Disease relevance of Hcrt

• STUDY OBJECTIVES: The sleep disorder narcolepsy is now considered a neurodegenerative disease because there is a massive loss of neurons containing the neuropeptide, hypocretin, and because narcoleptic patients have very low cerebrospinal fluid levels of hypocretin [1].
• Increased and decreased muscle tone with orexin (hypocretin) microinjections in the locus coeruleus and pontine inhibitory area [2].
• Increased hypocretin tone during REM deprivation may be important in mediating some of the effects of REM sleep deprivation such as antidepressant effects, hyperphagia and increased sympathetic activity [3].
• Activation of FOS in hypocretin neurons of the rat by insulin-induced hypoglycemia [4].

Psychiatry related information on Hcrt

• Hcrt cells are silent in slow wave sleep and tonic periods of REM sleep, with occasional burst discharge in phasic REM [5].
• Hcrt cells discharge in active waking and have moderate and approximately equal levels of activity during grooming and eating and maximal activity during exploratory behavior [5].
• Administration of Hcrt can reverse symptoms of narcolepsy in animals, may be effective in treating human narcolepsy, and may affect a broad range of motivated behaviors [6].
• Hcrt release in waking is increased markedly during periods of increased motor activity relative to levels in quiet, alert waking [6].
• The hypocretin mRNA accumulates during food deprivation [7].

High impact information on Hcrt

• Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors [8].
• We found that Hcrt cells have broad action potentials with elongated later positive deflections that distinguish them from adjacent antidromically identified cells [5].
• By this mechanism, the hypocretin projection to prefrontal cortex may play a larger role in prefrontal or "executive" aspects of alertness and attention than previously anticipated [9].
• Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress [10].
• Hypocretin-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropin-releasing factor systems, suggesting that Hcrt-1 reinstated drug seeking through induction of a stress-like state [10].

Chemical compound and disease context of Hcrt

• Orexin/hypocretin neurons in the lateral hypothalamus and adjacent perifornical area (LH/PFA) innervate midbrain dopamine (DA) neurons that project to corticolimbic sites and subserve psychostimulant-induced locomotor activity [11].
• Using two-photon imaging in prefrontal brain slices, we show that nicotine and the wakefulness neuropeptide hypocretin (orexin) excite the same identified synapses of the thalamocortical arousal pathway within the prefrontal cortex [12].
• CONCLUSION: The present data indicate that a large fall in plasma glucose in early phase of acute hypoglycemia does not represent an appropriate stimulus for massive activation of HCRT neurons in the LHA of rats [4].

Biological context of Hcrt

• Evidence for a role for Hcrt in food intake regulation is inconsistent [6].
• These results indicate that the Hcrt system modulates ingestive behaviors but does not play a necessary role in the entrainment or expression of food-anticipatory circadian rhythms [13].
• Our previous experimental work on these neurons showed that they may be involved in energy metabolism and water balance, which is in agreement with the current literature about Hcrt functions [14].
• The high concentration of unconjugated saporin produced some loss of neuronal nuclei-immunoreactive (NeuN-ir) neurons and hypocretin immunoreactive neurons, but only a transient increase in non-rapid eye movement sleep [15].
• Hypocretin 2 (orexin B) is a hypothalamic neuropeptide thought to be involved in regulating energy homeostasis, autonomic function, arousal, and sensory processing [16].

Anatomical context of Hcrt

• The present data provide direct evidence that Hcrt/OX expression in the lateral hypothalamus is modulated by the glucocorticoids status [17].
• Hcrt may act via the calcium-dependent regulation of glutamate release in certain nuclei of the central nervous system [18].
• We found that intravenous Hcrt administration caused a marked (> 60 %) and sustained (> 50 min) increase in glutamate release within the amygdala, but no change in release in the cerebellar cortex [18].
• Hcrt/ORX receptors are present in the hypothalamus and anterior pituitary gland [19].
• Hcrt-containing neurons, which are located exclusively in the lateral hypothalamic area, provide a dense innervation to the medial septum/diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics [20].

Associations of Hcrt with chemical compounds

• Hcrt also has a major role in modulating the release of glutamate and other amino acid transmitters [6].
• To see if these neurons are similarly or differentially modulated by neurotransmitters of the major brainstem arousal systems, the effects of noradrenaline (NA) and carbachol, a cholinergic agonist, were examined on identified Hcrt/Orx and MCH neurons in rat hypothalamic slices [21].
• This result together with the previously reported stimulation of Hcrt expression by insulin confirms that Hcrt neurons, but not MCH neurons, are sensitive to glucose availability and suggests that they respond through different mechanisms and/or different pathways to intracellular glucopenia and hypoglycemic conditions [22].
• Thus Hcrt effects within the septum should increase hippocampal acetylcholine release and thereby promote hippocampal arousal [23].
• The Hcrt effect was dependent on external Na(+), reduced by external Ba(2+), and also reduced in recordings with CsCl-containing electrodes, suggesting a dual underlying ionic mechanism that involved inhibition of a K(+) current, presumably an inward rectifier, and a Na(+)-dependent component [23].

Regulatory relationships of Hcrt

• In addition, hypocretin-containing neurons also express leptin receptor immunoreactivity [24].
• Intra-accumbens shell muscimol treatment significantly increased the percentage of orexin/hypocretin-containing neurons expressing Fos in the lateral, but not medial, portion of the perifornical/lateral hypothalamic area [25].

Other interactions of Hcrt

• Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations [24].
• Our data indicate that a direct interaction between leptin, hypocretin, and NPY exists in the hypothalamus that may contribute to the central regulation of metabolic and endocrine processes in both rodents and primates [24].
• Both corticotropin releasing factor and neuropeptide Y are involved in the effect of orexin (hypocretin) on the food intake in rats [26].
• Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus [27].
• Effect of 2-mercaptoacetate and 2-deoxy-D-glucose administration on the expression of NPY, AGRP, POMC, MCH and hypocretin/orexin in the rat hypothalamus [28].

Analytical, diagnostic and therapeutic context of Hcrt

• We confirmed by in situ hybridization that prepro-Hcrt/OX mRNA expression is restricted to the lateral hypothalamus area with extension to the perifornical nucleus and the posterior hypothalamic area [17].
• Lateral hypothalamic prepro-Hcrt/OX mRNA expression was decreased by 50% after adrenalectomy (99.8+/-5.0 vs 49.2+/-4.4 nCi/g, p<0.01) [17].
• In the present in vivo microdialysis study we have investigated the effect of intravenous administration of Hcrt-1 (orexin-A) to anaesthetized rats on glutamate and GABA release in the amygdala, a region with moderate Hcrt innervation, and in the cerebellar cortex, a region with sparse or no Hcrt innervation [18].
• The roles played by these peptide/protein in OX/Hcrt neurons are still unclear.Double immunocytochemical stainings highlight putative somasomatic, axosomatic and axodendritic contacts between OX/Hcrt and MCH neurons [29].
• Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression [30].

References