Neocortical 40 Hz oscillations during carbachol-induced rapid eye movement sleep and cataplexy.

Higher cognitive functions require the integration and coordination of large populations of neurons in cortical and subcortical regions. Oscillations in the gamma band (30-45 Hz) of the electroencephalogram (EEG) have been involved in these cognitive functions. In previous studies, we analysed the extent of functional connectivity between cortical areas employing the 'mean squared coherence' analysis of the EEG gamma band. We demonstrated that gamma coherence is maximal during alert wakefulness and is almost absent during rapid eye movement (REM) sleep. The nucleus pontis oralis (NPO) is critical for REM sleep generation. The NPO is considered to exert executive control over the initiation and maintenance of REM sleep. In the cat, depending on the previous state of the animal, a single microinjection of carbachol (a cholinergic agonist) into the NPO can produce either REM sleep [REM sleep induced by carbachol (REMc)] or a waking state with muscle atonia, i.e. cataplexy [cataplexy induced by carbachol (CA)]. In the present study, in cats that were implanted with electrodes in different cortical areas to record polysomnographic activity, we compared the degree of gamma (30-45 Hz) coherence during REMc, CA and naturally-occurring behavioural states. Gamma coherence was maximal during CA and alert wakefulness. In contrast, gamma coherence was almost absent during REMc as in naturally-occurring REM sleep. We conclude that, in spite of the presence of somatic muscle paralysis, there are remarkable differences in cortical activity between REMc and CA, which confirm that EEG gamma (≈40 Hz) coherence is a trait that differentiates wakefulness from REM sleep.

Activation of serotonin 5-HT1-receptors decreased gripping-induced immobility episodes in taiep rats.

The taiep rat is a myelin mutant that shows a disorganized sleep-wake cycle and immobility episodes (IEs) when the animals are gripped at the base of the tail. During IEs electroencephalographic recordings show a rapid eye movement (REM) sleep-like pattern. These alterations are quite similar to those reported in narcolepsy-cataplexy. Pharmacologically, systemic administration of alpha(2) adrenoceptor agonists increases gripping-induced IEs, whereas alpha(2) antagonists decrease them. However prazosin, an alpha(1) antagonist, increases gripping-induced IEs. In male 8-month-old taiep rats we have studied the effect of systemic administration of serotonergic autoreceptor agonists and antagonists on gripping-induced IEs. 8-Hydroxy-2-(di-n-propylamino) tetraline hydrobromide (8-OH-DPAT), a 5-HT(1A) agonist, and 3-trifluoromethylphenylpiperazine hydrochloride (TFMPP), a 5-HT(1B) agonist, produce a significant decrease in the frequency and mean duration of IEs. Systemic administration of spiperone and 1-(2-methoxyphenyl)-4[4-(2-phthalimido) butyl]piperazine hydrobromide (NAN-190), 5-HT(1) antagonists, increase IEs and their mean duration. When the specific serotonin antagonist N-[2[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY 100635, 100 microg/kg) was injected 15 min before 8-OH-DPAT, this specific antagonist reverses the effects caused by the 5-HT(1A) agonist. These results show that serotonergic 5-HT(1)-receptors are involved in the susceptibility of gripping-induced IEs in taiep rats. Similar results have been reported in the food-elicited cataplexy test in narcoleptic dogs.

Characterization of the spontaneous and gripping-induced immobility episodes on taiep rats.

In 1989, we described a new autosomic-recessive myelin-mutant rat that develops a progressive motor syndrome characterized by tremor, ataxia, immobility episodes (IEs), epilepsy, and paralysis. taiep is the acronym of these symptoms. The rat developed a hypomyelination, followed by demyelination. At an age of 7-8 months, taiep rats developed IEs, characterized electroencephalographically by REM sleep-like cortical activity. In our study, we analyzed the ontogeny of gripping-induced IEs between 5 and 18 months, their dependence to light-dark changes, sexual dimorphism, and susceptibility to mild stress. Our results showed that IEs start at an age of 6.5 months, with a peak frequency between 8.5 and 9.5 months. IEs have two peaks, one in the morning (0800-1000 h) and a second peak in the middle of the night (2300-0100 h). Spontaneous IEs showed an even distribution with a mean of 3 IEs every 2 h. IEs are sexually dimorphic being more common in male rats. The IEs can be induced by gripping the rat by the tail or the thorax, but most of the IEs were produced by gripping the tail. Mild stress produced by i.p. injection of physiological saline significantly decreased IEs. These results suggested that IEs are dependent on several biological variables, which are caused by hypomyelination, followed by demyelization, which causes alterations in the brainstem and hypothalamic mechanisms responsible for the sleep-wake cycle regulation, producing emergence of REM sleep-like behavior during awake periods.

Sleep and EEG disturbances in a rat neurological mutant (taiep) with immobility episodes: a model of narcolepsy-cataplexy.

The electroencephalographic sleep patterns recorded during short periods of time (3 h) of a neurological mutant rat (taiep) were studied. This rat exhibits, among other signs, immobility episodes that are similar to those observed in narcolepsy-cataplexy. We describe findings of long term (6 months) electroencephalographic studies done in 9 mutant and 5 control rats. The mutant rats present electroencephalographic and behavioral disorders consisting of: (a) bursts of cortical waxing and waning waves occurring during the drowsy state; in some animals this activity represents up to 25% of the total drowsiness time; (b) shortened sleep time; (c) fragmented paradoxical sleep; (d) immobility episodes when the animals are subjected to an emotional excitement; and (e) electrographic activity of paradoxical sleep without atonia during the immobility episodes. These findings show that the taiep mutant shows several aspects of narcolepsy-cataplexy and it may represent an experimental model for the study of this pathology.

The neurobiology of narcolepsy-cataplexy syndrome.

The pathophysiology of narcolepsy is closely related to the abnormalities of REM sleep that are the electrophysiologic signature of the syndrome. Evidence from studies of canine narcolepsy and postmortem human narcoleptic brain tissue provide strong evidence that cholinergic and monoaminergic systems involved in REM sleep regulation are abnormal in narcolepsy but the primary neurochemical abnormality has not yet been determined. There is now conclusive evidence that a genetic basis is required for all or almost all cases of narcolepsy. In the vast majority of narcoleptics, a gene closely linked to the HLA-DR/DQ region appears to confer narcoleptic susceptibility, but the penetrance of the gene is low and additional environmental and perhaps genetic factors are required to express the disease. In a minority of narcoleptics, there may be a second autosomal dominant gene not linked to HLA-DR2 that facilitates the occurrence of narcolepsy. This gene may be related to the mu-immunoglobulin heavy-chain switch-like segment that has been implicated in canine narcolepsy. There appear to be at least two narcoleptic phenotypes associated with the narcoleptic susceptibility gene or genes: narcolepsy-cataplexy syndrome and monosymptomatic narcolepsy, or narcolepsy with REM sleep abnormalities but without cataplexy. Idiopathic hypersomnia without cataplexy or REM sleep abnormalities may represent a third phenotype, although most cases of idiopathic hypersomnia are probably unrelated to the HLA-D linked gene. The link between the genetic basis of narcolepsy and its neurochemical abnormalities is still entirely unknown. Although the hypothesis that a transient immune-mediated reaction leads to a permanent alteration of monoaminergic function is appealling, there is no direct evidence to support this hypothesis. Several important questions concerning the neurobiology of narcolepsy remain to be answered. What is the specific gene in the HLA-D region that is linked to human narcolepsy and what are the products or functions of the gene that predispose to narcolepsy? Does the human mu-switch region contain genetic material homologous to the 85-kb band linked to canarc-1 that predisposes to narcolepsy? What are the environmental factors required for expression of the disease in susceptible individuals and do they incite immunologic processes? Which of the neurochemical abnormalities are primary, which are secondary or compensatory, and how do they relate to the predisposing genetic and environmental elements? Additional familial, genetic, and neurochemical studies over the next decade should lead to more complete understanding of the neurobiology of narcolepsy and ultimately to better treatments for this chronic disabling disease.