EMOTIONAL CONTAGION AND AROUSAL DEFICITS IN CDKL5 DEFICIENCY DISORDER: INSIGHTS FROM PUPILLOMETRY AND OREXIN MODULATION

Emotional contagion (ECo) represents a fundamental component of empathy and has been extensively characterized in rodents. Socio-emotional impairments are often reported in neurodevelopmental disorders; therefore, characterizing ECo in translational mouse models is essential to bridge behavioral phenotypes with underlying neural circuitry. CDKL5 Deficiency Disorder (CDD) is a rare X-linked neurodevelopmental disorder characterized by early-onset seizures, severe developmental delay, intellectual disability, sleep disturbances, and autistic-like behaviors. CDKL5 knock-out mice, a translational model of CDD, exhibit hyperactivity and impulsivity, suggesting dysregulation of arousal systems that may impact socio-emotional processing. We recently demonstrated that pupillometry enables the quantification of ECo in mice by capturing both covert and overt changes in arousal and emotional processing. Using this approach, we investigated ECo in CDKL5 knock-out mice. We found that CDD mice display heightened responses to direct aversive stimulation but reduced sensitivity to the emotional state of a conspecific, indicating a dissociation between self-directed and socially driven emotional responses. Orexin signaling is a central regulator of the sleep-wake cycle and plays a key role in arousal and emotional modulation. We therefore investigated the effects of Suvorexant, a dual orexin receptor antagonist approved for insomnia, to explore its therapeutic potential in restoring arousal balance in CDD. Suvorexant reduced locomotor hyperactivity in CDKL5 knock-out mice without affecting wild-type littermates and significantly rescued the altered orienting response to visual stimuli, indicating improved arousal regulation. Together, these findings provide new insight into emotional and arousal dysfunctions in CDD, and provide a framework for future mechanistic and therapeutic studies.