A Single-Cell Omics Technical Guide for Advancing Neuropsychiatric Research

Single-cell omics technology has advanced rapidly since its inception, offering increasing precision, resolution, and technical diversity to explore cell-specific molecular features in the human brain and neuropsychiatric disorders. While traditional bulk genomic analyses have provided valuable insights into the molecular processes of these disorders, single-cell omics allows for the investigation of cellular heterogeneity in the brain, which is crucial for dissecting underlying pathology. Neuropsychiatric disorders-such as dementia and depression-are complex and heterogenous brain disorders driven by intricate interactions of genetic and environmental factors. Methodological developments in single-cell omic technologies have enabled their application directly to human brain tissue for the study of neuropsychiatric disorders, yielding cell-specific insights in transcriptomics and epigenomics, with emerging findings in proteomics, metabolomics, multi-omics, and beyond. This review discusses different single-cell omic technologies, focusing on their application to postmortem human brain tissue, highlighting key findings from the use of these methods in neuropsychiatric disorders, and providing considerations for future implementation to elucidate the molecular landscape of brain changes associated with these conditions.