From cells to selves and back: human neurodiversity at single cell resolution.

Abstract

Human brain development is characterized by a complex cellular and molecular landscape, which vary both within and between individuals. Here we explore the transformative impact of single-cell omics technologies on our understanding of human neurodiversity and neurocomplexity. We trace historical progressions of cellular and molecular biology, highlighting the cell as a pivotal "place holder" for biological inquiry, as a basis to better understand the current revolution of single-cell profiling enabling the study of individual genomes and environmental interactions at unprecedented resolution. Starting from the challenges of defining cell types and states within neurodevelopment, we emphasize the significance of moving beyond categorical distinctions to understand the molecular basis of inter-individual neurodiversity, including genetics, environment, and developmental stochasticity. We introduce the concept of "in vitro epidemiology", leveraging brain organoids and multiplexing approaches to model population-scale cohorts in vitro and thus enabling the dissection of gene-environment interactions at single-cell resolution. We further discuss technical advancements and computational methodologies that are driving the field forward, including the efforts to create comprehensive cell atlases of the human brain and the emerging challenges in data integration and analysis. Finally, we anticipate future perspectives for single-cell studies and brain organoids in advancing our understanding of neurobiology, and cell-based strategies for drug discovery and personalized treatment.