The Hypocretins Set The Arousal Threshold

Narcolepsy is a common cause of chronic sleepiness distinguished by intrusions into wakefulness of physiological aspects of REM sleep such as cataplexy and hallucinations (62) and can be defined as a dysfunction of the mechanisms that control the boundaries between states of vigilance. How does the hypocretinergic system exert such control in the transitions between states of vigilance Among the neurons of the perifornical lateral hypothalamus, between 40 and 53 increase their firing rates...

Clinical Syndrome

Narcolepsy is primarily characterized by a disabling excessive daytime sleepiness (EDS). The EDS is thought to be secondary to the inability to regulate sleep-wake states properly, a condition also leading to disrupted nighttime sleep. The other primary symptoms are, as mentioned above, cataplexy, sleep paralysis, hypnagogic hypnopompic hallucinations, automatic behaviors, and disrupted nighttime sleep. These symptoms are all thought to be secondary to improperly regulated sleep states and...

Hypocretin Replacement In Canine Narcolepsy

In contrast to murine narcolepsy models, canine narcolepsy is a naturally occurring animal model. Although the mutation in the hcrtr-2 gene was found in narcolepsy in Dobermans and Labradors (1), to date seven of seven sporadic narcoleptic dogs tested were found to be ligand deficient, sharing a common pathology with most human narcoleptic subjects (23,45-47). Both familial and sporadic narcoleptic dogs have been used for various pharmacological experiments including use of the compounds...

Hypocretin Replacement Therapies In Genetically Engineered Narcoleptic Mice

Using hypocretin neuron-ablated narcoleptic mice (orexin ataxin-3 transgenic mice) (8), Mieda et al. (43) recently demonstrated that replacement of central hypocretin by either pharmacologic (icv injection of hypocretin-1) or genetic (ectopic expression of hypocretin in the brain) manipulations allowed the rescue of the narcolepsy-cataplexy phenotype in these mice (43). These narcoleptic mice frequently exhibited behavioral arrests (i.e., cataplexy) during the active period (8). ICV...

Does Overexpression Of Orexin Peptides Bring About Only Good Things

Now we know that spatially or temporally specific activation of orexin receptors is not necessary to prevent narcolepsy-cataplexy. The next important question is does ectopic overexpression of orexin peptides only restore the narcoleptic phenotype of orexin ataxin-3 transgenic mice, or does it do anything more To examine the effects of orexin overexpression itself on spontaneous sleep wake patterns, we monitored the EEG EMG of CAG orexin transgenic mice and their wild-type littermates. Most...

Dynamic Control Of Behavioral State The Flipflop Switch

When animals switch between behavioral states, they spend little time in intermediate states. This is clearly adaptive for survival, as an animal that performed daily tasks in a state of muddled drowsiness, neither fully awake nor asleep, would be in danger from predators Fig. 2. The ventrolateral preoptic area (VLPO) contains sleep-promoting neurons. Neurons of the VLPO produce GABA and galanin and inhibit all the arousal systems during NREM sleep. Many of these cells are active during REM...

Hypothalamic Timing Of Sleep And Wakefulness

Circadian rhythms strongly govern the timing of REM sleep, the onset of wakefulness, and behavioral alertness (152). These endogenously generated, daily rhythms are controlled by the suprachiasmatic nucleus (SCN), a small cluster of neurons just above the optic chiasm in the anterior hypothalamus. The SCN acts as a master clock, keeping time with an accuracy of a few minutes each day (153) and adjusting bodily rhythms to seasonal variations in day length. Most likely, each SCN neuron is a...

References

Lin, L., Faraco, J., Li, R., et al. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365-376. 2. Chemelli, R.M., Willie, J., Sinton, C., et al. (1999) Narcolepsy in orexin knockout mice molecular genetics of sleep regulation. Cell 98, 437-451. 3. Nishino, S., Ripley, B., Overeem, S., et al. (2001) Low CSF hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann. Neurol. 50, 381-388. 4. Nishino, S.,...

Some Considerations On Ligand Replacement Therapy

The Primary Cause of Hypocretin Ligand Deficiency, Secondary Changes in Hypocretin Ligand Deficiency, and the Occurrence of EDS and Cataplexy Although the study by Meida et al. (43) suggested that hypocretin neuron-ablated mice retain the ability to respond to hypocretin neuropeptides, it is not known whether human narcloleptic subjects react to the replacement of hypocretin peptides in a similar way as the genetically engineered murine model. The etiological mechanisms of hypocretin...

Hypothalamic Sleeppromoting Systems

Von Economo (116) and Nauta (63) showed that large clinical or experimental lesions of the anterior hypothalamus produce insomnia. Subsequent studies determined that injury to the preoptic area (the most rostral part of the anterior hypothalamus) produced marked reductions in sleep (117-119), whereas electrical or chemical stimulation of this region increased NREM sleep (120-123). Many of these sleep-active neurons are concentrated in the ventrolateral preoptic area (VLPO) and extend up into...

Of Cataplexy And Excessive Daytime Sleepiness

Beside the discovery of canarc-1, biomedical research in narcolepsy has been also greatly facilitated by using narcoleptic canines. Based on the data obtained from the canine model, our current understanding of the neuropharmacological control of cataplexy and excessive sleepiness (as well as some prospects for the new treatment of narcolepsy) is discussed here. For more details on neuropharmacological results, see the review article by Nishino and Mignot (13). 7.1. REM Sleep Cataplexy and...

Noradrenaline

The noradrenergic cells of the pontine LC form dense clusters adjacent to the fourth ventricle and give rise to a diffuse innervation of the whole CNS (81). They fire tonically at their highest rate during active waking and less during SWS and go virtually silent during REM sleep (82). The LC neurons are electrotonically coupled via gap junctions, and the whole nucleus can fire synchronously. During waking, their highest firing rates are associated with behavioral signs of arousal and...

Molecular Genetic Studies Of Orexin Receptors

Earlier genetic studies revealed that dogs with a mutation of the OX2R gene or OX2R-knockout mice displayed a narcolepsy-like phenotype (9,10), whereas OX1R knockout mice did not reveal any obvious abnormality in the sleep wake states (10). These studies provide strong evidence for the roles of OX2R in regulating the vigilance state in human and animals. However, double receptor knockout (OX1R- and OX2R-null) mice appear to be a phenocopy of prepro-orexin knockout mice, suggesting that OX1R...

Hypocretin1 Release In Extracellular Space In Rats Over 24 H And With Sleeprelated Manipulations

Together with CSF hypocretin measures, we also initiated hypocretin measures in microdialysis perfusates in freely moving rats with simultaneous sleep recordings (18). Like other neurotransmitters, hypocretin concentration in the microdialysis perfusate is dependent on the microdialysis membrane length and flow rate. The pore size of the dialysis membrane is another important factor to be considered in peptide sampling (see next paragraph). We found that hypocretin is easily adsorbed into the...

Neuroendocrine Studies

We describe here the principal results of a comprehensive study of the activity of various neuroendocrine ensembles in hypocretin-deficient patients (28-31). Seven male narcoleptic patients with typical cataplectic attacks, typical multi sleep latency test (MSLT) findings, and undetectable hypocretin levels in the CSF were studied. They were compared with seven controls who were carefully matched for age, sex, BMI, and body composition. The participants were medication free. On average the...

Body Weight And Food Intake

In 1934, Daniels (2) was the first to suggest that narcolepsy is associated with obesity. He observed that narcoleptic patients with or without cataplexy were more frequently obese than was expected in the general population. He proposed that a reduced basal metabolic rate was involved in the pathogenesis, based on metabolic studies in several of these patients (2). During the next decades interest in this aspect declined. It was generally believed that daytime naps reduce physical activity and...

Genetic Rescue Of Narcolepsy In Orexin Neuronablated Mice

Herpes Other Parts Body

To examine whether the narcolepsy-cataplexy phenotype of orexin neuron-ablated mice could be rescued by ectopic production of orexin peptides, we produced transgenic mice that overexpress a prepro-orexin transgene under the control of a P-actin cytomegalovirus hybrid promoter, which is an ubiquitous promoter (CAG orexin transgenic mice) (16,17). Several stable transgenic lines overexpressed orexin, as determined by Northern blots, radioim-munoassays, and anti-orexin-A immunohistochemistry. In...

Conclusions

Orexins and hypocretins (32) were first characterized as stimulators of appetite and food consumption. Recently a number of reports have suggested additional roles for these peptides in the control of narcolepsy (33) and diverse autonomic functions, including cardiovascular control, hormone secretion, and energy metabolism. Orexins appeared to be involved in the modulation of autonomic and cardiovascular functions. Double-label immunohistochemistry confirmed that orexin-A and dynorphine-A...

The Hypocretinorexin System And Narcolepsy

Narcoleptic Mice

Human narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and other abnormal manifestations of REM sleep, such as hypnagogic hallucinations and sleep paralysis (11). Narcolepsy is not a rare disease, affecting approximately 1 in 2000 in the general population, which is equivalent to Parkinson's disease (12) or multiple sclerosis (13). EDS in narcolepsy is overwhelming and is characterized by recurring episodes of sleep during the daytime (11)....

Assessment Of Receptorg Protein Interactions Using [35SGTPyS Autoradiography

In Vitro P5S GTPcfi Autoradiography Mimics In Vivo G Protein Activation This section describes the process by which G proteins are activated when an agonist binds to a receptor. This process illustrates how 35S GTPyS is used in vitro to label functionally active receptor-G protein complexes. Figure 1A shows that in the absence of a receptor-bound agonist, receptor-associated G proteins are held in an inactive state owing to the high-affinity binding of guanosine diphosphate (GDP) to the Ga...

Roles Of Orexin In The Regulation Of Feeding Behavior And Body Weight Homeostasis

Upregulation of prepro-orexin mRNA suggests that orexin neurons monitor the animal's nutritional status (4). Indeed, our electrophysiological studies on orexin neurons showed that leptin robustly inhibited most orexin neurons, causing hyperpolarization and a decrease in firing rate. Furthermore, leptin administration depresses orexin expression in the hypothalamus of normal mice. We also showed that ghrelin activates a population of isolated orexin neurons by depolarization with increases in...

Csf Hypocretin1 Levels From Typical Narcolepsy To The Narcolepsy Borderland

Hypocretin Narcolepsy Brain

The involvement of the hypocretin system in the pathophysiology of human narcolepsy was first demonstrated though studies of human CSF samples (37). Measuring CSF hypocretin-1 is becoming an established diagnostic procedure (40), and it is possible that, in the future, hypocretin-1 will be measurable in plasma. 6.1. Typical Cases Narcolepsy with Definite Cataplexy and HLA Positivity Nishino et al. (37) were the first group to measure hypocretin-1 levels in narcolepsy-cataplexy patients and in...

Overview Of Brainstem And Other Stateregulatory Systems

To understand the role of the hypothalamus in behavioral state control, it is helpful to first review some of the brainstem and midbrain systems (Fig. 1) that control sleep and wakefulness (for review, see ref. 1). The reticular formation is a loose collection of neurons extending from the caudal medulla up through the core of the midbrain (2). Through projections to the thalamus, the reticular formation induces a single-spike mode of firing in thalamic and cortical neurons that is necessary...

Narcolepsy And Autoimmunity The Evidence

Table 1 summarizes the evidence for and against an autoimmune basis for narcolepsy. The tight association between narcolepsy and HLA-DQB1*0602 is generally greater than HLA associations observed with known autoimmune disorders such as multiple sclerosis or type I diabetes mellitus (a notable exception may be ankylosing spondylitis and HLA-B27) Furthermore, like most autoimmune diseases, narcolepsy tends to affect younger individuals (peripubertal onset). Unlike most autoimmune diseases, which...

Orexin Neurons May Integrate Sleepwake Behavior With Other Hypothalamic Functions

For an animal to properly attend to and respond to its environment requires coordination of many physiologic functions. For example, a mouse foraging for food must be alert, hungry, and physically active with relatively high sympathetic tone (blood pressure, heart rate, metabolic rate, and so on). The orexin neurons are well positioned to coordinate these disparate physiologic functions. Anatomic and physiologic studies highlight the multifunctional nature of the orexin system. The orexin...

Hypocretin Status In Hypersomnia In Various Neurological Conditions

Symptomatic narcolepsy is relatively rare, but sleepiness without other narcoleptic symptoms can often occur with a variety of neurological disorders they are more likely to be caused by multifocal or global disturbances of the brainstem, diencephalon and cerebral cortex. Recently, several clinical studies also suggested that disruption of the hypothalamic hypocretin system in EDS is associated with various neurological conditions. Arii et al. (55) reported on a 16-yr-old girl with hypersomnia...

The Hypothalamuspituitaryadrenal Hpa Axis

Difference Between Raas And Hpa Axis

The stress response mediated through activation of the HPA axis is essential to meet physical and psychological challenges. The HPA axis consists of corticotrophin-releasing factor hormone (CRF CRH) and arginine vasopressin (AVP) neurons in the hypothalamus, which stimulate adrenocorticotrophic hormone (ACTH) secretion from corticotrophs in the anterior pituitary through CRF-R1 and V1b receptors, respectively. ACTH, in turn, stimulates adrenal cortical glucocorticoid secretion. Negative...

Hypocretin Status In Various Neurological Conditions

Prader Willi Mild

Hypocretin Status in Symptomatic Narcolepsy-Cataplexy Associated with Distinct CNS Lesions Soon after the involvement of hypocretin impairment in idiopathic narcolepsy was noted, Melberg et al. (98) reported a reduced CSF hypoocretin-1 level (96 pg mL) in a previously reported 51-yr-old male case with autosomal dominant cerebellar ataxia (ADCA) and deafness and narcolepsy (DN). In this Swedish pedigree (ADCA-DN OMIM, Online Mendelian Inheritance in Man, accession number 604121), four out...

The Thyroid Hormone Axis

The effects of central orexins on TSH secretion have not been investigated in detail. Mitsuma et al. (26) administered orexin-A (50 pg kg iv) and observed a dose-dependent decrease in plasma TSH. They also observed a reduction in hypothalamic TRH secretion in response to orexin-A and suggested a hypothalamic mechanism for the action of systemic orexin-A since no pituitary effect was observed. No significant changes in TRH secretion were observed when orexin-A was administered to hypothalamic...

Major Dsm Syndromes And Their Clinical Differentiation From Narcolepsy

A salient feature of the schizophrenias is a prominent deficit in higher thought processing. All four of Bleuler's classically described core symptoms (loosening of associations, affective flattening, autistic features, and ambivalence) can be observed in each of the five subtypes of schizophrenia. Extreme loosening of associations is among the most valuable criteria but must be differentiated from similar symptoms in mania, impaired consciousness, fatigue, or distraction. Bizarre behaviors...