kilduff2005

Guest Editorial: Hypocretin/Orexin and Its Multifaceted Roles

Historical Context

The period from 1998 to 2000 marked a significant advancement in sleep research, focusing on the hypocretin/orexin neuropeptide system. This was highlighted by:

1998: Discovery of the hypocretin/orexin neuropeptide system, with two research groups independently identifying its sequence and localization.
1999: Linkage of hypocretin with narcolepsy in animal models, culminating in the identification of gene defects in canines suffering from this sleep disorder.
2000: Discovery of neuropathological findings related to human narcolepsy, establishing a connection between reduced hypocretin levels and the disorder.

Discovery of Hypocretin/Orexin Peptides

Identification of Peptides:
- Two papers from 1998 detailed the hypocretin gene, its location on the chromosome, mRNA encoding two peptides, and anatomical locations of the neurons producing these peptides.
Research Contributions:
- de Lecea et al.: Focused on presynaptic vesicles and excitatory effects on hypothalamic cells.
- Sakurai et al.: Clarified the sequence of orexin peptides, receptors OX1R (Hcrtr1) and OX2R (Hcrtr2), and their potential appetite-stimulating effects.

Genetic Links to Narcolepsy

In 1999, a canine model led to identifying a mutation in the Hcrtr2 receptor, pointing towards genetic anomalies associated with narcolepsy.
The orexin knockout mouse showed behaviors similar to cataplexy, reinforcing the genetic connection.
The hunt for genetic mutations in human narcoleptics revealed one patient with a mutation in the Hcrt gene, but more commonly, human narcolepsy involves degeneration of hypocretin neurons in the hypothalamus.

Significant Research Developments (2000-2005)

Sakurai's Review: Provides a comprehensive overview of hypocretin neurons, their mechanistic properties, and relationships to narcolepsy in various rodent models. The role of orexin receptors in cataplexy is further examined, indicating both receptors are essential for this condition.
Characterization Techniques: The orexin/GFP mouse model aided in understanding the response of hypocretin neurons to neurotransmitters, with norepinephrine and serotonin being inhibitory, while acetylcholine is excitatory.

Energy Balance and Wakefulness

Hypocretin neurons link energy levels and wakefulness:
- Orexin/ataxin-3 mice that lose hypothalamic hypocretin neurons become obese despite lower food intake.
- Studies of narcoleptic individuals suggest a correlation between hypocretin levels and increased body mass index (BMI).
- Specific metabolic cues like glucose and leptin inhibit these neurons, which may relate to post-meal sleepiness. Ghrelin, linked to hunger, has an excitatory effect.

Hypocretin Levels in Sleep Disorders

Baumann and Bassetti's review discusses the significance of Hcrt-1 levels in various sleep disorders:
- Most narcolepsy patients exhibit low or undetectable Hcrt-1 in their CSF, but exceptions exist.
- Some symptomatically hypersomnolent individuals do not display hypocretin deficiencies, highlighting distinct pathophysiology of different hypersomnia types.

Implications Beyond Sleep Disorders

The research highlights additional functions of hypocretins, including:
- Cardiovascular Regulation: Potential interactions between hypocretin activity and blood pressure regulation.
- Stress Response: Hypocretins influence stress hormone systems, suggesting broader neuroendocrine roles beyond sleep and appetite.
- Motor Activity: Activation of hypocretin neurons is correlated with purposeful movement, emphasizing their role beyond wakefulness.

Future Directions and Conclusions

More research is needed to elucidate the pathways of hypocretin signaling and address degeneration causes in narcolepsy.
The scientific community should evaluate the long-term effects of hypocretin replacement therapies and their impact on neuroendocrine systems.
Assessing the role of altered hypocretin signaling in neurological conditions may provide insights into managing other disorders involving sleep and wakefulness.