Human Cortical Stimulation and Genetically Linked Cell Assemblies

Researchers linked the response of the human cortex to stimulation with the genes activated in different cells

On August 5, Nature published a study of living slices, which are thin fragments of tissue, from the human temporal cortex. The authors delivered electrical impulses to the tissue, recorded the firing of individual neurons, and compared these responses with measurements of RNA and the accessibility of DNA regions in cell nuclei. The final version of the article compared these results with cortical samples obtained after stimulation in vivo.

The team placed slices of temporal cortex on a microelectrode array. The array delivered brief electrical pulses while recording the firing of individual neurons.

Across 37 experiments using samples from 12 people, the researchers identified 19 neuronal ensembles, defined as groups of cells that fire together within a very short time window. After stimulation, these ensembles showed stronger coordinated activation and more frequent high intensity firing. In 11 of 19 ensembles, activation strength increased over time. The neurons participating in the ensembles also changed more often.

For the molecular part of the experiment, the researchers analyzed 50 067 cell nuclei from samples provided by six people. RNA indicates which genes a cell is currently using, while the accessibility of DNA regions indicates which genes can be activated. Stimulation increased firing frequency more often in pyramidal neurons, which transmit excitatory signals, than in interneurons, which regulate signaling between neurons. Several subtypes of excitatory neurons showed altered activity in genes involved in rapid responses to stimulation, signaling between neurons, and the function of channel proteins that allow charged particles to pass through cell membranes.

The final version of the article compared these data with findings from human cortex after stimulation in vivo and identified shared cell-specific gene expression signatures. The experiment connected three levels of response: electrical impulses, coordinated neuronal activity, and the responses of specific cell types. The authors suggest that this map could help identify which cells future neurostimulation approaches should target.