Matías Cavelli

Power and coherence of cortical High Frequency Oscillations during wakefulness and sleep

Recently, a novel type of fast cortical oscillatory activity that occurs between 110 and 160 Hz (high‐frequency oscillations (HFO)) was described. HFO are modulated by the theta rhythm in hippocampus and neocortex during active wakefulness and REM sleep. As theta‐HFO coupling increases during REM, a role for HFO in memory consolidation has been proposed. However, global properties such as the cortex‐wide topographic distribution and the cortico‐cortical coherence remain unknown. In this study, we recorded the electroencephalogram during sleep and wakefulness in the rat and analyzed the spatial extent of the HFO band power and coherence. We confirmed that the HFO amplitude is phase‐locked to theta oscillations and is modified by behavioral states. During active wakefulness, HFO power was relatively higher in the neocortex and olfactory bulb compared to sleep. HFO power decreased during non‐REM and had an intermediate level during REM sleep. Furthermore, coherence was larger during active wakefulness than non‐REM, while REM showed a complex pattern in which coherence increased only in intra and decreased in inter‐hemispheric combination of electrodes. This coherence pattern is different from gamma (30–100 Hz) coherence, which is reduced during REM sleep. This data show an important HFO cortico‐cortical dialog during active wakefulness even when the level of theta comodulation is lower than in REM. In contrast, during REM, this dialog is highly modulated by theta and restricted to intra‐hemispheric medial‐posterior cortical regions. Further studies combining behavior, electrophysiology and new analytical tools are needed to plunge deeper into the functional significance of the HFO.

Wakefulness-promoting role of the inferior colliculus

The inferior colliculus (IC) is a mesencephalic auditory nucleus involved in several functions including the analysis of the frequency and intensity of sounds as well as sound localization. In addition to auditory processes, the IC controls the expression of defensive responses. The objective of the present study was to test the hypothesis that the IC contributes to the maintenance of wakefulness. For this purpose, several experimental approaches were performed in urethane-anesthetized guinea pigs. Electrical or chemical stimulation of the IC resulted in electroencephalographic (EEG) desynchronization, theta rhythm in the hippocampus and an increase in heart rate; all of these effects suggest an arousal reaction. Furthermore, by means of extracellular unit recordings, we determined that most IC neurons increased their spontaneous and tone-evoked responses in association with EEG desynchronization. We also studied the effect on sleep and wakefulness of bilateral acute inhibition of the IC by microinjections of muscimol (a GABAA agonist), as well as the effect of bilateral IC lesions in chronically-instrumented (drug-free) guinea pigs. Acute (via muscimol microinjections), but not chronic (via electrolytic lesions) inhibition of the IC decreased wakefulness., We conclude that the IC plays an active role in the maintenance of wakefulness. Further, we propose that this nucleus may mediate arousal responses induced by biologically significant sounds.

Microinjection of the dopamine D2-receptor antagonist Raclopride into the medial preoptic area reduces REM sleep in lactating rats

The medial preoptic area (mPOA) is a brain structure classically related to both non-REM (NREM) sleep and maternal behavior. Although the dopaminergic system is known to play a role in the control of the states of sleep and wakefulness, its effects within the mPOA on sleep are still not clear. Microinjection of the dopamine D2 receptor antagonist Raclopride into the mPOA has been shown to promote nursing postures in lactating dams with no effects on active maternal behavior. We hypothesized that the facilitation of nursing postures may be also associated with the promotion of NREM sleep. In order to test the hypothesis, Raclopride was microinjected into the mPOA and maternal behavior and sleep were assessed in lactating rats. The changes observed included a reduction of the latency to start nursing and an increase of the time to reunite the entire litter. Contrary to our hypothesis, NREM sleep was not affected by Raclopride. On the other hand, REM sleep and its transitional stage from NREM sleep, were significantly reduced by this pharmacological agent. These data suggest that dopamine D2 receptors within the mPOA are involved in the transition from NREM to REM sleep.

Heart rate variability during carbachol-induced REM sleep and cataplexy

The nucleus pontis oralis (NPO) exerts an executive control over REM sleep. Cholinergic input to the NPO is critical for REM sleep generation. In the cat, a single microinjection of carbachol (a cholinergic agonist) into the NPO produces either REM sleep (REMc) or wakefulness with muscle atonia (cataplexy, CA). In order to study the central control of the heart rate variability (HRV) during sleep, we conducted polysomnographic and electrocardiogram recordings from chronically prepared cats during REMc, CA as well as during sleep and wakefulness. Subsequently, we performed statistical and spectral analyses of the HRV. The heart rate was greater during CA compared to REMc, NREM or REM sleep. Spectral analysis revealed that the low frequency band (LF) power was significantly higher during REM sleep in comparison to REMc and CA. Furthermore, we found that during CA there was a decrease in coupling between the RR intervals plot (tachogram) and respiratory activity. In contrast, compared to natural behavioral states, during REMc and CA there were no significant differences in the HRV based upon the standard deviation of normal RR intervals (SDNN) and the mean squared difference of successive intervals (rMSSD). In conclusion, there were differences in the HRV during naturally-occurring REM sleep compared to REMc. In addition, in spite of the same muscle atonia, the HRV was different during REMc and CA. Therefore, the neuronal network that controls the HRV during REM sleep can be dissociated from the one that generates the muscle atonia during this state.

EEG dissociation induced by muscarinic receptor antagonists: Coherent 40 Hz oscillations in a background of slow waves and spindles

Graphical abstract Figure. No Caption available. HighlightsMuscarinic receptor antagonists produce behavioral and EEG dissociation.EEG gamma activity was studied following atropine and scopolamine administration.As expected, EEG slow waves and spindles were observed.These events were accompanied by high EEG gamma (30–45 Hz) power and coherence.This high frequency connectivity may explain the behavioral and EEG dissociation. Abstract Mesopontine and basal forebrain cholinergic neurons are involved in the control of behavioral states and cognitive functions. Animals treated with cholinergic muscarinic receptor antagonists display a dissociated state characterized by behavioral wakefulness (W) associated with high amplitude slow oscillations and spindles in the electroencephalogram (EEG), similar to those that occur during non‐REM (NREM) sleep. Oscillations in the gamma frequency band (≈ 40 Hz) of the EEG also play a critical role during W and cognition. Hence, the present study was conducted to determine the effect of muscarinic antagonists on the EEG gamma band power and coherence. Five cats were implanted with electrodes in different cortices to monitor the EEG. The effects of atropine and scopolamine on power and coherence within the low gamma frequency band (30–45 Hz) from pairs of EEG recordings were analyzed and compared to gamma activity during sleep and W. Muscarinic antagonists induced a NREM sleep‐like EEG profile that was accompanied by a large increase in gamma power and coherence. The values of gamma coherence were similar to that occurring during alert W (AW), and greater than in quiet W, NREM and REM sleep. We conclude that under atropine or scopolamine, functional interactions between cortical areas in the gamma frequency band remain high, as they are during AW. This significant functional connectivity at high frequency may explain why the animals remain awake in spite of the presence of slow waves and spindles.

Nasal respiration entrains neocortical long-range gamma coherence during wakefulness

Recent studies have shown that slow cortical potentials in archi-, paleo- and neocortex, can phase-lock with nasal respiration. In some of these areas, gamma activity (γ: 30-100 Hz) is also coupled to the animal’s respiration. It has been hypothesized that this interaction plays a role in coordinating distributed neural activity. In a similar way, inter-cortical interactions at γ frequency has been also associated as a binding mechanism by which the brain generates temporary opportunities necessary for implementing cognitive functions. The aim of the present study is to explore if nasal respiration entrains inter-cortical interactions at γ frequency. Six adult cats chronically prepared for electrographic recordings were employed in this study. Our results show that slow cortical respiratory potentials are present in several areas of the neocortex and olfactory bulb during wakefulness. Also, we found cross-frequency coupling between the respiratory phase and the amplitude of γ activity in all recorded areas. These oscillatory entrainments are independent of muscular activity, because are maintained during cataplexy induced by carbachol microinjection into the nucleus pontis oralis. Importantly, we observed that respiratory phase modulates the inter-cortical gamma coherence between neocortical pairs of electrodes during wakefulness. However, during NREM and REM sleep, breathing was unable to entrain the oscillatory activity, neither in the olfactory bulb nor in the neocortex. These results suggest a single unified phenomenon involving cross frequency coupling and long-range γ coherence across the neocortex. This fact could be related to a temporal binding process necessary for cognitive functions during wakefulness.

Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile

Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.