The role of the ventromedial nucleus of the hypothalamus in epileptogenesis

The Department of Biomedical Sciences at the University of New England has received a four-year National Institute of Health biomedical grant of $568,000 to advance research on the mechanisms of epileptogenesis and sudden unexpected death in epilepsy (SUDEP). This project focuses on the ventromedial nucleus of the hypothalamus (VMH) as a potential gateway through which forebrain seizure activity propagates to brainstem centers governing respiration and cardiac function. Understanding how seizures spread to these vulnerable brainstem regions is critical to explaining why some seizures evolve into the tonic seizures associated with elevated SUDEP risk. Previous animal-model work identified a pattern: after eight induced seizures followed by a 28-day seizure-free interval, the VMH undergoes a reorganization that permits subsequent seizures to propagate from forebrain networks into brainstem circuits, producing tonic seizures that can increase SUDEP risk. Preliminary, unpublished data suggest that deletion of a single gene in the VMH may prevent this brainstem seizure propagation, pointing to gene-expression changes in the VMH as potential mechanistic drivers and therapeutic targets.

The current project will build on these findings using a multipronged approach. Genomics and extensive bioinformatic analysis will be central to the study, with spatial transcriptomics employed to map gene expression and signaling pathways at cellular resolution within the VMH. This relatively new technology will enable the team to link molecular changes in specific cell types to altered circuit function and seizure propagation patterns.

The goal is to identify gene pathways within the VMH whose alteration over time contributes to the transition toward tonic, brainstem-propagating seizures and heightened SUDEP risk, and to determine whether such pathways represent druggable targets. The four-year NIH funding will support continuation and expansion of the animal-model studies, molecular and transcriptomic assays, and the computational analyses needed to interpret large genomic datasets.

While discovery research carries inherent uncertainty, the work is positioned to provide novel insights into how seizures change over time and to identify potential molecular interventions targeted to the VMH that could prevent life-threatening seizure propagation to brainstem centers.