Chronic stress in epilepsy induces robust increase in vagal reflex that may underlie severe bradycardia in SUDEP

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with epilepsy and results from physiological disturbances that lead to cardiorespiratory arrest. The mechanisms underlying SUDEP remain unknown but recent evidence suggests that crosstalk between central stress circuits and autonomic motor circuits play a major role. Here, we used a novel mouse model of SUDEP where central corticotropin-releasing hormone circuits (apex of the hypothalamic-pituitary-adrenal axis) are hyperactive to investigate the relationship between stress, epilepsy, and autonomic control. We hypothesized that stress exaggerates vagal reflexes underlying severe bradycardias observed during SUDEP. Epilepsy was induced in mice via microinjection of the chemical convulsant, kainic acid, into ventral hippocampus. Shortly after seizure induction (11.5 ± 6.6 days), 38% (8/21) of mice with hyperactive stress circuits spontaneously died, with no deaths observed in chronically epileptic controls (0/10). In vivo telemetry revealed a resting tachycardia 7 days after seizure induction in both stressed epileptic mice (Δ53.1 ± 40.0 bpm; n=12; p=0.0035) and control epileptic mice (Δ26.1 ± 12.1 bpm; n=6; p=0.0415) compared to stressed saline controls (Δ-11.2 ± 30.0 bpm; n=8) that was attenuated by day 14, 21, and 28. Seizures also elicited a tachycardia immediately before or at the start of seizures, with no difference in magnitude between mice with hyperactive stress circuits (Δ43.86 ± 30.61 bpm; n=6) and controls (Δ 75.64 ± 61.12 bpm; n=6; p=0.2813). Interestingly, in most detected seizures (n=9), this tachycardia was interrupted by transient, reflex-like bradycardias (12.0 ± 6.2 sec, n=10) that were more pronounced in epileptic mice with hyperactive stress circuits (Δ -179.1 ± 48.9 bpm; n=4) than controls (Δ -97.9 ± 42.8 bpm; n=6; p=0.0238). As serotonergic signaling is implicated in SUDEP, a potential cause of bradycardia during seizures is activation of the Bezold-Jarisch chemoreflex (BJC) which is triggered by serotonin type-3 receptors (5HT3R) in vagal afferent terminals throughout the cardiopulmonary system and elicits a reflex bradycardia and apnea similar to physiological events during SUDEP. Shortly after seizure induction (10 days), the magnitude of BJC-induced bradycardia was increased in mice with hyperactive stress circuits (Δ-410.1 ± 74.8 bpm; n=6) compared to stressed saline controls (-212.9 ± 139.9 bpm; n=12; p=0.0041) and control epileptic mice (Δ-163.2 ± 123.9 bpm; n=7; p=0.0080). By day 30, the exaggerated reflex in stressed mice was attenuated (Δ-222.8 ± 114.9 bpm, n=8) compared to day 10 (p=0.0124) but remained significantly greater than control epileptic mice at day 30 (Δ-63.1 ± 15.4 bpm; n=4; p=0.0292). Together, we found that epilepsy leads to a resting tachycardia in all mice shortly after seizure induction, with the lack of specificity to SUDEP prone mice suggesting elevated resting HR is not the primary driver of SUDEP. However, stressed epileptic mice have an exaggerated BJC that peaks in severity when SUDEP mortality is highest, suggesting an etiology for severe bradycardias that promote SUDEP. R01NS102937 NINDS to CRB/JLM This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.