Hcrt, also known as orexin, is a neuropeptide produced exclusively in the hypothalamus. Hcrt neurons project widely throughout the brain and are involved in regulating numerous behavioral and physiological responses. Hcrt is associated with pathways related to feeding behavior, sleep-wake regulation, and stress response [1,3]. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying Hcrt's functions [4].

In narcolepsy, bi-allelic variants in HCRT cause autosomal recessive narcolepsy with cataplexy. Affected individuals exhibit severe cataplexy along with narcolepsy symptoms in infancy, with cataplexy symptoms improving over time [2]. In two mouse models of narcolepsy type 1 (NT1), the HCRT-KO and DTA models, NT1 mice showed an altered dark-phase activity profile, increased state transitions, and an inability to sustain activity periods >40 min, which can be considered an activity-based NT1 biomarker. These features were observable early in HCRT neuron degeneration in DTA mice [4].

In conclusion, Hcrt plays essential roles in regulating feeding behavior, sleep-wake states, and is closely associated with narcolepsy. The use of HCRT-KO and related mouse models has significantly contributed to understanding the pathophysiology of narcolepsy, revealing key phenotypic features and potential biomarkers related to Hcrt deficiency [2,4].

References:

1. Sakurai, T, Amemiya, A, Ishii, M, Bergsma, D J, Yanagisawa, M. . Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. In Cell, 92, 573-85. doi:. https://pubmed.ncbi.nlm.nih.gov/9491897/

2. Hakami, Wejdan, Thabet, Farah, Alhashem, Amal, Alkuraya, Fowzan S, Tabarki, Brahim. 2024. Bi-allelic variants in HCRT cause autosomal recessive narcolepsy. In Neurogenetics, 25, 79-83. doi:10.1007/s10048-024-00744-0. https://pubmed.ncbi.nlm.nih.gov/38240911/

3. Reading, P J. 2019. Update on narcolepsy. In Journal of neurology, 266, 1809-1815. doi:10.1007/s00415-019-09310-3. https://pubmed.ncbi.nlm.nih.gov/31004212/

4. Piilgaard, Louise, Rose, Laura, Justinussen, Jessica L, Wellendorph, Petrine, Kornum, Birgitte Rahbek. . Non-invasive detection of narcolepsy type I phenotypical features and disease progression by continuous home-cage monitoring of activity in two mouse models: the HCRT-KO and DTA model. In Sleep, 46, . doi:10.1093/sleep/zsad144. https://pubmed.ncbi.nlm.nih.gov/37210587/