Narcolepsy: How’s your Hypothalamus Doing?

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By: Jonathon Chio and Fadl Nabbouh

Google dictionary defines sleep as, “a condition of body and mind such as that which typically recurs for several hours every night, in which the nervous system is relatively inactive, the eyes closed, the postural muscles relaxed, and consciousness practically suspended.” While it is unknown why we sleep, sleep increases our cognition and well-being.1 Multiple theories have aspired to explain why we sleep; indicating that sleep 1) keeps organisms out of danger, 2) allows organisms to conserve energy, 3) allows the body to repair, and 4) permits the brain to consolidate neuronal networks. Despite the benefits of sleep, uncontrolled occurrence of sleep is debilitating. An inability to regulate sleep and wakefulness is a layman description of narcolepsy, a neurological disorder with relatively unknown etiology that typically starts at age 15 to 25; effecting 1/2000 individuals and both genders equally.2,3

Narcolepsy affects regions of the brain that regulate sleep-wake cycles,4 and its symptoms decrease the patients’ quality of life (QOL). Two main symptoms are excessive daytime sleepiness and cataplexy; both of which are associated with occurrence of positive emotions. The former is described as sudden bouts of sleep that last between a few seconds to several minutes, while the latter is a sudden loss of muscle control despite maintaining consciousness. Other indications are associated with abnormal occurrence of rapid-eye movement (REM) sleep; including hallucinations, microsleep, night-time wakefulness, and sleep paralysis. Although the severity of symptoms decreases over time, patients’ QOL suffer due to the associated complications in all facets of their lives. Increased frequency of sleep episodes and cataplexy, render patients susceptible to physical harm, obesity, and traffic accidents. The latter is of particular concern, as according to a study conducted by the University of Maryland, over 75% of patients report falling asleep behind the wheel and 56% report being almost involved in an accident.5 Furthermore, narcolepsy patients exhibit decreased cognitive function and greater depression. Establishing a cause-and-effect relationship between narcolepsy and these factors is challenging.

Research on narcolepsy etiology has been centered on major neurotransmitters involved in sleep regulation, one of which is orexin (OX)/hypocretin (HCRT). Differences in nomenclature can be attributed to the same neurotransmitter having been discovered by two independent laboratories.6 While the terms are interchangeable, HCRT will be used for the rest of this article. HCRT is generated from enzymatic processing of prepro-HCRT to yield HCRT1 and HCRT2, of which the latter plays a dominant role in sleep regulation.6,7 HCRT-secreting neurons are found in the posterolateral hypothalamus and project to a variety of neuronal networks. These networks include cholinergic and gamma-aminobutyric acid (GABA)-ergic networks, which then project to the cortex, thalamus, and brain stem.6,8 Generally, cholinergic systems promote wakefulness, while GABA-ergic systems favour sleep.6 Moreover, HCRT regulates other physiological functions, such as thermal regulation, metabolism, feeding, autonomic tone, pain sensation, and addiction.8,9

Pre-clinical animal models have been a valuable research tool to understand narcolepsy etiology and develop treatments. These models can naturally develop narcolepsy or be genetically modified to exhibit the narcoleptic phenotype.9 These data indicate that a deficient HCRT system leads to imbalance between cholinergic and GABA-ergic systems; thus, causing inappropriate transitions between wakefulness and sleep.6,7,10 However, clinical translation of these results are mediocre. Similar to pre-clinical models, narcoleptic patients exhibit a dysfunctional HCRT system by losing 90% of HCRT-secreting neurons and having very low levels of HCRT in their cerebrospinal fluid (CSF). However, unlike patients, most animal models are caused by deletion or mutation of genes for HCRT and its receptor (HCRTR).7

Although no distinct genetic mutations have been found in human narcolepsy to date, there is still a modest genetic component.9 While first degree relatives of narcoleptic patients have about a 1% chance of developing the disorder, there is a 0.1% chance in people without an affected first degree relative. Unique to humans is the relationship between autoimmunity and narcolepsy. Genome-wide association studies have linked narcolepsy to polymorphisms occurring in regions rich with immunologically relevant genes.7 Further, there is higher prevalence of narcolepsy after HIN1 vaccine administration. A protein present in the H1N1 vaccine has been identified to cross-react with the HCRTR antigen;11 potentially tricking immune cells to destroy host neurons containing HCRTR. However, since autoantibodies that are unique to narcoleptic patients have not been discovered, further research is warranted to explore the relationship.7,8

Similar to determining narcolepsy etiology, diagnosis of narcolepsy is also difficult. While excessive daytime sleepiness is a prominent symptom, it is also suggestive of various sleep disorders, depression, and epilepsy. Relative to other sleep disorders, cataplexy is unique to narcolepsy and is often recognized by the physician as the telltale sign of narcolepsy.4 Occurrence of cataplexy is often used as a reason to conduct additional testing, such as analysis of CSF hypocretin levels, as low levels may be indicative of narcolepsy. Other tests that can be conducted are nocturnal polysonogram and multiple sleep latency test (MSLT), which tests brain activity during sleep and amount of time it takes a patient to fall asleep respectively. For a narcoleptic patient, results of their polysonogram and MSLT will demonstrate that a patient enters REM sleep rapidly. Finally, doctors may also implement an Epworth Sleepiness Scale, where a high score may suggest narcolepsy in a patient.12

The majority of the clinically available treatments devised to date are stimulants with arousing effects.8 As these compounds combat against the symptoms of narcolepsy, they are arguably inefficient. However, preclinical data of treatments that target known causes of narcolepsy is promising. Given that HCRT system deficiencies can explain various aspects of narcolepsy, HCRT replacement therapy is a viable option. Delivery of HCRT can be achieved by intranasal, intravenous, intracisternal, or intracerebroventricular modes of administration while more targeted and specific techniques include transplantation of hypocretin-secreting neurons developed from pluripotent stem cells and recombinant adeno-associated viral vector based delivery of HCRT gene.11 However, as HCRT controls multiple physiological functions, a critical pitfall of this therapy is the potential of adverse and unforeseen side effects.

In summary, preclinical animal models and clinical studies have sparked a surge of research that has substantially improved our understanding of narcolepsy. Through identifying the importance of HCRT and exploring possible roles of genetics and autoimmunity in etiology, these discoveries have led to some success in diagnosis and treatment. However, our premature understanding of narcolepsy continues to hinder us from effectively treating the root cause(s).

As HCRT plays key roles in sleep-wakefulness regulation and other physiological processes, stronger understanding of the HCRT system has twofold benefits. It can resolve existing barriers in narcolepsy research, and perhaps most importantly, expand our knowledge regarding the networks active in a healthy brain.


  1. Why Do We Sleep, Anyway? [Internet]. 2016 [cited 14 May 2016]. Available from:
  2. Siegel J. Narcolepsy. Cell. 1999;98(4):409-412.
  3. Chemelli R, Willie J, Sinton C et al. Narcolepsy in orexin Knockout Mice. Cell. 1999;98(4):437-451.
  4. Nishino S, Okura M, Mignot E. Narcolepsy: genetic predisposition and neuropharmacological mechanisms: REVIEW ARTICLE. Sleep Medicine Reviews. 2000 Feb 29;4(1):57-99.
  5. Narcolepsy [Internet]. 2012 [Cited 14 May 2016]. Available from:
  6. Cao M and Chow M. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. Nature and Science of Sleep. 2016;:81.
  7. Mahlios J, De la Herrán-Arita A, Mignot E. The autoimmune basis of narcolepsy. Current Opinion in Neurobiology. 2013;23(5):767-773.
  8. Burgess C and Scammell T. Narcolepsy: Neural Mechanisms of Sleepiness and Cataplexy. Journal of Neuroscience. 2012;32(36):12305-12311.
  9. Bear M, Connors B, Paradiso M. Neuroscience. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
  10. Black S, Yamanaka A, Kilduff T. Challenges in the development of therapeutics for narcolepsy. Progress in Neurobiology. 2015.
  11. Elliott LSwick T. Treatment paradigms for cataplexy in narcolepsy: past, present, and future. Nature and Science of Sleep. 2015;:159.
  12. Symptoms and Treatment of Narcolepsy [Internet]. 2016 [Cited May 14 2016]. Available from: