A Brief History of Hypocretin/Orexin and Narcolepsy

160

135

Wakefulness depends on the activity of hypocretin-orexin neurons because their lesion results in narcolepsy. How these neurons maintain their activity to promote wakefulness is not known. Here, by recording for the first time from hypocretin-orexin neurons and comparing their properties with those of neurons expressing melanin-concentrating hormone, we show that hypocretin-orexin neurons are in an intrinsic state of membrane depolarization that promotes their spontaneous activity. We propose that wakefulness and associated energy expenditure thus depend on that property, which allows the hypocretin-orexin neurons to maintain a tonic excitatory influence on the central arousal and peripheral sympathetic systems.

Section: Properties Of Hcrt/orx Neuronsmentioning

confidence: 99%

The Wake-Promoting Hypocretin–Orexin Neurons Are in an Intrinsic State of Membrane Depolarization

Eggermann¹,

Bayer²,

Serafin³

et al. 2003

160

135

“…The neurons of the lateral hypothalamus and perifornical area that express hypocretin-orexin (hcrt-orx) Sakurai et al, 1998) are thought to play a major role in promoting the state of wakefulness (for review, see Siegel et al, 2001;Beuckmann and Yanagisawa, 2002;Sutcliffe and de Lecea, 2002;Taheri et al, 2002). Indeed, various conditions that interfere with the integrity of the neurons, the peptides they secrete, or the receptors to the peptides are associated with a deficiency in wakefulness and the development of narcolepsy (Chemelli et al, 1999;Lin et al, 1999;Nishino et al, 2000;Peyron et al, 2000;Thannickal et al, 2000;Hara et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Exclusive Postsynaptic Action of Hypocretin-Orexin on Sublayer 6b Cortical Neurons

Bayer¹,

Serafin²,

Eggermann³

et al. 2004

145

121

The hypocretin-orexin (hcrt-orx) neurons are thought to maintain wakefulness because their loss results in narcolepsy. This role may be fulfilled by the excitatory action that the hcrt-orx peptide exerts on multiple brainstem and forebrain systems that, in turn, promote cortical activation. Here, we examined whether hcrt-orx may also exert a postsynaptic excitatory action at the level of the cortex, where hcrt-orx fibers project. However, we found that neurons in layers 2-5 in the primary somatosensory cortex (SSp) were unresponsive to hcrt-orx. We then found that although all neurons tested in sublayer 6a were also unresponsive to hcrt-orx, all those tested in sublayer 6b were highly sensitive to the peptide. The sublayer selectivity of hcrt-orx was not restricted to the somatosensory cortex, because it was also found to be present in the primary visual cortex, the motor cortex, and the cingulate cortex. In the SSp, in which the hcrt-orx effect was investigated further, it was demonstrated to be postsynaptic, to result from an interaction with Hcrtr2-OX 2 receptors and to depend on the closure of a potassium conductance. Similar to the selectivity of action in the thalamus, where hcrt-orx excites the nonspecific thalamocortical projection neurons and not the specific sensory relay neurons, here in the cortex, it excites a specific subset of cortical neurons which, through corticocortical projections, may also be involved in promoting widespread cortical activation.

“…The neurons of the lateral hypothalamic and perifornical areas (LHA/PF) that express hypocretin/orexin (hcrt/orx) Sakurai et al, 1998) are thought to play a major role in promoting wakefulness (for review, see Siegel et al, 2001;Beuckmann and Yanagisawa, 2002;Sutcliffe and de Lecea, 2002;Taheri et al, 2002). Alteration of the hcrt/orx system is associated with narcolepsy in dogs, mice, and humans (Chemelli et al, 1999;Lin et al, 1999;Nishino et al, 2000;Peyron et al, 2000;Thannickal et al, 2000;Hara et al, 2001), and one dominating feature of that pathology is an abnormal sleepiness.…”

Section: Introductionmentioning

confidence: 99%

The Wake-Promoting Hypocretin/Orexin Neurons Change Their Response to Noradrenaline after Sleep Deprivation

Grivel¹,

Cvetković²,

Bayer³

et al. 2005

Sleep deprivation is accompanied by the progressive development of an irresistible need to sleep, a phenomenon whose mechanism has remained elusive. Here, we identified for the first time a reflection of that phenomenon in vitro by showing that, after a short 2 h period of total sleep deprivation, the action of noradrenaline on the wake-promoting hypocretin/orexin neurons changes from an excitation to an inhibition. We propose that such a conspicuous modification of responsiveness should contribute to the growing sleepiness that accompanies sleep deprivation.