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mise à jour du 24 juillet 2003
Progress in Neuro-Psychophartnacology & Biological Psychiatry
2002; 26; 13-118

 Chronic stimulation of the cat vagus nerve

Effect on sleep and behavior
Alejandro Valdés-Cruz et all
Neuroscience Research Division, Instituto Nacional de Psiquiatria, Mexico


Introduction : One of the effects detected in the early experimental models of electrical vagal stimulation was sleep induction. Grastyan et al. were the first to describe the occasional appearance of sleep spindles during vagus nerve stimulation (VNS). Padel and Dell (1965), using encéphale isolé preparations obtained what they called "aortic vagus" response, characterized by immediate myosis, followed by cortical synchronization, maintained after VNS.

Further on, Puizillout and Foutz (1977) found that VNS produces complete cycles of all sleep stages, and increases slow wave sleep preceded by rapid eye movement (REM) sleep. In addition, it promotes the sudden transition from waking stage to REM sleep in sleep-deprived cats. More over, an enhanced frequency of REM sleep episodes was found, suggesting that VNS may be a triggering factor of this sleep stage.

However, depending on the vagal stimulation parameter used in experimental animal models, either electrographical synchronization or desynchronization, can be produced. In pioncer works in cats, VNS at frequencies of 24 to 50 Hz produced rapid activity of the orbito-frontal cortex (Breme and Bonnet, 1951). In subsequent works using encéphale isolé preparations in cats, VNS (50 Hz from 0.1 to 2 v intensity) produced cortical desynchronization and inhibition of sleep spindles (Zanchetti et al., 1952). On the othe hand, Penaloza-Rojas (1964) stimulating the vagus nerve with direct current found electrographic synchronization.

Chase and Nakamura (1968) and Chase et al. (1966 1967) reported that VNS-induced electrographic changes are associated with the activation of different types of nerve fibers; frequencies of 70 Hz and over 3 v produce electroencephalogram (EEG) desynchronization. Using the same frequency but with lower intensities, synchronization is induced, suggesting that this effect results from stimulation of only myelinated fibers. Stimulation intensities and frequencies that induce desynchronization are those capable of stimulating the fibers that conduct from 1 to 15 m/s (Chase and Nakamura, 1968).

The nucleus of the solitary tract (NTS) receiving the majority of vagus nerve afferences has been involved in sleep-wakefulness cycle mechanisms. Vigier and Portalier (1979) described projections of the area postrema to the NTS and the locus coeruleus. Besides, afferents and efferents have been described from these nuclei to the dorsal motor nucleus of the vagus nerve (Vigier and Rouvière, 1979).

Recently, the effect of VNS on the experimental model of epilepsy named "kindling" in the cat was reported, and some changes in the sleep-wakefulness cycle produced by VNS were described (Femàndez-Guardiola et al., 1998, 1999). Nevertheless, there are no studies in which the VNS effect on the sleep-wakefulness cycle of freely moving cats bas been analyzed. Thus, the purpose of the present study is to report the changes on the different sleep stages, as well as on the behavior induced by chronic VNS. [...]

Discussion : Our results complement the previous findings about VNS sleep studies, in which the animals were under anesthesia or encéphale isolé preparation. Thus, we recorded the EEG during 23 h in freely moving cats, and observed sleep changes outside VNS periods as well as the behavior while VNS was performed.

Behavioral effects Abdominal contractions and compulsive eating could be induced by efferent parasympathetic projections of the vagus nerve towards the esophagus, stomach, and gut . Swallowing and licking are behaviors produced by the activation of the ambiguous nucleus, which controls the phonation and swallowing muscles. The vomit reflex is a result of theactivation of the area postrema through the NTS. Ipsilateral myosis, blinking, ocular movements in bursts, and upward gaze are induced by the activation of the oculomotor nucleus and the Edinger-Westphal nucleus, through central afferent projections of the NTS ).

Effect on sleep The effect of VNS on REM sleep could be due to the central afferent projections of the vagus nerve. These originate in the nodose ganglion and most fibers are directed towards the NTS. The role of the NTS in sleep seems to be diverse. In cats, different groups of neurons have been observed to display changes in their triggering pattem depending on the animal's sleep stage.

The importance of endogenous opioids of the NTS on slow wave sleep has been marked. In addition, the NTS has cholinergic and excitatory amino acid projections toward structures involved in different mechanisms of REM sleep such as the PBL, the TAM, the locus coeruleus alpha and subcoeruleus. In addition, it has been proposed that the NTS could play a role in REM sleep by way of its serotoninergic projections towards the PBL. Also, the NTS presents an increase in C-fos in animals with REM sleep increased by auditory stimulation.

The importance of PBL and locus coeruleus during the tonic and phasic events of REM sleep has been well documented. A lasting induction of REM sleep has been attained by direct cholinergic stimulation of both PBL and TAM , with persistent increase of PGO potentials in both cases. The rise in density of these potentials in the present experiments could be due to the cholinergic activation favored by VNS in these areas through the NTS.

On the other hand, it should be noted that sudden transitions from wakefulness to REM sleep (narcoleptic reflex) were described before in cats with VNS in encéphale isolé preparations and in sleep-deprived cats. In our present work, freely moving cats with no anesthesia and VNS present a narcoleptic reflex despite exhibiting increased REM sleep.

Some afferent fibers to the NTS with high density of orexin immunoreactivity may be of importance for the narcoleptic reflex, as orexins (hypocretins) play a key role in narcolepsy.

Conclusion : We conclude that VNS influences REM sleep through vagal afferences related with areas that play a role in this sleep stage. The relevance of 23-h recordings must be emphasized, since long-term changes were observed that were reflected on PGO wave increase, total REM sleep time, and sudden transitions from waking stage to REM sleep.