**4. Circadian regulation of sleep-wake cycles and some of its disturbances**

Sleep disorders are complex phenomena. A detailed correlation of sleep-wake regulation and clinical states is beyond the scope of this chapter, but a few examples can help to bridge the basic science concepts to everyday clinical scenarios. Since the first description of the hypocretin/orexin system 20 years ago, a body of literature investigating the physiologic and pathophysiology role of this system, as well as the potential for drug development, has emerged. Disruption of this system has been linked to pathological sleep-wake states such as insomnia and narcolepsy. A role for the hypocretin/orexin system in other sleep disorders and in sleepiness associated with other neurological disorders has also deserved some investigation. Recent results indicate that subjects with head trauma or encephalitis may have moderately but significantly decreased hypocretin levels. A few selected subjects with Guillain-Barré syndrome, Parkinson's disease (PD), multiple system atrophy, and other neurodegenerative disorders have also been found to have shallow hypocretin levels. Importantly, central actions of orexin regulate motivated behaviors, stress response, and energy/glucose metabolism by coordinating regions of the central autonomic network and the endocrine system, these multiple actions of orexin being critical to maintaining life.

depicting massive losses of orexin neurons [60]. It is not yet entirely clear what leads to this massive loss of the orexin neurons. By contrast, the number of melanin-concentrating hormone (MCH) neurons is not reduced in number, indicating that the cell loss is relatively

Hypothalamic Control of Sleep-Wake Circadian Cycle http://dx.doi.org/10.5772/intechopen.79899 37

Idiopathic hypersomnia is characterized by excessive daytime sleepiness, without sudden muscle paralysis (cataplectic attacks) nor abrupt transitions from wakefulness into REM sleep but with a dopaminergic and overall aminergic impairment associated with this condition. Some authors have described low but detectable levels of hypocretin in these patients [61],

Sleep disturbances often occur in patients with Parkinson's disease (PD) and can even precede the motor symptoms, showing, in this way, the close relation at a central level between autonomic (non-motor symptoms) and sleep centers. Excessive daytime sleepiness has been reported in almost half of the PD patients [64, 65]. In postmortem brain studies, hypocretin-1 tissue concentrations in the prefrontal cortex were almost 40% lower in these patients, with the total number of hypocretin neurons being almost half compared with controls [66, 67]. A progressive loss of MCH neurons has also been described, increasing with the disease pro-

Sleep disturbances occur in 70% of patients with multiple system atrophy (MSA), a progressive neurodegenerative disease of undetermined etiology, characterized by parkinsonian features, cerebellar, autonomic, and urogenital dysfunction and corticospinal disorders [68]. The clinical features include reduced and fragmented sleep, excessive daytime sleepiness, rapid eye movement (REM), sleep behavior disorder (RBD), stridor, and sleep-disordered breathing [69, 70]. In these patients, Benarroch and coworkers found up to 70% reduction in the total number of hypocretin neurons in these populations of patients and described abundant glial

Guillain-Barré syndrome is a post-infectious polyradiculopathy affecting mainly the peripheral nervous system, frequently presenting also with autonomic nervous system failure symptoms. Not infrequently, these patients also show other signs of hypothalamic disturbance. Guillain-Barré syndrome has been the only disorder besides narcolepsy in which undetectable levels of

while others reported normal levels [62, 63]. Postmortem studies are not available yet.

**4.2. Hypocretin studies in neurodegenerative disorders**

cytoplasmic inclusions in the hypocretin distribution area [71].

**4.3. Immune-mediated neurological disorders**

specific for hypocretin neurons.

*4.1.2. Idiopathic hypersomnia*

*4.2.1. Parkinson's disease*

gression [67].

*4.2.2. Multiple system atrophy*

*4.3.1. Guillain-Barré syndrome*

Considering these putative clinical targets, there has been an ongoing research in the development of selective hypocretin/orexin receptor agonists and antagonists. Recently, suvorexant became the first US Food and Drug Administration (FDA)-approved hypocretin/orexin receptor antagonist for the treatment of insomnia [54], and Nagahara and coworkers published a work on the first hypocretin/orexin agonist with good potency and pharmacological selectivity [55].

#### **4.1. Primary hypersomnias**

#### *4.1.1. Narcolepsy*

As previously mentioned, narcolepsy has been associated with changes in the orexinergic/ hypocretinergic neurons. It is a disabling neurologic condition affecting around 1 in 2000 individuals, characterized by excessive daytime sleepiness, frequently running with sudden muscle paralysis (cataplectic attacks), and transitions from wakefulness into REM sleep [56]. Human narcolepsy is a genetically complex disorder and environmentally influenced. The association of HLA with human narcolepsy suggests that it may have an autoimmune origin. Available treatment strategies are mainly symptomatic and include amphetamine-like stimulants and antidepressants, being met with unsatisfactory results.

Canines with narcolepsy were found to have a mutation in the orexin-2 (hypocretin-2) receptor [57] while mice lacking the orexin peptide or the neurons containing orexin (hypocretin) displayed behavioral and EEG signs of narcolepsy [11, 58]. Human subjects with narcolepsy have been found to have a lack or very low levels of hypocretin neurons (with an 85–95% reduction in the number of neurons) and orexin-A in the CSF [59]. These findings have been corroborated by postmortem examination of brain tissue of subjects with narcolepsy, depicting massive losses of orexin neurons [60]. It is not yet entirely clear what leads to this massive loss of the orexin neurons. By contrast, the number of melanin-concentrating hormone (MCH) neurons is not reduced in number, indicating that the cell loss is relatively specific for hypocretin neurons.

#### *4.1.2. Idiopathic hypersomnia*

**4. Circadian regulation of sleep-wake cycles and some of its** 

tiple actions of orexin being critical to maintaining life.

lants and antidepressants, being met with unsatisfactory results.

**4.1. Primary hypersomnias**

*4.1.1. Narcolepsy*

Sleep disorders are complex phenomena. A detailed correlation of sleep-wake regulation and clinical states is beyond the scope of this chapter, but a few examples can help to bridge the basic science concepts to everyday clinical scenarios. Since the first description of the hypocretin/orexin system 20 years ago, a body of literature investigating the physiologic and pathophysiology role of this system, as well as the potential for drug development, has emerged. Disruption of this system has been linked to pathological sleep-wake states such as insomnia and narcolepsy. A role for the hypocretin/orexin system in other sleep disorders and in sleepiness associated with other neurological disorders has also deserved some investigation. Recent results indicate that subjects with head trauma or encephalitis may have moderately but significantly decreased hypocretin levels. A few selected subjects with Guillain-Barré syndrome, Parkinson's disease (PD), multiple system atrophy, and other neurodegenerative disorders have also been found to have shallow hypocretin levels. Importantly, central actions of orexin regulate motivated behaviors, stress response, and energy/glucose metabolism by coordinating regions of the central autonomic network and the endocrine system, these mul-

Considering these putative clinical targets, there has been an ongoing research in the development of selective hypocretin/orexin receptor agonists and antagonists. Recently, suvorexant became the first US Food and Drug Administration (FDA)-approved hypocretin/orexin receptor antagonist for the treatment of insomnia [54], and Nagahara and coworkers published a work on the first hypocretin/orexin agonist with good potency and pharmacological selectivity [55].

As previously mentioned, narcolepsy has been associated with changes in the orexinergic/ hypocretinergic neurons. It is a disabling neurologic condition affecting around 1 in 2000 individuals, characterized by excessive daytime sleepiness, frequently running with sudden muscle paralysis (cataplectic attacks), and transitions from wakefulness into REM sleep [56]. Human narcolepsy is a genetically complex disorder and environmentally influenced. The association of HLA with human narcolepsy suggests that it may have an autoimmune origin. Available treatment strategies are mainly symptomatic and include amphetamine-like stimu-

Canines with narcolepsy were found to have a mutation in the orexin-2 (hypocretin-2) receptor [57] while mice lacking the orexin peptide or the neurons containing orexin (hypocretin) displayed behavioral and EEG signs of narcolepsy [11, 58]. Human subjects with narcolepsy have been found to have a lack or very low levels of hypocretin neurons (with an 85–95% reduction in the number of neurons) and orexin-A in the CSF [59]. These findings have been corroborated by postmortem examination of brain tissue of subjects with narcolepsy,

**disturbances**

36 Hypothalamus in Health and Diseases

Idiopathic hypersomnia is characterized by excessive daytime sleepiness, without sudden muscle paralysis (cataplectic attacks) nor abrupt transitions from wakefulness into REM sleep but with a dopaminergic and overall aminergic impairment associated with this condition. Some authors have described low but detectable levels of hypocretin in these patients [61], while others reported normal levels [62, 63]. Postmortem studies are not available yet.

#### **4.2. Hypocretin studies in neurodegenerative disorders**

#### *4.2.1. Parkinson's disease*

Sleep disturbances often occur in patients with Parkinson's disease (PD) and can even precede the motor symptoms, showing, in this way, the close relation at a central level between autonomic (non-motor symptoms) and sleep centers. Excessive daytime sleepiness has been reported in almost half of the PD patients [64, 65]. In postmortem brain studies, hypocretin-1 tissue concentrations in the prefrontal cortex were almost 40% lower in these patients, with the total number of hypocretin neurons being almost half compared with controls [66, 67]. A progressive loss of MCH neurons has also been described, increasing with the disease progression [67].

#### *4.2.2. Multiple system atrophy*

Sleep disturbances occur in 70% of patients with multiple system atrophy (MSA), a progressive neurodegenerative disease of undetermined etiology, characterized by parkinsonian features, cerebellar, autonomic, and urogenital dysfunction and corticospinal disorders [68]. The clinical features include reduced and fragmented sleep, excessive daytime sleepiness, rapid eye movement (REM), sleep behavior disorder (RBD), stridor, and sleep-disordered breathing [69, 70]. In these patients, Benarroch and coworkers found up to 70% reduction in the total number of hypocretin neurons in these populations of patients and described abundant glial cytoplasmic inclusions in the hypocretin distribution area [71].

#### **4.3. Immune-mediated neurological disorders**

#### *4.3.1. Guillain-Barré syndrome*

Guillain-Barré syndrome is a post-infectious polyradiculopathy affecting mainly the peripheral nervous system, frequently presenting also with autonomic nervous system failure symptoms. Not infrequently, these patients also show other signs of hypothalamic disturbance. Guillain-Barré syndrome has been the only disorder besides narcolepsy in which undetectable levels of hypocretin have been consistently observed [63, 72]. Patients with the lowest levels tend to have a more severe and rapid disease course, running with tetraplegia and respiratory failure. The mechanism underlying the lack or very decreased levels of hypocretin in Guillain-Barré syndrome remains unknown, but an immune-mediated hypothalamic dysfunction has been hypothesized.

are needed to determine the inner mechanisms associated with sleep-wake cycle and their

Hypothalamic Control of Sleep-Wake Circadian Cycle http://dx.doi.org/10.5772/intechopen.79899 39

Faculdade de Medicina da Universidade de Lisboa, Centro Cardiovascular da Universidade

[1] Kirsch DB. There and back again: A current history of sleep medicine. Chest. 2011;**139**:

[2] Berger H. Über das Elektroenzenkephalogram des Menschen. Archiv für Psychiatrie

[3] Bremer F. Preoptic hypnogenic area and reticular activating system. Archives Italiennes

[4] Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG.

[5] Lindsley DB, Bowden JW, Magoun HW. Effect upon the EEG of acute injury to the brainstem activating system. Electroencephalography and Clinical Neurophysiology.

[6] Villablanca J. Counterpointing the functional role of the forebrain and of the brainstem in the control of the sleep-waking system. Journal of Sleep Research. 2004;**13**:179-200 [7] Berladetti F, Borgia R, Mancia M. Prosencephalic mechanisms of EEG desynchronization in the "cerveau isolé" of the cat. Electroencephalography and Clinical Neurophysiology.

[8] de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, et al. The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences of the United

Electroencephalography and Clinical Neurophysiology. 1949;**1**:455-473

regulatory processes.

**Conflict of interest**

**Author details**

**References**

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States of America. 1998;**95**:322-327

The authors declare no conflict of interest.

de Lisboa, Instituto de Fisiologia, Portugal

und Nervenkrankheiten. 1931;**94**:16-60

de Biologie. 1973;**111**:85-111

Miguel Meira e Cruz, Sérgio Matoso Laranjo and Isabel Rocha\*

\*Address all correspondence to: isabelrocha0@gmail.com

#### **4.4. Orexin and sleep-related physical disorders: cardiovascular disease**

Almost all bodily functions are dependent on the autonomic nervous system (ANS), which exerts precise control over visceral functions. Sleep disruption causes an increased activity of the sympathetic nervous system in association with an elevated blood pressure, and the risks of hypertension and cardiovascular disease are increased as a consequence of either strong acute or long-term sleep disruption [73]. The hypocretin/orexin system also contributes to the regulation of cardiovascular functions via the autonomic nervous system. Hypocretin/ orexin neurons project to several brain regions involved in the regulation of cardiovascular activity, namely the paraventricular nucleus (PVN), nucleus tractus solitarius, and the rostral ventrolateral medulla (RVLM), all areas of the central autonomic network [74].

Over-activation of the hypocretin/orexin system has been implicated in the pathogenesis of hypertension. It has been shown that the central administration of orexins A and B increases arterial blood pressure and elicits tachycardia in animal models [74]. Conversely, orexin/ ataxin-3 transgenic rats, lacking orexin neurons, have a significantly reduced sympathetic nervous system tone and a lower systolic blood pressure when compared with controls [75]. In addition, spontaneously hypertensive rats (SHRs) have increased levels of hypocretin/ orexin [74] that, when blocked by the oral administration of almorexant or by intracerebroventricular injections of TCSOX229, led to a significant reduction of systolic blood pressure while not affecting arterial blood pressure in normotensive animals [76, 77]. These data suggest that hypocretin/orexin may play a significant role in the pathogenesis of hypertension. In humans, Dauvilliers and coworkers reported a lower cardiac activation associated with periodic leg movements during sleep in narcoleptic patients which was proposed to be related to changes in baroreflex sensitivity [78]. The same group found a large percentage of diastolic non-dippers, with 64% failing to achieve the 15% fall point on diastolic blood pressure [79], and recent data suggested that narcoleptic patients displayed a nighttime non-dipping blood pressure pattern with increased systolic blood pressure during nighttime REM sleep [80].

The blunted cardiac activation and sleep-related blood pressure fall in narcoleptic patients may be clinically relevant and may indicate an increased risk for cardiovascular events among attributable to a potentially clinically significant hypocretin/orexin deficiency.

## **5. Conclusion**

In summary, despite being present throughout the animal kingdom, the precise sleep function is still relatively elusive. However, it is evident that sleep regulation is fundamental for survival having the hypothalamus a significant role in those modulatory processes through the orexin/hypocretin and the MCH neurons. Nevertheless, further studies on sleep physiology are needed to determine the inner mechanisms associated with sleep-wake cycle and their regulatory processes.
