Large-scale neurophysiology and single-cell profiling in human neuroscience

Abstract

Advances in large-scale single-unit human neurophysiology, single-cell RNA sequencing, spatial transcriptomics and long-term ex vivo tissue culture of surgically resected human brain tissue have provided an unprecedented opportunity to study human neuroscience. In this Perspective, we describe the development of these paradigms, including Neuropixels and recent brain-cell atlas efforts, and discuss how their convergence will further investigations into the cellular underpinnings of network-level activity in the human brain. Specifically, we introduce a workflow in which functionally mapped samples of human brain tissue resected during awake brain surgery can be cultured ex vivo for multi-modal cellular and functional profiling. We then explore how advances in human neuroscience will affect clinical practice, and conclude by discussing societal and ethical implications to consider. Potential findings from the field of human neuroscience will be vast, ranging from insights into human neurodiversity and evolution to providing cell-type-specific access to study and manipulate diseased circuits in pathology. This Perspective aims to provide a unifying framework for the field of human neuroscience as we welcome an exciting era for understanding the functional cytoarchitecture of the human brain.

Figure 1:. The Central Dogma of neuroscience.

Cells in the human brain share the same genomic information but develop distinct patterns of gene expression. In turn, gene expression profiles correlate, and in many cases, regulate the abundance of proteins that build the cells and determine their distinct properties, such as morphology and physiology. Ensembles of neuronal cells give rise to synaptically-coupled neuronal networks that generate network-level properties. Coordinated activity of neurons in neural circuit give rise to motor output and cognition. Importantly, neuronal activity feeds back to control gene expression through activity-dependent molecular and cellular changes.

Figure 2:. Central approaches to advance the study of human brain.

Intraoperative recordings on neural activity while patients are doing cognitive tasks can be conducted ethically and with patient consent to gain insight into neural correlates of human behavior (top left). Tissue resected from the brain can be maintained in ex vivo culture condition to facilitate single-cell electrophysiology and molecular profiling (bottom left). In parallel, postmortem tissue specimens provide generalizable insights across brain regions and broader patient population (right).