Lin, Qianyu, Kang, Chris, Xavier, Andre M, Sanchez-Martin, Irene, Mehta, Ashesh D, Cheadle, Lucas (February 2026) Deciphering epileptogenic and activity-dependent gene programs in the human brain. bioRxiv. ISSN 2692-8205 (Submitted)
![[thumbnail of 10.64898.2026.02.18.706645.pdf]](https://repository.cshl.edu/style/images/fileicons/application_pdf.png) |
PDF
10.64898.2026.02.18.706645.pdf - Submitted Version Available under License Creative Commons Attribution. Download (6MB) |
Abstract
Neuronal activity is fundamental to brain function, yet chronically elevated activity underlies neurological disorders such as drug-resistant epilepsy (DRE). In animal models, activity induces defined transcriptional programs within activated neurons; however, the nature, cellular specificity, and pathological relevance of such programs in the human brain remain poorly understood. Here, we apply single-nucleus and spatial transcriptomics to epileptogenic, non-epileptogenic, and intraoperatively stimulated non-epileptogenic cortical tissue obtained from individuals with DRE. Across 26 cell types profiled, glutamatergic neurons projecting from cortical layers 2/3, 5, and 6 to intratelencephalic targets exhibit pronounced sensitivity to the epileptogenic microenvironment, inducing shared immediate-early genes alongside cell-type-specific programs linked to synaptic remodeling and cellular stress. Approximately one-third of transcripts enriched in the epileptogenic microenvironment were also induced by acute stimulation, suggesting that a fraction of epilepsy-associated gene expression reflects conserved responses to heightened activity rather than disease-specific programs. While transcripts induced by both epileptogenic and acute activity converged upon immediate-early genes and heat-shock proteins, only acute stimulation triggered a rapid, multicellular induction of transcripts involved in mitochondrial ATP synthesis. This divergence suggests that neurons within epileptogenic cortex may be unable to mount appropriate metabolic adaptations to sustained energetic demands. In parallel, both microglia and circulating CD14+ monocytes exhibit signs of immune activation in epilepsy, suggesting myeloid-driven inflammatory rewiring that extends beyond the brain. Together, these findings illuminate human activity-dependent gene programs and reveal signatures of neuronal vulnerability and inflammation in DRE.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders diseases & disorders > nervous system diseases and disorders diseases & disorders > nervous system diseases and disorders > epilepsy |
| CSHL Authors: | |
| Communities: | CSHL labs > Cheadle lab CSHL Post Doctoral Fellows |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 18 February 2026 |
| Date Deposited: | 20 Mar 2026 15:57 |
| Last Modified: | 20 Mar 2026 15:57 |
| PMCID: | PMC12934787 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42104 |
Actions (login required)
 |
Administrator's edit/view item |