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Ramos O.V.,Websciences International | Torterolo P.,University of the Republic of Uruguay | Lim V.,Websciences International | Chase M.H.,Websciences International | And 3 more authors.
Brain Research | Year: 2011

The microinjection of nerve growth factor (NGF) into the cat pontine tegmentum rapidly induces rapid eye movement (REM) sleep. To determine if NGF is involved in naturally-occurring REM sleep, we examined whether it is present in mesopontine cholinergic structures that promote the initiation of REM sleep, and whether the blockade of NGF production in these structures suppresses REM sleep. We found that cholinergic neurons in the cat dorso-lateral mesopontine tegmentum exhibited NGF-like immunoreactivity. In addition, the microinjection of an oligodeoxyribonucleotide (OD) directed against cat NGF mRNA into this region resulted in a reduction in the time spent in REM sleep in conjunction with an increase in the time spent in wakefulness. Sleep and wakefulness returned to baseline conditions 2 to 5 days after antisense OD administration. The preceding antisense OD-induced effects occurred in conjunction with the suppression of NGF-like immunoreactivity within the site of antisense OD injection. These data support the hypothesis that NGF is involved in the modulation of naturally-occurring sleep and wakefulness. © 2011 Elsevier B.V. All rights reserved.


Xi M.,Websciences International | Xi M.,VA Greater Los Angeles Healthcare System | Fung S.J.,Websciences International | Fung S.J.,VA Greater Los Angeles Healthcare System | And 5 more authors.
Neuroscience | Year: 2015

Anatomical studies have demonstrated that hypocretinergic and GABAergic neurons innervate cells in the nucleus pontis oralis (NPO), a nucleus responsible for the generation of active (rapid eye movement (REM)) sleep (AS) and wakefulness (W). Behavioral and electrophysiological studies have shown that hypocretinergic and GABAergic processes in the NPO are involved in the generation of AS as well as W. An increase in hypocretin in the NPO is associated with both AS and W, whereas GABA levels in the NPO are elevated during W. We therefore examined the manner in which GABA modulates NPO neuronal responses to hypocretin. We hypothesized that interactions between the hypocretinergic and GABAergic systems in the NPO play an important role in determining the occurrence of AS or W. To determine the veracity of this hypothesis, we examined the effects of the juxtacellular application of hypocretin-1 and GABA on the activity of NPO neurons, which were recorded intracellularly, in chloralose-anesthetized cats. The juxtacellular application of hypocretin-1 significantly increased the mean amplitude of spontaneous EPSPs and the frequency of discharge of NPO neurons; in contrast, the juxtacellular microinjection of GABA produced the opposite effects, i.e., there was a significant reduction in the mean amplitude of spontaneous EPSPs and a decrease in the discharge of these cells. When hypocretin-1 and GABA were applied simultaneously, the inhibitory effect of GABA on the activity of NPO neurons was reduced or completely blocked. In addition, hypocretin-1 also blocked GABAergic inhibition of EPSPs evoked by stimulation of the laterodorsal tegmental nucleus. These data indicate that hypocretin and GABA function within the context of a neuronal gate that controls the activity of AS-on neurons. Therefore, we suggest that the occurrence of either AS or W depends upon interactions between hypocretinergic and GABAergic processes as well as inputs from other sites that project to AS-on neurons in the NPO. © 2015 IBRO.


Cavelli M.,University of the Republic of Uruguay | Castro S.,University of the Republic of Uruguay | Schwarzkopf N.,University of the Republic of Uruguay | Chase M.H.,WebSciences International | And 3 more authors.
Behavioural Brain Research | Year: 2015

Higher cognitive functions require the integration and coordination of large populations of neurons in cortical and subcortical regions. Oscillations in the high frequency band (30-100. Hz) of the electroencephalogram (EEG), that have been postulated to be a product of this interaction, are involved in the binding of spatially separated but temporally correlated neural events, which results in a unified perceptual experience. The extent of this functional connectivity can be examined by means of the mathematical algorithm called "coherence", which is correlated with the "strength" of functional interactions between cortical areas. As a continuation of previous studies in the cat [6,7], the present study was conducted to analyze EEG coherence in the gamma band of the rat during wakefulness (W), non-REM (NREM) sleep and REM sleep.Rats were implanted with electrodes in different cortical areas to record EEG activity, and the magnitude squared coherence values within the gamma frequency band of EEG (30-48 and 52-100. Hz) were determined.Coherence between all cortical regions in the low and high gamma frequency bands was greater during W compared with sleep. Remarkably, EEG coherence in the low and high gamma bands was smallest during REM sleep.We conclude that high frequency interactions between cortical areas are radically different during sleep and wakefulness in the rat. Since this feature is conserved in other mammals, including humans, we suggest that the uncoupling of gamma frequency activity during REM sleep is a defining trait of REM sleep in mammals. © 2015 Elsevier B.V.


Engelhardt J.K.,WebSciences International | Silveira V.,University of the Republic of Uruguay | Morales F.R.,WebSciences International | Morales F.R.,University of California at Los Angeles | And 5 more authors.
Brain Research | Year: 2010

This report presents the results of a study of the frequency potentiation of inhibitory postsynaptic currents (IPSCs) in hypoglossal motoneurons and its modulation by serotonin. A release-site model of synaptic plasticity was used to characterize the frequency-related potentiation of evoked IPSCs. Data were obtained to determine if the frequency potentiation of IPSCs occurs as a consequence of a low baseline quantal content of evoked IPSCs using whole cell patch-clamp recordings from hypoglossal motoneurons in the neonatal rat brainstem slice preparation. In these motoneurons, EPSCs and GABAergic IPSCs were blocked by the application of CNQX, AP-5 and bicuculline. Glycinergic IPSCs were evoked by threshold stimulation of inhibitory neurons in the nucleus of Roller, which is located ventro-lateral to the hypoglossal nucleus. IPSC responses to trains of stimuli were recorded in control solutions and in solutions containing serotonin, which is known to reduce IPSPs in this preparation. The amplitude of non-potentiated IPSCs was reduced and their frequency potentiation was enhanced when serotonin was added to the bath. These data were examined using a release-site model of synaptic plasticity in which facilitation is attributed to a time-dependent increase in the probability of transmitter release; depression is attributed to a time-dependent decrease in the number of sites available for release. Using this model, the effect of serotonin on frequency potentiation was explained by a combination of a reduction in the baseline probability of transmitter release and an increase in the time constant of decay of the increase in probability of release that follows a stimulus. © 2010 Elsevier B.V.


Zhang J.-H.,WebSciences International | Fung S.J.,WebSciences International | Xi M.,WebSciences International | Sampogna S.,WebSciences International | And 2 more authors.
Brain Research | Year: 2010

The present study was designed to investigate the effects of recurrent periods of apnea/hypoxia on the morphology of neurons in sites that control NREM and REM sleep. In addition, we determined whether the administration of a GABA agonist, eszopiclone, was capable of preventing the degenerative, i.e., apoptotic, sequelae of hypoxia in these sleeppromoting neurons. Adult guinea pigs were divided into control (normoxic) and hypoxic groups; a separate group of hypoxic animals was administered eszopiclone. Recurrent periods of hypoxia and normoxia lasted for a duration of 3 h. Subsequently, the brains were sectioned, and areas in the CNS that control NREM sleep as well as REM sleep were examined after staining with an antibody raised against single-stranded DNA, which labels apoptotic neurons. In the group of control (normoxic) animals, apoptotic neurons were not observed in CNS regions that control NREM or REM sleep. In hypoxic animals, a large number of apoptotic neurons were found in the preceding regions. In the hypoxic animals that were administered eszopiclone, there were almost no apoptotic neurons in the brain regions that control NREM or REM sleep. These results demonstrate that recurrent periods of apnea induce extensive apoptosis in CNS nuclei that control NREM and REM sleep and that eszopiclone is capable of preventing neuronal degeneration in these sites. We suggest that the degeneration of neurons in sites that control the states of sleep is responsible for those sleep disturbances that arise as a consequence of hypoxia in individuals with sleep-related breathing disorders. © 2010 Elsevier B.V. All rights reserved.


Torterolo P.,University of the Republic of Uruguay | Sampogna S.,WebSciences International | Chase M.H.,WebSciences International | Chase M.H.,University of California at Los Angeles
Brain Research | Year: 2013

Within the postero-lateral hypothalamus neurons that utilize hypocretin or melanin-concentrating hormone (MCH) as neuromodulators are co-distributed. These neurons have been involved in the control of behavioral states, and a deficit in the hypocretinergic system is the pathogenic basis of narcolepsy with cataplexy. In this report, utilizing immunohistochemistry and retrograde tracing techniques, we examined the hypocretinergic innervation of the nucleus pontis oralis (NPO), which is the executive site that is responsible for the generation of REM sleep in the cat. The retrograde tracer cholera toxin subunit b (CTb) was administered in pontine regions where carbachol microinjections induced REM sleep. Utilizing immunohistochemical techniques, we found that approximately 1% of hypocretinergic neurons in the tuberal area of the hypothalamus project to the NPO. In addition, approximately 6% of all CTb+ neurons in this region were hypocretinergic. The hypocretinergic innervation of the NPO was also compared with the innervation of the same site by MCH-containing neurons. More than three times as many MCHergic neurons were found to project to the NPO compared with hypocretinergic cells; both neuronal types exhibited bilateral projections. We also identified a group of non-hypocretinergic non-MCHergic neuronal group of neurons that were intermingled with both hypocretinergic and MCHergic neurons that also projected to this same brainstem region. These neurons were grater in number that either hypocretin or MCH-containing neurons; their soma size was also smaller and their projections were mainly ipsilateral. The present anatomical data suggest that hypocretinergic, MCHergic and an unidentified companion group of neurons of the postero-lateral hypothalamus participate in the regulation of the neuronal activity of NPO neurons, and therefore, are likely to participate in the control of wakefulness and REM sleep. © 2012 Elsevier B.V. All rights reserved.


Torterolo P.,University of the Republic of Uruguay | Chase M.H.,WebSciences International | Chase M.H.,University of California at Los Angeles
Sleep Science | Year: 2014

In 1998, a group of phenotypically distinct neurons were discovered in the postero-lateral hypothalamus which contained the neuropeptides hypocretin 1 and hypocretin 2 (also called orexin A and orexin B), which are excitatory neuromodulators. Hypocretinergic neurons project throughout the central nervous system and have been involved in the generation and maintenance of wakefulness. The sleep disorder narcolepsy, characterized by hypersomnia and cataplexy, is produced by degeneration of these neurons. The hypocretinergic neurons are active during wakefulness in conjunction with the presence of motor activity that occurs during survival-related behaviors. These neurons decrease their firing rate during non-REM sleep; however there is still controversy upon the activity and role of these neurons during REM sleep. Hence, in the present report we conducted a critical review of the literature of the hypocretinergic system during REM sleep, and hypothesize a possible role of this system in the generation of REM sleep. © 2014 Published by Elsevier B.V. on behalf of Brazilian Association of Sleep.


Castro S.,University of the Republic of Uruguay | Cavelli M.,University of the Republic of Uruguay | Vollono P.,University of the Republic of Uruguay | Chase M.H.,WebSciences International | And 3 more authors.
Neuroscience Letters | Year: 2014

Oscillations in the gamma frequency band (mainly ≈40. Hz) of the electroencephalogram (EEG) have been involved in the binding of spatially separated but temporally correlated neural events that result in a unified perceptual experience. The extent of these interactions can be examined by means of a mathematical algorithm called "coherence", which reflects the "strength" of functional interactions between cortical areas. As a continuation of a previous study of our group, the present study was conducted to analyze the inter-hemispheric coherence of the EEG gamma frequency band in the cat during alert wakefulness (AW), quiet wakefulness (QW), non-REM (NREM) sleep and REM sleep. Cats were implanted with electrodes in the frontal, parietal and occipital cortices to monitor EEG activity. The degree of coherence in the low (30-45. Hz) and high (60-100. Hz) gamma frequency bands from pairs of EEG recordings was analyzed. A large increase in coherence between all inter-hemispheric cortical regions in the low gamma bands during AW was present compared to the other behavioral states. Furthermore, both low and high gamma coherence between inter-hemispheric heterotopic cortices (different cortical areas of both hemispheres) decreased during REM sleep; this is a pattern that we previously reported between the cortical areas of the same hemisphere (intrahemispheric coherence). In the high gamma band, coherence during REM sleep also decreased compared to the other behavioral states. In contrast, between most of the inter-hemispheric homotopic cortical areas (equivalent or mirror areas of both hemispheres), low gamma coherence was similar during NREM compared to REM sleep. We conclude that in spite of subtle differences between homotopic and heterotopic inter-hemispheric cortices, functional interactions at high frequency decrease during REM sleep. © 2014 Elsevier Ireland Ltd.


Xi M.,WebSciences International | Chase M.H.,WebSciences International | Chase M.H.,University of California at Los Angeles
Sleep | Year: 2010

Study Objectives: We previously reported that the microinjection of hypocretin (orexin) into the nucleus pontis oralis (NPO) induces a behavioral state that is comparable to naturally occurring active (rapid eye movement) sleep. However, other laboratories have found that wakefulness occurs following injections of hypocretin into the NPO. The present study tested the hypothesis that the discrepancy in behavioral state responses to hypocretin injections is due to the fact that hypocretin was not administered during the same states of sleep or wakefulness. Design: Adult cats were implanted with electrodes to record sleep and waking states. Hypocretin-1 (0.25 μL, 500μM) was microinjected into the NPO while the animals were awake or in quiet (non-rapid eye movement) sleep. Measurements and Results: When hyprocretin-1 was microinjected into the NPO during quiet sleep, active sleep occurred with a short latency. In addition, there was a significant increase in the time spent in active sleep and in the number of episodes of this state. On the other hand, the injection of hyprocretin-1 during wakefulness resulted not only in a significant increase in wakefulness, but also in a decrease in the percentage and frequency of episodes of active sleep. Conclusions: The present data demonstrate that the behavioral state of the animal dictates whether active sleep or wakefulness is induced following the injection of hypocretin. Therefore, we suggest that hypocretin-1 enhances ongoing states of wakefulness and their accompanying patterns of physiologic activity and that hypocretin-1 is also capable of promoting active sleep and the changes in various processes that occur during this state.


Devera A.,University of the Republic of Uruguay | Pascovich C.,University of the Republic of Uruguay | Lagos P.,University of the Republic of Uruguay | Falconi A.,University of the Republic of Uruguay | And 4 more authors.
Brain Research | Year: 2015

Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the postero-lateral hypothalamus and incerto-hypothalamic area. These neurons send dense projections to the dorsal raphe nucleus (DRN). Serotonergic neurons of the DRN are involved in the control of sleep and play a critical role in major depression. Previously, we demonstrated that microinjections of MCH into the DRN resulted in an increase in REM sleep and produce a depressive-like effect. In the present study we examined the mechanisms that mediate these effects by employing neuroanatomical and electrophysiological techniques. First, we determined that rhodamine-labeled MCH (R-MCH), when microinjected into the lateral ventricle, is internalized in serotonergic and non-serotonergic DRN neurons in rats and cats. These data strongly suggest that these neurons express MCHergic receptors. Second, in rats, we demonstrated that the microinjection of MCH into the lateral ventricle results in a significant decrease in the firing rate in 59% of the neurons recorded in the DRN; the juxtacellular administration of MCH reduced the discharge in 80% of these neurons. Some of the neurons affected by MCH were likely serotonergic on the basis of their electrophysiological and pharmacological properties. We conclude that MCH reduces the activity of serotonergic neurons of the DRN. These and previous data suggest that the MCHergic modulation of serotonergic activity within the DRN is involved in the regulation of REM sleep as well as in the pathophysiology of depressive disorders. © 2014 Elsevier B.V.

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