0047 Mapping orexin 2 receptor pathways that improve sleepiness and cataplexy

Abstract Introduction Narcolepsy type 1 is caused by selective loss of orexinergic neurons, resulting in poor maintenance sleep and wakefulness, emergence cataplexy. Orexinergic neurons innervate many brain regions, specific narcolepsy symptoms likely arise from dysfunction distinct regions. Orexin 2 receptors (OX2R) are expressed nearly all wake- REM sleep-regulatory OX2R agonists improve mouse models human patients. However, the key regions pathways through which signaling stabilizes wake suppresses cataplexy only partially understood. In this study, we restored expression mice lacking OX2R, assessed if an OX2R-selective agonist improves aspects their symptoms. Methods We produced a murine model with diphtheria toxin receptor (DTR) knocked into endogenous prepro-orexin locus (orexinDTR mice). After injection (DTX), orexinDTR have severe neurons. crossed transcription-disrupted (TD) to produce new (OX2R TD::orexinDTR To induce focal microinjected adeno-associated viral vector coding for Cre recombinase mice. At 6 weeks after DTX injection, administered OX-201 or vehicle orally expressing evaluated effects on including sleepiness Results tuberomammillary nucleus (TMN) basal forebrain (BF) significantly improved wakefulness but did not suppress contrast, ventrolateral periaqueductal grey lateral pontine tegmentum (vlPAG/LPT) suppressed without improving wakefulness. Conclusion These findings demonstrate that TMN BF can stabilize sleep, vlPAG/LPT region Support (if any) This work was funded Takeda Pharmaceutical Company Limited.