Resolving cellular and anatomical complexity of the brainstem using single-cell genomics

The National Institute of Mental Health awarded the Allen Institute $1,880,723 on March 13, 2026, under the Mental Health Research Grants program (CFDA 93.242) to resolve cellular and anatomical complexity of the brainstem using single-cell genomics.

The award funds creation of a refined atlas of brainstem cell types through single-cell transcriptomic profiling, spatial transcriptomic profiling, and mapping of projection patterns to transcriptomic cell types. The brainstem contains highly heterogeneous neurons that require a high-dimensional combinatorial gene expression code for resolution. Cell type characterization enables genetic access to specific cell groups, dissection of cellular heterogeneity, identification of key players in disease and aging, and development of targeted interventions and therapies.

The Allen Institute, a nonprofit research organization headquartered in Seattle, Washington, serves as the prime recipient. Performance occurs in Washington, with a period of performance through December 31, 2028. The project builds on a comprehensive, high-resolution atlas of cell types across the entire adult mouse brain, where brainstem cell type diversity exceeded initial expectations and demonstrated that individual neurons intermingle across regions with function strongly determined by input and output relationships rather than shared gene modules.

Abstract

The brain is an extraordinarily complex organ containing many millions of neurons and non-neuronal cells that are organized into highly specialized yet intricately integrated circuits controlling various activities, such as sensory perception, motor control, and cognitive processes. The brainstem is a critical region responsible for regulating essential bodily functions, like heart rate, blood pressure, and digestion, and thus maintaining body homeostasis. The individual neurons in brainstem can be classified into types based on shared characteristics like gene expression. Binning individual cells into cell types is fundamental for advancing our understanding of complex biological systems, like the brain, from normal tissue function to disease processes. The characterization of cell types enables creation of tools to gain genetic access to groups of cells, IT enables dissection of cellular heterogeneity, identify key players in various contexts like disease and aging, and lay the groundwork for targeted interventions and therapies. We recently built a comprehensive, high-resolution atlas of cell types across the entire adult mouse brain and the cell type diversity in brainstem exceeded our expectations. Brainstem is home to a highly heterogeneous group of neurons that does not share a specific gene module, yet these neurons are highly similar to one another. In addition, these cell types intermingle in various regions and their function is strongly determined by their input/output relationship. This suggests that a high-dimensional combinatorial gene expression code is needed to resolve the unique transcriptomic cell types in this region. Our goal is to create a refined atlas of cell types in brainstem using a combination of single cell transcriptomic profiling, spatial transcriptomic profiling, and mapping of projection patterns to transcriptomic cell types in brainstem. In addition, we will computationally align brain stem cell types from mouse, non-human primate, and human to define a cross-species consensus atlas of brain stem. Cell type homologies across species can be established based on conserved marker expression. This enables inference of cellular properties, such as long- range projection targets, that are difficult to measure in humans. The proposed efforts will lead to a significantly improved understanding of brainstem cell types and their function and lay the foundation for a better understanding of disease processes related to that region.