Disease relevance of Hcrt

• Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background [1].
• Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models [1].
• Orexin neurons project throughout the central nervous system (CNS) to nuclei known to be important in the control of feeding, sleep-wakefulness, neuroendocrine homeostasis, and autonomic regulation. orexin mRNA expression is upregulated by fasting and insulin-induced hypoglycemia [2].
• The 3.2-kb 5'-flanking region of the human prepro-orexin gene is sufficient for the specific expression of an Escherichia coli lacZ reporter gene in orexin neurons [3].
• We recently reported increased amount of orexin A in the phenylketonuria (PKU) mouse brain [4].

Psychiatry related information on Hcrt

• Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes [5].
• Transgenic mice, in which orexin neurons are ablated, fail to respond to fasting with increased wakefulness and activity [6].
• In contrast, OX2R(-/-) mice are only mildly affected with cataplexy-like attacks of REM sleep, whereas orexin(-/-) mice are severely affected [5].
• These data suggest that GABA(B) receptors modulate Hcrt neuronal activity via both pre- and postsynaptic mechanisms, which may underlie the promotion of non-rapid eye movement sleep and have implications for the use of GABA(B) agonists in the treatment of substance addiction through direct interaction with the Hcrt system [7].
• These results are consistent with the hypothesis that an age-related deterioration occurs in the Hcrt system that may contribute to age-related sleep disorders [8].

High impact information on Hcrt

• We propose that orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation [9].
• Neurons containing the neuropeptide orexin (hypocretin) are located exclusively in the lateral hypothalamus and send axons to numerous regions throughout the central nervous system, including the major nuclei implicated in sleep regulation [9].
• Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy [9].
• Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons [9].
• Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation [9].

Chemical compound and disease context of Hcrt

• We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 +/- 8 mmHg in wild type and 92 +/- 3 in knockout) and conscious (125 +/- 6 mmHg in wild type and 109 +/- 2 in knockout) conditions. alpha-Adrenergic blockade with prazosin or ganglion blockade with hexamethonium canceled the difference in basal AP [10].
• Here we provide several lines of evidence that orexin A induces wakefulness by means of the TMN and histamine H(1) receptor (H1R) [11].
• Calcium imaging using orexin/YC2.1 transgenic mouse brain revealed that NA-induced inhibition of orexin neurons is not altered by sleep deprivation or circadian time in mice [12].
• Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates [13].
• We thus compared the effects of orexin A and some established secretagogues on duodenal HCO3- secretion in fed rats with effects in rats exposed to short (overnight) food deprivation [14].

Biological context of Hcrt

• A commentary on the neurobiology of the hypocretin/orexin system [15].
• Down regulation of the prepro-orexin gene expression in genetically obese mice [16].
• However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved [1].
• Hypocretin/orexin (Hcrt) is a critical neurotransmitter for the maintenance of wakefulness and has been implicated in several other functions, including energy metabolism and reward [7].
• Hcrt/Orx produced an increase in frequency and amplitude of spontaneous EPSCs without equivalent effect on IPSCs, by triggering action potentials and enhancing spike-evoked synaptic transmission in glutamatergic afferents [17].

Anatomical context of Hcrt

• Prepro-Hcrt/OX mRNA expression, measured by in situ hybridization was restricted to the lateral hypothalamus area [18].
• Acute third ventricle (i3vt) injections of Hcrt/OX peptides in ob/ob mice transiently increased their metabolic rate and stimulated lipid substrate utilization [18].
• Hcrt-2 actions were stronger than those of Hcrt-1, and the action persisted in TTX and in low calcium/high magnesium artificial cerebrospinal fluid, consistent with direct actions mediated by Hcrt receptor-2 [19].
• Collectively, our findings indicate that Hcrt/Orx signaling in the reticular activating system involves elevation of [Ca(2+)](i) by a PKC-involved influx of Ca(2+) across the plasma membrane, in part, via L-type calcium channels [20].
• The paraventricular thalamic nucleus (PVT) receives one of the most dense innervations by hypothalamic hypocretin/orexin (Hcrt) neurons, which play important roles in sleep-wakefulness, attention, and autonomic function [19].

Associations of Hcrt with chemical compounds

• Activity of isolated orexin neurons is inhibited by glucose and leptin and stimulated by ghrelin [6].
• We also found a decrease in basal orexin mRNA levels in the lateral hypothalamus of the D3-/- mice, which was unaltered by acute "binge" cocaine [21].
• The robust excitation evoked by Hcrt-2 on cortically projecting glutamate PVT neurons could generate substantial excitation in multiple layers of the mPFC, adding to the more selective direct excitatory actions of Hcrt in the mPFC and potentially increasing cortical arousal and attention to limbic or visceral states [19].
• In contrast, Hcrt/Orx responses were strongly attenuated by lowering extracellular Ca(2+) ( approximately 20 microM) but were not inhibited by concentrations of KB-R7943 (10 microM) selective for blockade of sodium/calcium exchange [20].
• Nifedipine (10 microM), inhibited Hcrt/Orx responses but was more effective at abolishing spiking than plateau responses [20].
• Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age [22].
• These results establish what is, to our knowledge, a novel interaction between the N/OFQ and Hcrt systems in which the corticotropin-releasing factor and N/OFQ systems coordinately modulate the Hcrt neurons to regulate SIA [23].

Physical interactions of Hcrt

• Complex disruption of energy homeostasis in orexin neuron-deficient transgenic mice (orexin/ataxin-3 mice) is also manifested as late-onset obesity despite eating less [24].

Regulatory relationships of Hcrt

• Thus, OE1 contains crucial cis-acting elements regulating prepro-orexin gene expression specifically in the LHA [3].
• In transgenic mice, both OE1 and OE2 are necessary for expressing the human prepro-orexin gene in the LHA and for repressing its expression in the medial regions of the hypothalamus [3].
• Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system [25].
• Our results show that CRF-immunoreactive terminals make direct contact with hypocretin-expressing neurons in the lateral hypothalamus and that numerous hypocretinergic neurons express the CRF-R1/2 receptors [26].
• Ghrelin-induced feeding was also suppressed in orexin knockout mice [27].

Other interactions of Hcrt

• The expression of gastric ghrelin and hypothalamic orexin was decreased in PP-overexpressing mice [28].
• There are two phylogenetically conserved regions located 287 bp (orexin regulatory element (OE) 1) and 2.5 kb (OE2) upstream of the transcription initiation site of the human prepro-orexin gene [3].
• Adult mutants display increased hypothalamic CRH and NPY levels, but peptide levels of melanin concentrating hormone and Orexin A and B are unchanged [29].
• However, RF shifted the peak of Fos expression of the orexin neurons from night to day [30].
• The expression of mNpas2 mRNA, a transcription factor thought to be involved in regulation of the food entrainable oscillator as well as mPer1 and mBmal1 mRNA, was reduced in the forebrain of orexin/ataxin-3 mice [30].

Analytical, diagnostic and therapeutic context of Hcrt

• Whole-cell recordings revealed that Hcrt/Orx had actions on both presynaptic neurons and at postsynaptic sites [17].
• To characterize the physiological role(s) of orexins in the mouse, we cloned and characterized the mouse orexin receptor(s), mOX1R and mOX2R, using rapid amplification of cDNA (mouse brain) ends, RT-PCR, and gene structure analysis [31].
• After depriving mice of sleep for 2-8 hr, orexin KO mice recovered their NREM and rapid eye movement sleep deficits at comparable rates and to the same extent as WT mice, with similar increases in EEG delta power, suggesting that their homeostatic control of sleep is normal [32].
• Microdialysis studies showed that application of orexin A to the TMN increased histamine release from both the medial preoptic area and the frontal cortex by approximately 2-fold over the baseline for 80 to 160 min in a dose-dependent manner [11].
• Perfusion of orexin A (5 and 25 pmol/min) for 1 hr into the TMN of rats through a microdialysis probe promptly increased wakefulness for 2 hr after starting the perfusion by 2.5- and 4-fold, respectively, concomitant with a reduction in rapid eye movement (REM) and non-REM sleep [11].

References