Orexins

To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence. Cross-sectional. Sleep laboratory. One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52). None. Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1. Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients...

Several neurotransmitter systems and circulating factors regulate rapid eye movement (REM) sleep, non-REM (NREM) sleep, and wakefulness (W). The nuclei involved in the occurrence of W are located in the brainstem, hypothalamus, and the basal forebrain (BFB). These corresponding to the brainstem include the dorsal raphe nucleus (serotonergic neurons); locus coeruleus (noradrenergic neurons); ventral tegmental area, substantia nigra compacta, and ventral periaqueductal gray matter (dopaminergic neurons); and laterodorsal and pedunculopontine tegmental nuclei (cholinergic neurons). The structures found in the hypothalamus comprise the tuberomammillary nucleus (histaminergic neurons) and the posterior and lateral hypothalamus around the fornix (orexinergic neurons). The cholinergic neurons of the BFB are located mainly in the diagonal band of Broca, substantia innominata, and the medial septal area. The NREM sleep-inducing system comprises neurons located in the preoptic area, which contains Gamma-Aminobutyric Acid (GABA) and galanin, and cells containing melanin-concentrating hormone located in the lateral hypothalamus and incertohypothalamic area. The latter is also involved in the regulation of REM sleep. Somnogens, including adenosine (formed mainly by the breakdown of adenosine nucleotides), prostaglandin D2 (which is mainly present in the leptomeninges, choroid plexus, and oligodendrocytes), nitric oxide (synthesized predominantly from L-arginine), and cytokine promote also sleep, mainly NREM sleep. Melatonin is a hormone secreted during the night from the pineal gland and has a weak sleep-promoting effect in humans. The subcoeruleus nucleus has been proposed as the critical area for REM sleep regulation in the cat. Its equivalent in the rat is called the sublaterodorsal nucleus. The REM sleep generation region includes mainly glutamatergic and GABAergic neurons.
Sleep timing depends on two factors, sleep debt (process S; homeostasis) and circadian control (process C). When process S approaches the upper boundary, it triggers sleep. On the other hand, the markers of process C include melatonin and core body temperature

Stress is considered to be an important cause of disrupted sleep and insomnia. However, controlled and experimental studies in rodents indicate that effects of stress on sleep–wake regulation are complex and may strongly depend on the nature of the stressor. While most stressors are associated with at least a brief period of arousal and wakefulness, the subsequent amount and architecture of recovery sleep can vary dramatically across conditions even though classical markers of acute stress such as corticosterone are virtually the same. Sleep after stress appears to be highly influenced by situational variables including whether the stressor was controllable and/or predictable, whether the individual had the possibility to learn and adapt, and by the relative resilience and vulnerability of the individual experiencing stress. There are multiple brain regions and neurochemical systems linking stress and sleep, and the specific balance and interactions between these systems may ultimately determine the alterations in sleep–wake architecture. Factors that appear to play an important role in stress-induced wakefulness and sleep changes include various monominergic neurotransmitters, hypocretins, corticotro-pin releasing factor, and prolactin. In addition to the brain regions directly involved in stress responses such as the hypothalamus, the locus coeruleus, and the amygdala, differential effects of stressor controllability on behavior and sleep may be mediated by the medial prefrontal cortex. These various brain regions interact and influence each other and in turn affect the activity of sleep–wake controlling centers in the brain. Also, these regions likely play significant roles in memory processes and participate in the way stressful memories may affect arousal and sleep. Finally, stress-induced changes in sleep-architecture may affect sleep-related neuronal plasticity processes and thereby contribute to cognitive dysfunction and psychiatric disorders.

Based on empirical evidence that suggests that failing to recognize a stimulus as emotionally relevant results in hypoactivity of the orexinergic cells in the hypothalamus, this article proposes a physiological model of boredom that makes depression a consequence of a chronic reduction of monoamines in the brain combined with increased levels of norepinephrine and cortisol. The studies proposed here look to find supportive evidence for two assumptions of this model: 1. That the negative affect associated with boredom results from a conscious assessment of the situation; 2. That activity of the orexinergic neurons can increase both positive and negative affect, depending on the assessed valence of a stimulus.

There is an unmet need of pharmacological and non-pharmacological treatment options for migraine patients. Exercise can be used in the treatment of several pain conditions, including. However, what exact role exercise plays in migraine prevention is unclear. Here, we review the associations between physical exercise and migraine from an epidemiological, therapeutical and pathophysiological perspective. The review was based on a primary literature search on the PubMed using the search terms "migraine and exercise". Low levels of physical exercise and high frequency of migraine has been reported in several large population-based studies. In experimental studies exercise has been reported as a trigger factor for migraine as well as migraine prophylaxis. Possible mechanisms for how exercise may trigger migraine attacks, include acute release of neuropeptides such as calcitonin gene-related peptide or alternation of hypocretin or lactate metabolism. Mechanisms for migraine prev...

Cardiac arrest (CA) affects >550,000 people annually in the United States whereas 80–90% of survivors suffer from a comatose state. Arousal from coma is critical for recovery, but mechanisms of arousal are undefined. Orexin-A, a hypothalamic excitatory neuropeptide, has been linked to arousal deficits in various brain injuries. We investigated the orexinergic system's role in recovery from CA-related neurological impairments, including arousal deficits. Using an asphyxial CA and resuscitation model in rats, we examine neurological recovery post-resuscitation in conjunction with changes in orexin-A levels in cerebrospinal fluid (CSF) and orexin-expressing neurons. We also conduct pharmacological inhibition of orexin post-resuscitation. We show that recovery from neurological deficits begins between 4 and 24 h post-resuscitation, with additional recovery by 72 h post-resuscitation. Orexin-A levels in the CSF are lowest during periods of poorest arousal post-resuscitation (4 h) and recover to control levels by 24 h. Immunostaining revealed that the number of orexin-A immunoreactive neurons declined at 4 h post-resuscitation, but increased to near normal levels by 24 h. There were no significant changes in the number of neurons expressing melanin-concentrating hormone, another neuropeptide localized in similar hypothalamus regions. Last, administration of the dual orexin receptor antagonist, suvorexant, during the initial 24 h post-resuscitation, led to sustained neurological deficits. The orexin pathway is critical during early phases of neurological recovery post-CA. Blocking this early action leads to persistent neurological deficits. This is of considerable clinical interest given that suvorexant recently received U.S. Food and Drug Administration approval for insomnia treatment.. Abstract text download from ncbi.nlm.nih.gov

The present study describes the nuclear organization of the cholinergic, catecholaminergic, serotonergic and orexinergic systems in the brains of the springhare and Beecroft’s scaly-tailed squirrel following immunohistochemical labelling. We aimed to investigate any differences in the nuclear organization of these neural systems when compared to previous data on other species of rodents, as these two rodent species have relatively large brains – 1.2 to 1.4 times larger than would be expected for mammals of their body mass and 1.7 – 1.9 times larger than would be expected for rodents of their body mass. A series of coronal sections were taken through two brains of each species and immunohistochemically labelled with antibodies against choline acetyltransferase, tyrosine hydroxylase, serotonin and orexin-A. Generally, the nuclear complement of these systems revealed extensive similarities between both species and to previously studied rodents. While no differences were observed in the nuclear complement of the serotonergic and orexinergic systems, some differences were observed in the nuclear complement of the cholinergic and catecholaminergic systems. These include the presence of cholinergic neurons in the cerebral cortex and nucleus of the trapezoid body in the springhare; while the Beecroft’s scaly-tailed squirrel exhibited cholinergic neurons in the pretectal area of the midbrain. For the catecholaminergic system it was observed that Beecroft’s scaly-tailed squirrel possessed immunoreactive neurons in the accessory olfactory bulb. Despite these four differences, most not previously observed in rodents, the remaining complement of cholinergic and catecholaminergic nuclei were identical to that observed in other rodents, including the presence of the rodent specific catecholaminergic rostral dorsal midline medullary (C3) nucleus in the medulla oblongata. Thus, even with a significant increase in relative brain size, the overall complement of nuclei forming these systems shows minimal changes in complexity within a specific mammalian order.

Orexins are peptide neurotransmitters which are produced in the lateral and posterior part of the hypothalamus in the brain. There are two Orexin receptors which has been identified till date viz. Orexin 1 (OX  1) and Orexin 2 (OX 2 receptor).

To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. Subjects were recruited from multiple community sources for National Institutes of Health supported studies or normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. Levels of orexin-A, amyloid beta 42 (Aβ42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 s...

We need to know in order to understand the sleep disorder narcolepsy, sleep and wakefulness, sleep, sleeping,''said Claperede on the body is a function of the strength of will automatically be delayed for a while, but when a higher level of fatigue would be defeated and the people succumb to sleep.'' Protection of biological instinct as a condition of sleep and the body representing the De Sanctic A.Forel, O, and P Wogt Janet has a different interpretation, and finally a study of brain cells during sleep, shrinking cracks between neurons and thus the expansion of fluids through here allows the brain to cleanse, Research also is likely to lead to diseases of the brain in the direction of these toxic proteins opinions of arındırılamamasının say... The main question that researchers are looking for answers , especially the vulnerable despite the drop were caused by animals slept. The largest effect on the brain's ability to repair, and memory, sleep learning is already known. But experts to sleep lightly "cleaning" function that thinks. Due to the limited amount of energy that the brain can spend the researchers have to choose one of two functions: awake and aware, or in sleep and cleaning.

BACKGROUND AND PURPOSE:
Many studies have demonstrated a role of hypocretin 1 (orexin 1) receptors in home-cage food consumption in rodents. However, the role of these receptors in operant food self-administration or relapse to food seeking in animal models is unknown.

EXPERIMENTAL APPROACH:
In Experiment 1, we trained food-restricted rats (16-20 g per day) to lever press for high-fat (35%) pellets (3-6 h per day, every other day). We then tested the effect of the hypocretin 1 receptor antagonist SB 334867 (10, 20 mg kg(-1), i.p) on pellet self-administration. In Experiment 2, we trained rats to self-administer the food pellets, and following extinction of the food-reinforced responding, we tested the effect of hypocretin 1 (3 and 6 mug, i.c.v) on reinstatement of food-seeking and the effect of SB 334867 on this reinstatement. In Experiment 3, we tested the effect of SB 334867 on reinstatement induced by non-contingent pellet exposure (pellet-priming) or the pharmacological stressor yohimbine (2 mg kg(-1), i.p).

KEY RESULTS:
SB 334867 attenuated high-fat pellet self-administration. In contrast, SB 334867 had no effect on reinstatement of lever presses induced by hypocretin 1, pellet-priming or yohimbine.

CONCLUSIONS AND IMPLICATIONS:
These data indicate that during dieting, hypocretin 1 receptors contribute to operant high-fat pellet self-administration, but not to relapse to food seeking induced by acute re-exposure to the food itself or by the induction of a stress-like state.

Ghrelin is a stomach-produced hormone that stimulates ingestive behavior and increases motivated behavior to obtain palatable foods. Ghrelin receptors (growth hormone secretagogue receptors; Ghsr) are expressed in the lateral hypothalamic area (LHA), and LHA-targeted ghrelin application increases ingestive behavior in male rodents. However, the effects of LHA ghrelin signaling in females are unexplored. Here we investigated whether LHA ghrelin signaling is necessary and sufficient for control of ingestive and motivated behavior for food in male and female rats. Ghrelin delivered to the LHA increased food intake and motivated behavior for sucrose in both male and female rats, whereas increased food-seeking behavior and body weight were only observed in females. Females had slightly higher Ghsr levels in the LHA compared to males, and importantly, acute blockade of the Ghsr in the LHA significantly reduced food intake, body weight, and motivated behavior for sucrose in female but not ...

To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. Subjects were recruited from multiple community sources for National Institutes of Health supported studies or normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. Levels of orexin-A, amyloid beta 42 (Aβ42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 s...

Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric I...

Orexin A (OXA), a hypothalamic neuropeptide, regulates food intake, sleep-wake cycle and energy balance by binding to its receptor (OX1R). Apart from brain, OXA and OX1R are also present in peripheral organs including reproductive tissues. Mammalian reproduction depends on uptake and proper utilization of glucose in the testes. This study, therefore, examined role of OXA/OX1R system in regulation of glucose homeostasis in adult mouse testis under in vivo and ex vivo conditions. Binding of OXA to OX1R was blocked using an OX1R antagonist, SB-334867. Mice were given a single bilateral intratesticular injection of the antagonist at doses of 4 and 12μg/mouse and sacrificed 24 h post-injection. In order to understand the direct role of OXA in testes of adult mice, an ex vivo experiment was performed where binding of OXA to OX1R in the testis was blocked by using the same OX1R antagonist. The antagonist treatment affected testicular glucose and lactate concentration with concomitant down-...

Since its first discovery in 1998, it has become clear that the orexinergic system plays an important role in regulating a number of functions including food, sex, social connections, and most prominently reward-related behaviors. Orexinergic neurons in the lateral hypothalamus project extensively to other brain areas, two most important of which are the ventral tegmental area and the nucleus accumbens that are involved in reward processing. In this review, we have presented the work in our laboratory along with the work of others and have discussed the possible functions we can infer from the research. We discuss the anatomy of the orexinergic system and its components followed by a presentation of other connected brain areas. The second part of this review discusses observed results from the morphine conditioned place preference test that sheds light on the possible role of the involved areas in reward processing. The complex circuits involved in reward processing are only beginning to be understood and we need to deepen our understanding regarding the nature of the interactions between all brain areas involved.

The nuclear organization of the cholinergic, catecholaminergic, serotonergic and orexinergic systems in the brains of three species of strepsirrhine primates is presented. We aimed to investigate the nuclear complement of these neural systems in comparison to those of simian primates, megachiropterans and other mammalian species. The brains were coronally sectioned and immunohistochemically stained with antibodies against choline acetyltransferase, tyrosine hydroxylase, serotonin and orexin-A. The nuclei identified were identical among the strepsirrhine species investigated and identical to previous reports in simian primates. Moreover, a general similarity to other mammals was found, but specific differences in the nuclear complement highlighted potential phylogenetic interrelationships. The central feature of interest was the structure of the locus coeruleus complex in the primates, where a central compactly packed core (A6c) of tyrosine hydroxylase immunopositive neurons was surr...

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORX...

Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we herein investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepat...

BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system. Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (-16.1±1.6 and -11.0±1.1 mm Hg, respectively;P<0.001 compared with vehicle). However, when...

Neuropeptides orexin A and orexin B, which are exclusively produced by neurons in the lateral hypothalamic area, play an important role in the regulation of a wide range of behaviors and homeostatic processes, including regulation of sleep/wakefulness states and energy homeostasis. The orexin system has close anatomical and functional relationships with systems that regulate the autonomic nervous system, emotion, mood, the reward system, and sleep/wakefulness states. Recent pharmacological studies using selective antagonists have suggested that orexin receptor-1 (OX1R) is involved in physiological processes that regulate emotion, the reward system, and autonomic nervous system. Here, we examined Ox1r (-/-) mice with a comprehensive behavioral test battery to screen additional OX1R functions. Ox1r (-/-) mice showed increased anxiety-like behavior, altered depression-like behavior, slightly decreased spontaneous locomotor activity, reduced social interaction, increased startle respons...