Electrical Stimulation’s Effects on Neurons, Gene Expression Mapped in Living Human Brain Tissue

Neurons from living human brain tissue have helped researchers trace how electrical stimulation reshapes brain cell communication and gene activity—work that could guide more precise neuromodulation strategies for cognitive decline and other neurological conditions in the future.

In a study published in Nature, researchers from UCLA Health and the University of Texas Southwestern Medical Center developed an ex vivo platform using human temporal cortex tissue donated by neurosurgery patients and maintained alive in the laboratory for several days. The approach allowed the team to apply electrical stimulation resembling deep brain stimulation, record neuronal activity, and map gene expression changes across individual brain cell types.

The paper, titled “Stimulation modulates gene-linked cell assemblies in the human brain,” addresses a key gap in understanding how stimulation-based therapies affect human brain tissue at the cellular and molecular levels. Although deep brain stimulation is already used for disorders such as Parkinson’s disease and obsessive-compulsive disorder, its effects on different human brain cell types and the genes they activate have not been well defined.

To investigate those mechanisms, the researchers integrated microelectrode array stimulation with simultaneous recording and single-nucleus genomics from resected temporal cortex obtained from neurosurgery patients. In the abstract, the authors wrote that they developed the platform “to directly investigate the mechanisms of neuromodulation elicited by human brain stimulation.” They reported that stimulation strengthened coordinated groups of neurons, or cell assemblies, and then connected those physiological changes to cell-type-specific gene regulatory networks.

After stimulation, brain cells became more synchronized in how they communicated. “These assemblies exhibited stimulation-dependent increases in activation strength and membership flexibility, with analogous properties to compositional drift observed in memory-related assemblies in vivo,” the authors write. The team also found that neurons and non-neuronal support cells, including astrocytes, activated distinct genetic programs in response to stimulation.

“Not only was it a privilege and challenge to work with donated living human brain tissue, but to see it reveal the genes and cell types underlying human brain plasticity as new targets for future therapies makes the work feel even more meaningful,” said senior author Genevieve Konopka, PhD, chair of the department of neurobiology at UCLA Health.

The donated samples came from the temporal cortex, a region on the sides of the brain’s outer layer that is important for memory and related cognitive functions. The authors noted that stimulation of cortical circuits is being explored as a therapeutic strategy for restoring cognitive function, but the biological mechanisms underlying its effects in humans have remained largely unexplored.

The study also points to several open questions. Additional work is needed to determine the molecular effects of long-term stimulation, how stimulated cells influence neighboring cells, and whether similar mechanisms are active in deeper brain regions, which are harder to obtain from living donors. Still, the authors concluded that the work establishes “a foundation for identifying targetable genetic signatures linked with physiology” that could potentially be harnessed through neuromodulation strategies.

“By understanding exactly which genes turn on in which cells during stimulation, we can start to design more precise approaches to deep brain stimulation and potentially augment this clinical strategy with pharmacological therapies to help slow cognitive decline,” added Konopka.

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