Circadian Rhythm Disruption in DEE: Neuroendocrine and Sleep–Wake Dysregulation in Animal Models of Epilepsy

Rationale: Developmental and Epileptic Encephalopathies (DEEs) are a group of severe epilepsy syndromes that typically begin in infancy or early childhood and are characterised by drug-resistant seizures, abnormal brain development, and significant cognitive and behavioural impairments. In DEEs, both the underlying genetic causes and the epileptic activity contribute to neurodevelopmental decline. Although DEEs are often diagnosed in childhood, many persist into adolescence and adulthood, with ongoing seizures, intellectual disability, psychiatric comorbidities, and severe disruption to daily function. Importantly, individuals with DEEs frequently exhibit chronic sleep disturbances and circadian rhythm dysfunction, including fragmented sleep, abnormal sleep timing (e.g., phase advances), and hormone rhythm disruption (e.g., melatonin, cortisol). These circadian abnormalities can exacerbate seizure burden, impair cognition, and negatively affect overall quality of life. Despite increasing recognition of circadian dysfunction in epilepsy, its mechanisms—particularly the interplay between central (SCN-driven) and peripheral circadian systems—remain poorly understood. This project aims to investigate circadian rhythm disturbances in validated rodent models of genetic and acquired epilepsy, focusing on how seizure activity impacts both behavioural and molecular circadian outputs. By exploring sleep–wake cycles, hormonal rhythms, and brain activity across time-of-day, we aim to uncover novel targets for chronotherapy—treatments timed to the body's biological rhythms—for patients living with DEEs. This project aims to elucidate how epilepsy disrupts both central and peripheral circadian control systems using well-established rodent models. Objectives: Characterise alterations in sleep–wake architecture and circadian hormone rhythms (corticosterone, melatonin) in genetic and acquired epilepsy models. Assess SCN-driven circadian entrainment via electrophysiological recordings from implanted electrodes. Identify potential therapeutic windows aligned with endogenous rhythmicity to inform chronotherapeutic interventions. Project Scope and Methods: Animal Models: Use rodent models of genetic epilepsy of DEEs. Circadian Phenotyping: Monitor sleep–wake cycles using electroencephalogram (EEG) (electrode implants targeting SCN and cortex), combined with actigraphy and video behavioral tracking. Hormone Profiling: Collect serial blood samples across 24 hours to quantify corticosterone and melatonin rhythms. Data Integration: Correlate hormonal rhythms, sleep–wake patterns, electrophysiological waves, and imaging signals to map circadian dysregulation in epilepsy. Skills Acquired: Small animal handling and stereotaxic neurosurgery (electrode implantations). Electrophysiology and behavioral neuroscience techniques. Hormonal assays and chronobiology methods. Experimental design, data interpretation, and translational neuroscience insight. Significance: Findings from this project could uncover mechanistic links between seizure activity and circadian misalignment, potentially revealing time-of-day–specific vulnerabilities. Such insights provide a foundation for developing chronotherapeutic strategies—optimising treatment timing to align with endogenous rhythms and improve seizure control and quality of life in DEE patients.