatrically healthy individuals and those with MDD. This study is the first to examine hemispheric molecular asymmetry using snRNA-seq and provides a novel framework for understanding asymmetrical cellular mechanisms in MDD and suicide, with implications for biomarker discovery and therapeutic targeting.