Activity-induced gene expression in the human brain

Chatterjee, S.; Park, B. J.; Vanrobaeys, Y.; Heiney, S. A.; Rhone, A. E.; Nourski, K. V.; Langmack, L.; Mukherjee, U.; Kovach, C. K.; Kocsis, Z.; Kikuchi, Y.; Petkov, C. I.; Hefti, M. M.; Bahl, E.; Michaelson, J. J.; Kawasaki, H.; Oya, H.; Howard, M. A.; Nickl-Jockschat, T.; Lin, L.-C.; Abel, T.

doi:10.1101/2023.09.21.558812

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bioRxiv · 10.1101/2023.09.21.558812

Activity-induced gene expression in the human brain

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Abstract

Direct electrical stimulation (eSTIM) is widely used clinically, from neurosurgical mapping to therapeutic interventions for neurological and neuropsychiatric disorders1-10. Despite over a century of application, its molecular and cellular underpinnings remain unknown. Here, using state-of-the-art single-nuclei multiomic profiling, we map changes in cell-type-specific gene expression and chromatin accessibility in vivo in the human cortex following eSTIM of neurosurgery patients. eSTIM impacts a network of cells that extends beyond excitatory neurons to include inhibitory neurons, astrocytes, oligodendrocytes and microglia. We observed an upregulation of canonical immediate-early genes (IEGs: FOS, NPAS4, EGR4) in excitatory and inhibitory neurons and induction of cytokine-related genes CCL3 and CCL4 in microglia. The cross-species conservation of this gene signature, together with our examination of a cohort of both epilepsy and cancer patients, underscores the fundamental role of these changes in stimulation-driven plasticity while controlling for disease and environmental confounds. Our study of changes in chromatin accessibility reveals a common code that involves a cell-type specific signature of transcription factor binding motifs for members of the EGR family. By addressing these previously unexplored questions about activity-induced gene expression in vivo in the human brain, our findings challenge the long-standing neuron-centric view of eSTIM, highlighting the broader role of non-neuronal cells, including microglia, in mediating the impact of brain stimulation.

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Chatterjee, S., Park, B. J., Vanrobaeys, Y., Heiney, S. A., Rhone, A. E., Nourski, K. V., Langmack, L., Mukherjee, U., Kovach, C. K., Kocsis, Z., Kikuchi, Y., Petkov, C. I., Hefti, M. M., Bahl, E., Michaelson, J. J., Kawasaki, H., Oya, H., Howard, M. A., Nickl-Jockschat, T., Lin, L.-C., Abel, T.. 2023-09-22. Activity-induced gene expression in the human brain. https://doi.org/10.1101/2023.09.21.558812

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