Introduction

Energy balance is maintained via a homeostatic system involving both the brain and the periphery. A key component of this system is the hypothalamus. Over the past two decades, major advances have been made in identifying an increasing number of neuropeptides within the hypothalamus that contribute to the process of energy homeostasis. Under stable conditions, equilibrium exists between anabolic peptides, which stimulate feeding behavior as well as decrease energy expenditure and lipid...

References

Peyron, X. Gao, P. E. Foye, P. E. Danielson, C. Fukuhara, E. L. Battenberg, V. T. Gautvik, F. S. Bartlett 2nd, W. N. Frankel, A. N. van den Pol, F. E. Bloom, K. M. Gautvik and J. G. Sutcliffe, The hypocretins hypothalamus-specific peptides with neuroexcitatory activity, Proc Natl Acad Sci U S A 95, 322-327 (1998). 2. T. Sakurai, A. Amemiya, M. Ishii, I. Matsuzaki, R. M. Chemelli, H. Tanaka, S. C. Williams, J. A. Richarson, G. P. Kozlowski, S. Wilson, J. R. Arch,...

J 200

T if > f J J J if < f S J Controls ICSD Narcolepsy Other Hypersomnias Other Sleep Disorders Figure 3 Cerebrospinal fluid hypocretin-1 concentrations are plotted for individuals across various conditions and disorders, including sleep disorders. Modified from Mignot et al 59.Each point represents the crude Hcrt-1 concentration in one individual. Horizontal bars indicate the median value for that clinical group. The horizontal dashed lines delineate the cut-off values for normal (> 200 pg...

Addiction333

What Brain Regions are the Critical ORX HCRT Targets 335 23. DOPAMINE - HYPOCRETIN OREXIN INTERACTIONS The Prefrontal Cortex and Ariel Y. Deutch, Jim Fadel, and Michael Bubser 2. ANATOMICAL BASIS OF DOPAMINE-OREXIN INTERACTIONS 340 2.1. Orexin Projections to Midbrain Dopamine 2.2. Overlap of Forebrain Hcrt Orexin and DA 2.3. The Dopaminergic Innervation of the Lateral Hypothalamus and 3. DOPAMINERGIC REGULATION OF OREXIN NEURONS 342 3.1. Amphetamine and Apomorphine Effects on Fos...

W

Ablation of orexin neurons in orexin ataxin-3 transgenic mice. Matched brain sections (bregma 22.1 mm) from 4-, 8-, and 15-week-old orexin ataxin-3 transgenic mice (right panels) and their transgene-negative littermates (left panels) were stained with anti-orexin antiserum. Bar, 100 m. (Modified from ref. 6). Figure 5. Ablation of orexin neurons in orexin ataxin-3 transgenic mice. Matched brain sections (bregma 22.1 mm) from 4-, 8-, and 15-week-old orexin ataxin-3 transgenic mice...

B

Hypocretin and dynorphin modulate GABA input to histamine neurons. (A) Orexin-A increases spontaneous IPSPs (blocked by bicuculline, 20 M). Note the bicuculline-insensitive increase in membrane noise induced by Orexin-A. (B) Activation of opioid receptors by the K-receptor agonist dynorphin and the receptor agonist (D-Ala, N-Me-Phe, glycinol)-enkephalin (DAMGO 1 M) suppress spontaneous IPSPs. (C) Co-application of Orexin-A and dynorphin overwrites Orexin-A effects. Modified from...

Electron microscopy

Electron microscopic analysis of Hcrt-immunolabeled perikarya confirms that immunoprecipitation (representing Hcrt) is predominantly associated with a membranous structure, in particular, the Golgi apparatus, while diffuse labelling in the cytosol can also be detected (Fig. 3).10,13 It is a characteristic feature that Hcrt neurons contain abundant endoplasmic reticuli and medium-sized mitochondria (Fig. 3). With regard to other cytoplasmic organelles, it is noteworthy to mention that a large...

Metabolic Signals Modulate Hypocretin Neuron Activity

In early studies of hypocretin2 reported that injections of the peptide into the CNS increased feeding. Food deprivation enhanced hypocretin mRNA, 2 leptin blocked the fasting-mediated rise in hypocretin mRNA,49 and 2-deoxyglucose reduced hypocretin mRNA.50 Hypocretin mRNA is also decreased in the genetically obese mice ob ob and db db.51 Hypocretin may alter insulin secretion.52 Insulin induced hypoglycemia enhances hypocretin mRNA and c-Fos.5354 The finding in hypocretin neurons that gene...

Role in Feeding Behaviour

The first anatomically identified inputs to the Hcrt neurons were two projections from the arcuate nucleus, a bilaterally symmetric structure bordering the base of the third ventricle just dorsal to the median eminence see refs 101-102. The arcuate nucleus is of particular interest with regard to energy metabolism, since it provides an entrance point for numerous anabolic and catabolic hormones into the brain, including leptin and insulin see refs 103-104. Indeed, in the pioneering studies of...

Cocaine and Amphetamine Regulated Transcript

Cocaine- and amphetamine-regulated transcript (CART) encodes several putative peptide fragments, some of which decrease feeding upon central administration.36,37 (see ref 38). CART is expressed in numerous brain nuclei, and the actual site of its anorexigenic actions has not yet been fully determined. In the rat LHA, CART is detected in the lion's share of MCH neurons of the zona incerta and medial LHA, whereas most peripeduncular MCH cells do not contain CART.39-40 In contrast, no Hcrt neurons...

Cat

Sleep waking cycle discharge of monoaminergic cells. Monoaminergic cells behave similarly across normal sleep cycles, with all showing maximal discharge in active waking, decreased discharge in quiet waking, greatly reduced discharge in sow wave sleep SWS and minimal discharge in REM sleep. In cataplexy, noradrenergic locus coeruleus cells are off, whereas histaminergic cells are on and serotonergic dorsal raphe cells have an intermediate pattern From ref 7 . 4. ARE HYPOCRETINS...

Uc Davis Sleep Hypocretin

Human narcolepsy is a chronic sleep disorder that affects 1 2000 of the general population. One of the major research aims of the Stanford Sleep Research Center is to find the etiology of the disease and to develop better treatments for human narcolepsy. However, human narcolepsy is very complex and multifactorial, and is 1 genetically heterogeneous, 2 a polygenic trait and 3 environmentally influenced.1 The development of a simpler animal model of narcolepsy was thus the high priority in the...

Dopamineregic Transmission and EEG Arousal

Narcoleptic Dobermans were also used for a series of pharmacological experiments to dissect modes of action of wake-promoting compounds. Amphetamine-like CNS stimulants currently used clinically for the management of sleepiness in narcolepsy enhance monoaminergic transmission presynaptically. Figure 4. Effects of various DA and NE uptake inhibitors and amphetamine-like stimulants on the EEG arousal of narcoleptic dogs and correlation between in vivo EEG arousal effects and in vitro DAT binding...

Symptoms Of Canine Narcolepsy

Affected dogs exhibit very pronounced attacks of cataplexy which are mainly triggered by positive emotional experiences , such as being fed a favorite food or engaging in play. Cataplectic attacks in dogs often begin as a buckling of both hind legs, and this is often accompanied by a drooping of the neck see Figure 1 . The dog may collapse to the floor and remain motionless for a few seconds or several minutes. In contrast to the some forms of epilepsy, excess salivation or incontinence are not...

Hypocretin Deficiency In Human Narcolepsy

In 1999, it was discovered that a genetically induced deficiency of hypocretin neurotransmission in dogs and mice leads to a complex of symptoms remarkably similar to that seen in human narcolepsy.6'7 These findings focused attention on the role of hypocretin in the pathophysiology of human narcolepsy. A mutation screening of the hypocretin genes was performed in 74 patients, including patients with and without a family history of narcolepsy and patients with and without HLA DQB1 0602.8 Of...

Nonrem Sleeprelated Symptoms

Increased daytime sleepiness is well described in human patients.7'13 Human patients often complain of involuntary or irresistible urge to sleep, which can occur while talking, standing, walking, eating, or driving. In addition to REM sleep-related abnormalities, another prominent feature of sleep wake patterns in orexin-' mice or orexin ataxin-3 mice was shortened durations of both wakefulness and non-REM sleep in the dark phase, causing increased fragmentation of sleep wake cycle Fig. 3 ....

Psychiatric Disorders

Many years of research have demonstrated the ability of the hypothalamus to control the homeostatic state and physiology in animals. Specific lesions experiments have characterized sub-nuclei of the hypothalamus that are important in sleep, feeding, autonomic control, sex drive and motivational behavior. The hypocretin neurons that are located in the dorso-lateral hypothalamus provide a dense innervation to the other nuclei within the hypothalamus as well as the monoaminergic systems, in...

Monoaminergic and Cholinergic Interactions and Cataplexy

The importance of increased cholinergic activity in triggering REM sleep or REM sleep atonia is well established see ref. 32 . Similarly, activation of the cholinergic systems using the acetylcholinesterase inhibitor physostigmine also greatly exacerbates cataplexy 33. This cholinergic effect is mediated via muscarinic receptors since muscarinic stimulation aggravates cataplexy, while its blockade suppresses it, and nicotinic stimulation or blockade has no effect.33 Monoaminergic transmission...

Distribution Of Hcrt Efferent Axons

Hypocretin Projections

The morphology of Hcrt-immunoreactive axons is heterogeneous and varies from thick, densely-varicose to fine, lightly-varicose.10 Hcrt-immunoreactive axons are found throughout the brain, with the highest density of terminal fields seen in the hypothalamus Fig. 1 .5,7,8 Figure 1. Schematic diagram of the pathways taken by Hcrt orexin axons, which widely innervate the rat brain through both ascending and descending projections.6 Copyright 1998 by the Society for Neuroscience. Figure 1. Schematic...

The Aminergic Systems

The relatively small number of aminergic neurons located in the locus coeruleus noradrenaline , dorsal raphe serotonin , ventral tegmental area substantia nigra dopamine , lateral dorsal tegmentum basal forebrain acetylcholine , and tuberomamillary nucleus histamine project with multifold arborisations to most regions of the central nervous system, partially overlapping with the projections of hypocretin neurons.32 Apart from some distinctions they display comparable morphological features,...

Hypocretin Actions In The Adrenal Gland

Mineralocorticoid Actions The Brain

Although it was originally thought that the sole locus of hypocretin production was in hypothalamus, some of the peptide may be produced in testis.32'38 Whether the hypocretin apparently produced in testis, or peptide produced in brain, gains access to the general circulation in sufficient amounts to act as a true hormone is unknown. However, hypocretin receptors are present in a variety of peripheral tissues, including the adrenal gland.33'42-45 In vitro studies have demonstrated significant...

Other Neurological Disorders

Low hypocretin levels are also observed in a large range of other neurological conditions. In these disorders the alteration of the hcrt level may reflect focal lesions in the hypothalamus or transient or chronic dysfunction of the hypothalamus. 4.1. Kleine-Levin Syndrome KLS KLS is a rare cause of hypersomnia characterized by a recurrent alteration of sleep-wake regulation and frequent abnormal feeding and sexual behaviors. Recent association reported with HLA DQB1 0201 together with the young...

Inheritance Of Narcolepsy In Canines

Narcolepsy And Cataplexy

Unrelated narcoleptic poodles, beagles and dachshunds donated to the Stanford were bred, but none of the offspring from two primary crosses or a backcross were affected.13 Thus, it appears that in these breeds, narcolepsy seems to be sporadic and an involvement of a high penetrant single major gene is unlikely. In humans, about 95 of narcoleptic subjects are sporadic, but familial occurrences were noted in about 5 of narcoleptic subjects.14 In 1976, the Stanford Sleep Research Center received 4...

The Hypothalamus And Addiction

Neuron 10x

Many levels of hypothalamic function are likely to influence addiction. While most of the previous work on the role of the hypothalamus in addiction assessed effects of the HPA hypothalamic-pituitary-adrenal axis and various physiological states, such as stress, on addiction,25-27 the LH-restricted expression of ORX HCRT suggests a direct role for these peptides in controlling addiction-related behaviors. Indeed, the ORX HCRT neurons project broadly to regions throughout the brain, including...

Future Prospects

While much has been learned about the cause of narcolepsy-cataplexy in humans and animal models we still do not known whether narcolepsy is an autoimmune disorder resulting from the degeneration of hypocretin neurons. Indeed, studies showing the absence of prepro-hypocretin mRNA and hypocretin immunoreactivity from the lateral hypothalamic area of human brains,21,22 are consistent with this possibility. However, attempts to confirm this autoimmune hypothesis directly96,97 have been, to date,...

Hypocretin Replacement Therapy

Hypocretin

Finally, a canine narcolepsy model both familial and sporadic narcoleptic dogs was used for the evaluation of replacement supplement therapies of hypocretin ligands.26 Using a ligand deficit sporadic narcoleptic dog, we have assessed the effects on cataplexy of intravenous IV administration of hypocretin-1 6 - 384 g kg . In a separate experiment, we found that a small portion of hypocretin-1 penetrates to the central nervous system by assessing the increase in CSF hypocretin levels after high...