Hypocretin Deficiency In Narcolepsy

Nishino et al.5S found lumbar CSF Hcrt-1 levels below the detection limit (40 pg/mL) in narcoleptics, while control subjects had an average of 280 pg/mL. This study provided the first clear link between hypocretin dysfunction and human narcolepsy. These findings have been extended and replicated by other groups59 (see below). It has thus far not been possible to measure Hcrt-2 in the CSF, as Hcrt-2 is likely degraded rapidly or is unstable in CSF.

Further pathologic evidence of selective hypocretin deficiency has come from immunohistochemical and in situ hybridization studies which have indicated a global loss of hypocretin in the brains of human narcoleptics (Figure 2).21,22 This loss of hypocretin cells seems selective, as melanin-concentrating hormone (MCH) neurons, which are normally located in the same region in the hypothalamus, are not downregulated.21 This same pathological phenotype has been found in the few cases of sporadic canine narcolepsy as well. An increased number of astrocytes in the lateral hypothalamus but not the thalamus of narcoleptic brains has also been detected,22 suggesting lateral hypothalamic area-specific gliosis.

Lack Orexin Narcolepsy

Figure 2 Absence of hypocretin transcripts in the lateral hypothalamus of narcoleptic patients (A) versus controls (B). MCH transcripts are detected in the same region in both narcoleptics (C) and controls (D), suggesting that the loss of hypocretin-containing neurons is selective. From Peyron et al21. F= fornix

Figure 2 Absence of hypocretin transcripts in the lateral hypothalamus of narcoleptic patients (A) versus controls (B). MCH transcripts are detected in the same region in both narcoleptics (C) and controls (D), suggesting that the loss of hypocretin-containing neurons is selective. From Peyron et al21. F= fornix

It is clear, however, that hypocretin stabilizes, rather than generates vigilance states.40 Animal studies have shown that hypocretin signaling is crucial in maintaining wakefulness and regulating REM sleep, and likely involves both aminergic and cholinergic neurons. While still incomplete, there are several hypotheses regarding the function(s) of hypocretin and how their loss leads to the symptoms of EDS and REM dissociation seen in narcolepsy. Hypocretinergic neurons send excitatory innervation to a variety of nuclei involved in the maintenance or generation of wake, including the noradrenergic neurons of the locus coeruleus (LC), the serotonergic neurons of the dorsal raphe (DR), and the histaminergic neurons of the tuberomammillary nucleus (TMN). The histaminergic neurons may play a particularly important role as histamine concentrations are low in narcoleptic dogs with the mutant Hcrtr2 receptor60 as well as in human narcoleptics.61 Additionally, mice lacking the HI histamine receptor appear to have no waking response to intraventricular injections of hypocretin-1.62 While dopaminergic signaling also promotes wakefulness (dopamine antagonists can induce sleep and amphetamines promote wakefulness by increasing extracellular concentrations of dopamine), interactions between the hypocretin and dopaminergic systems are poorly understood. Finally, hypocretin may also promote wakefulness by exciting cholinergic neurons of the laterodorsal and pedunculopontine tegmental (LDT/PPT) nuclei. Most LDT/PPT neurons are active during wakefulness and promote electroencephalographic desynchrony through projections to the thalamus.

How hypocretin deficiency mediates REM sleep abnormalities and cataplexy in narcolepsy is more controversial. Like REM sleep, cataplexy is modulated by monoaminergic (particularly D2/D3 dopaminergic and/or alpha-1(b) adrenergic) tone and cholinergic (M2/M3 muscarinic receptor) systems. Anatomically, cholinergic neurons in the basal forebrain and pontine reticular formation (PRF), and LDT/PPT, as well as dopaminergic neurons in the ventral tegmental area (VTA) appear to be involved. REM sleep atonia is induced by the activity of the cholinoceptive neurons in the PRF (nucleus reticularis pontis); these neurons descend through the medulla and inhibit motoneurons through activation of inhibitory glycinergic interneurons. It is presumed that connections between the limbic system, the basal forebrain and pontine nuclei explain how emotional events can trigger cataplexy, although these tracts have yet to be identified. The REM-active LDT/PPT neurons are inhibited by amines such as norepinephrine, and it is believed that the apparent disinhibition of REM sleep in narcolepsy is due to decreased aminergic activity from a loss of hypocretin signaling, and less aminergic activity would disinhibit the REM-generating neurons of the LDT/PPT.63 Therefore, hypocretin cells would be silent during REM sleep in this model. However, an alternative hypothesis is that hypocretin signaling may actually promote REM sleep, and therefore, both models may be correct, in that hypocretin cells may exhibit different patterns of activity — with some promoting wakefulness by activating aminergic brain regions and wake-active cells of the LDT/PPT, while others may excite the REM-active cells of the LDT/PPT. The finding that the dopaminergic neurons in the VTA mediate the experience of pleasure is also of potential importance in the narcolepsy phenotype, though an exact link has yet to be established.

Finally, hypocretin is most likely involved in the integration of sleep regulation and metabolic status, as narcoleptics are slightly more overweight than the general population.64,65 Hypocretin cells can respond electrophysiological^ to common circulating signals of metabolic state, including glucose, leptin and ghrelin,66 which may possibly increase wakefulness when needing to search for food in the fasting state. Therefore, it is likely that hypocretin plays an as yet to be defined role, in the complex interactions between the hypothalamic peptidergic systems in the regulation of appetite, feeding, and metabolism.

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