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Long-term enhancement of REM sleep following cholinergic stimulation
Abstract
A six day long increase in rapid eye movement (REM) sleep followed the unilateral microinjection of a single dose of the cholinergic agonist drug carbachol into the brain stem of cats. Effective drug injection sites were localized to the pontine peribrachial region containing cholinergic choline acetyltransferase (ChAT) labeled neurons. At the peak of the effect, which occurred 24-28 h post-injection, the relative amount of time devoted to REM sleep tripled, resulting in an absolute time increase from 3.12 to 11.28 h REM sleep per day. This pronounced and prolonged REM sleep increase was associated with marked enhancement of ponto-geniculo-occipital (PGO) waves and with PGO burst cell activity unilateral to the site of injection.
... El sueño REM es un estado fisiológico regulado por la interacción de diferentes neurotransmisores: acetilcolina (ACh) Hernández-Peón, 1965;Jouvet, 1972;Mignot, 2008), glutamato (Clément et al., 2011;Datta et al., 1998Datta et al., , 2001Kodama en al., 1998;Lu et al., 2006;Luppi et al 2012;Sakai y Koyama, 1996) y GABA (Boissard et al., 2002;Luppi et al., 2013;Xi et al., 1999). Se sabe bien que los mecanismos colinérgicos tienen un papel fundamental en la generación y mantenimiento del sueño REM (Baghdoyan et al., , 1989Datta et al., 1991;Márquez-Ruiz y Escudero, 2010;Murillo-Rodriguez et al., 2012;Pal y Mallick, 2007). ...
... Específicamente, se ha demostrado que la activación de regiones celulares colinérgicas del núcleo pedunculo-pontino tegmental (PPT) y del núcleo laterodorsal tegmental (LDT) que se encuentran dentro de la región C-PBL se asocia con la regulación del sueño REM, de hecho esta activación es facilitada por receptores de glutamato de tipo kainato (Datta et al., 1991;Quattrochi et al., 1989;Sakai et al., 1990). ...
... La microinyección de carbacol en el área peribraquial caudo-lateral (C-PBL), induce la instalación de potenciales PGO independientes de los estados del sueño durante 8 a 10 horas. Además, se incrementa el número de estos potenciales durante los episodios de SP y de sueño REM en un periodo de hasta seis días posteriores a la microinyección (Datta et al., 1991;Datta et al., 1992). Por otra parte, se ha logrado determinar que los receptores muscarínicos del tipo M2, son los que están involucrados en este fenómeno (Datta et al., 1993). ...
Purpose: In order to explore the potential role of GABA, acetylcholine and glutamate in the caudo-lateral peribrachial area (C-PBL) over Rapid-Eye-Movement sleep (REM) onset and maintenance as well as on synchronized sleep with ponto-geniculo-occipital (PGO) waves (SP) in cats, a muscimol, carbachol and L-glutamate local application was performed and behavioral states were assessed. Methods: Fourteen chronically implanted, adult, male cats underwent a 23 hour polysomnographic recording after 3 pharmacological manipulations: carbachol, muscimol and L-glutamate. Each cat received all three drugs randomly with a seven day interval. Results: 1) Carbachol increased waking, SP and REM sleep while
decreased slow wave sleep (SWS). 2) Muscimol decreased SP percentage and number while increased REM sleep onset. 3) Carbachol facilitated PGO activity increased the latency to both SWS1 and REM sleep but enhanced PGO activity while muscimol decreased it. Conclusions: Acetylcholine promoted PGO related states (SP) as well as REM sleep, while GABA reduced only SP and specifically PGO’s.
... For the purpose of testing the hypothesis that an endogenous cholinergic drive for REM sleep might originate in the cholinergic cell groups of the pontine tegmentum, carbachol has recently been microinjected into these regions (9)(10)(11). Carbachol induced shortlatency, short-lasting (2-4-hour) REM sleep only when injected in the perilocus coeruleous (LC)a or adjacent LCa (10,11). ...
... Carbachol induced shortlatency, short-lasting (2-4-hour) REM sleep only when injected in the perilocus coeruleous (LC)a or adjacent LCa (10,11). But when mapping was extended to lateral and caudal areas of the PBL, a surprisingly longlasting enhancement of REM sleep was observed (9). This study further demonstrated that the application of carbachol in the marginal nucleus ofthe peribrachial area induced immediate state independent ipsilateral lateral geniculate nucleus (LOB) ponto-geniculo-occipital (PGO) waves as well as a delayed (2-hour) increase in REM sleep. ...
... L:4.5; H:-2.5; R = 38°, according to Berman's (14) stereotaxic atlas], as described previously (9). ...
Six cats were chronically implanted with a standard set of sleep-scoring electrodes and bilateral stainless-steel guide tubes for microinjection of drugs in the peribrachial area (PBL). Pretreatment of drug injection sites in the PBL with the M2 antagonist methoctramine blocks both the immediate triggering of ponto-geniculo-occipital (PGO) waves and the later prolonged enhancement of REM sleep that is induced by carbachol. These results support the hypothesis that the carbachol effects are mediated via the M2 muscarinic receptor that is known to be present in the PBL.
... Este fenómeno también se ha mostrado con la depleción selectiva de 5-HT, mediante la aplicación de para-clorofenilalanina (PCPA) (Delorme et al., 1966;Ruch-Monachon et al., 1976). Por otra parte, la administración tópica de 6-hidroxi-dopamina (agonista monoaminergicos) (Matsumoto y Jouvet, 1964; número de estos potenciales que ocurren durante los episodios de SFOL y el sueño MOR, durante los siguientes 6 días a partir de su microinyección (Datta et al., 1991;Datta et al., 1992). Además, se ha logrado determinar que los receptores muscarínicos del tipo M2, son los que están involucrados en este fenómeno (Datta et al., 1993). ...
... Por otra parte, el desarrollo del presente estudio permitió corroborar que la aplicación de carbacol en la región PBL, provoca la ocurrencia de potenciales PGO independientes de los estados del sueño Datta et al., 1991) y además, permitió determinar con mayor precisión, que este fenómeno dura de 18 a 20 horas, tiempo en el que comienzan a disminuir. El obtener este dato fue posible gracias a los registros poligráficos del sueño de 23 horas. ...
En estudios clínicos y experimentales se ha mostrado que existe una relación entre las diferentes fases del ciclo sueño-vigilia y los fenómenos epilépticos. Durante la fase del sueño con movimientos oculares rápidos (MOR), no ocurren las crisis convulsivas generalizadas (CCGs) y las descargas interictales se restringen al foco primario, y desaparecen o disminuyen, en comparación con las que se presentan durante el sueño de ondas lentas o el estado de vigilia.
Por otra parte, se ha descrito la aparición de signos poligráficos (atonía muscular, movimientos oculares rápidos y desincronización electroencefalográfica) semejantes a los del sueño MOR, hacia el final y durante unos segundos después de las crisis convulsivas. Estos fenómenos han permitido proponer, que los mecanismos responsables del sueño MOR son semejantes a los mecanismos para la detención de las CCGs. Además, se ha demostrado que las estructuras pontinas del tallo cerebral, relacionadas con los mecanismos generadores del sueño MOR, como la formación reticular y el locus coeruleus, pueden estar involucradas en la inhibición de la epilepsia. Sin embargo, no se ha analizado con precisión que componente electrofisiológico o neurohumoral del sueño MOR puede ejercer esta influencia inhibitoria sobre la epilepsia.
Los potenciales ponto-geniculo-occipitales (PGO), se presentan desde unos segundos antes del sueño MOR esta fase del sueño ha sido denominada sueño fásico en ondas lentas (SFOL) y cuando estos potenciales aumentan su incidencia, tiene lugar la instalación del sueño MOR. Este fenómeno ha permitido establecer un consenso de que los potenciales PGO son un componente central de los mecanismos de instalación y mantenimiento del sueño MOR. Por otra parte, en estudios experimentales se ha mostrado que la epileptogénesis inducida por el kindling amigdalino durante el sueño MOR, tiene un retraso significativo en comparación a su desarrollo durante la vigilia y se ha propuesto, que los potenciales PGO de esta fase del sueño, pueden jugar un papel inhibitorio sobre la epileptogénesis y sobre la epilepsia.
Por otro lado, en el gato, se ha mostrado que la aplicación tópica de un agente colinérgico (Carbacol) en la región parabraquial (PBL) del tallo cerebral, induce con una latencia de 13 a 20 minutos, la aparición de potenciales PGO independiente de las fases del sueño, durante 20 a 24 horas. Asimismo, el carbacol provoca el aumento del número de episodios de sueño MOR, entre cuatro y cinco horas después de su aplicación. Es importante notar, que este hallazgo permite analizar de manera independiente, el probable papel inhibitorio de los potenciales PGO sobre la epilepsia, cuando éstos ocurren fuera del sueño MOR.
Por lo tanto el proposito de la presente tesis, fue analizar la influencia de estos potenciales inducidos por el Carbacol, sobre la epileptogénesis y la epilepsia ya establecida, inducidas por la aplicación tópica de Penicilina G Sódica en la amígdala del lóbulo temporal (AMG), en el gato.
En el protocolo experimental se incluyeron 9 gatos en preparación crónica, con electrodos para el registro poligráfico de sueño y con cánulas colocadas estereotáxicamente en la AMG y en la región PBL, para la aplicación de Penicilina G Sódica y Carbacol, respectivamente.
Los resultados mostraron que la presencia sostenida de potenciales PGO, independientes del sueño MOR, disminuye significativamente el número de crisis convulsivas generalizadas (CCGs) y la frecuencia de aparición de espigas epilépticas. Asimismo, estos potenciales PGO, acortaron significativamente la duración de los fenómenos epilépticos.
Además de estos resultados, se observó que la presencia de potenciales PGO sostenidos, evitó las alteraciones de la organización temporal del sueño, que se provocan con la aplicación del foco penicilínico. Asimismo, la latencia al sueño, el porcentaje y número de cada una de las fases del sueño, no se afectan cuando el foco penicilínico se acompaña de la aplicación de Carbacol en la región PBL. Más aún, los valores del número y porcentaje de los episodios de SFOL y sueño MOR, alcanzan valores significativamente mayores que los valores control.
Estos resultados apoyan la hipótesis de que los potenciales PGO ejercen una influencia inhibitoria significativa sobre la epileptogénesis y la epilepsia ya establecida. Asimismo, apoyan la hipótesis de que los mecanismos fisiológicos del sueño MOR, son semejantes a los mecanismos de inhibición de los fenómenos epilépticos.
... REM sleep is a physiological state regulated by the interaction of, among others neurotransmitters, acetylcholine (ACh) Hernandez-Peón, 1965;Jouvet, 1972;Mignot, 2008), glutamate (Clément et al., 2011;Datta et al., 1998Datta et al., , 2001Kodama et al., 1998;Lu et al., 2006;Luppi et al., 2012;Sakai and Koyama, 1996) and GABA (Boissard et al., 2002;Luppi et al., 2013;Xi et al., 1999). It is well known that pontine cholinergic mechanisms play a critical role in the generation and maintenance of REM sleep (Baghdoyan et al., 1987(Baghdoyan et al., , 1989Datta et al., 1991;Márquez-Ruiz and Escudero, 2010;Murillo-Rodriguez et al., 2012;Pal and Mallick;. Specifically, it has been observed that the activation of regions such as the cholinergic cell compartment of the pedunculopontine tegmental nucleus (PPT) and of the laterodorsal tegmental nucleus (LDT) within the caudo-lateral peribrachial area (C-PBL) is associated to REM sleep regulation, in turn this activation is facilitated by the kainate type of glutamate receptors (Datta et al., 1991;Quattrochi et al., 1989;Sakai et al., 1990). ...
... It is well known that pontine cholinergic mechanisms play a critical role in the generation and maintenance of REM sleep (Baghdoyan et al., 1987(Baghdoyan et al., , 1989Datta et al., 1991;Márquez-Ruiz and Escudero, 2010;Murillo-Rodriguez et al., 2012;Pal and Mallick;. Specifically, it has been observed that the activation of regions such as the cholinergic cell compartment of the pedunculopontine tegmental nucleus (PPT) and of the laterodorsal tegmental nucleus (LDT) within the caudo-lateral peribrachial area (C-PBL) is associated to REM sleep regulation, in turn this activation is facilitated by the kainate type of glutamate receptors (Datta et al., 1991;Quattrochi et al., 1989;Sakai et al., 1990). Moreover, it should be noted that the glutamate release at the medial pontine reticular formation (mPRF) is increased during natural REM sleep as well as after its cholinergic stimulation. ...
... Specifically, the pedunculopontine tegmentum (PPT), is involved in the REM generation through cholinergic cell activation, which in turn is regulated by glutamate (Datta, 2006). Since REM sleep is physiologically mediated by cholinergic mechanisms (Datta et al., 1991), the caudo-lateral part of PBL region is involved in the homeostatic regulation of REM sleep, and is the main structure responsible for PGO generation. A prolonged increase in REM sleep and other PGO related states, following PBL stimulation by carbachol, has been demonstrated (Calvo et al., 1992;Datta et al., 1992). ...
... Therefore, PGO-related phasic potentials resulting from PGO activity propagation (Calvo and Fernández-Guardiola, 1984), may affect the neuronal excitability of the amygdala and this change may thus prevent the hyperexcitation of the same structure, as occurring in the epileptiform activity. The present study corroborates as well, that carbachol microinfusion in the PBL region, induces PGO wave activity, irrespective of the sleep stage (Datta et al., 1991Datta et al., , 1992), and also establishes precisely that this phenomenon lasts from 18 to 20 h. PGOs have an inhibitory effect on seizure occurrence. ...
Purpose:
In order to explore the possible inhibitory role of the phasic phenomena of REM sleep ponto-geniculo-occipital (PGO) waves over epilepsy, seizure activity produced by topic administration of Na-penicillin (PCN) has been analyzed during sustained PGO waves irrespective of current state. PGO waves were induced by the injection of carbachol in the peribrachial area.
Methods:
The development of acute experimental epilepsy was compared among nine chronically implanted, adult, male cats, by means of polygraphic 23 h recordings. Our protocol consisted of sets of 4 trials: carbachol; PCN; carbachol followed by PCN and finally PCN followed by carbachol. Each cat received one single set and all trials were carried out with a seven days interval, in order to compare the epileptic activity both in the presence of PGOs and without them.
Results:
PGO waves 1) exert an inhibitory influence over number and duration of the Generalized Convulsive Seizures (GCSs) and 2) spike frequency; 3) increase the latency of GCSs; and 4) restores sleep alterations produced by experimental epilepsy.
Conclusions:
PGO waves exhibit an inhibitory influence over seizures induced by PCN. These data support the hypothesis that this phasic phenomenon of REM sleep have a depressant effect on epilepsy, inhibit seizures and normalize sleep architecture changes induced by seizures. We suggest that one possible function of PGO activity is to protect the brain from intense changes in neuronal excitability; namely convulsive activity.
... Microinjection of the cholinergic agonist carbachol into the anterodorsal paramedian pontine reticular formation elicits an immediate increase in REM sleep lasting 4-6 h that is electroencephalographically similar to physiologically normal REM [3,67]. In contrast, a single micro-injection of carbachol into the caudolateral PMT elicits a very different effect of REM sleep enhancement within normal sleep time lasting 6-10 days [18]. Using microinjections of a carbachol-conjugated latex nanosphere delivery system (LNDS) [46,67] that limits the diffusion of drug at these pontomesencephalic sites, our neuroanatomical studies identified cholinergic and non-cholinergic afferent neurons within the PMT associated with this long-term REM enhancement [68]. ...
... The pattern of Fos-IR staining in these cell groups of the PMT reflected the number of PGO wave events and followed the 6-day postinjection time course of LTPE. This time course also reflects previous results describing the evolution of long-term REM enhancement that have been produced by microinjections of carbachol nanospheres at sites more posterior in the PMT [18,68]. Many Fos-IR neurons were scattered in the LDT ( Fig. 2A) and PPT (Fig. 2B); clusters of a few Fos-IR neurons were seen in the PBN (Fig. 2C). ...
It is not known how the brain modifies its regulatory systems in response to the application of a drug, especially over the long term of weeks and months. We have developed a model system approach to this question by manipulating cholinergic cell groups of the laterodorsal and pedunculopontine tegmental (LDT/PPT) nuclei in the pontomesencephalic tegmentum (PMT), which are known to be actively involved in the timing and quantity of rapid eye movement (REM) sleep. In a freely moving feline model, a single microinjection of the cholinergic agonist carbachol conjugated to a latex nanosphere delivery system into the caudolateral PMT elicits a long-term enhancement of one distinguishing phasic event of REM sleep, ponto-geniculo-occipital (PGO) waves, lasting 5 days but without any significant change in REM sleep or other behavioral state. Here, we test the hypothesis that cholinergic activation within the caudolateral PMT alters the postsynaptic excitability of the PGO network, stimulating the prolonged expression of c-fos that underlies this long-term PGO enhancement (LTPE) effect. Using quantitative Fos immunohistochemistry, we found that the number of Fos-immunoreactive (Fos-IR) neurons surrounding the caudolateral PMT injection site decreased sharply by postcarbachol day 03, while the number of Fos-IR neurons in the more rostral LDT/PPT increased >30-fold and remained at a high level following the course of LTPE. These results demonstrate a sustained c-fos expression in response to pharmacological stimulation of the brain and suggest that carbachol's acute effects induce LTPE via cholinergic receptors, with subsequent transsynaptic activation of the LDT/PPT maintaining the LTPE effect.
... Increases in REM sleep density have been previously reported in adults with depression along with other REM alterations (frequency of rapid eye movements per REM period, shorter REM sleep onset latency) [38][39][40][41]. Plausibly, the association between REM sleep and internalizing behaviours in ASD could reflect underlying cholinergic neurochemical changes that may produce depression [42,43] and increase REM sleep [44]. To more fully elucidate this relationship in ASD, future research should consider additional measures of REM sleep including REM sleep stability (arousal/wake count in REM sleep, REM bout duration, number of REM bouts), rapid eye movement density, and frontal gamma activity (a marker of central adrenergic activity previously shown to be associated with amygdala activity and emotional reactivity [18]) as predictors of depression and anxiety. ...
Objective:
Insomnia and daytime behavioral problems are common issues in pediatric autism spectrum disorder (ASD), yet specific underlying relationships with NonRapid Eye Movement sleep (NREM) and Rapid Eye Movement (REM) sleep architecture are understudied. We hypothesize that REM sleep alterations (REM%, REM EEG power) are associated with more internalizing behaviors and NREM sleep deficits (N3%; slow wave activity (SWA) 0.5-3 Hz EEG power) are associated with increased externalizing behaviors in children with ASD vs. typical developing controls (TD).
Methods:
In an age- and gender-matched pediatric cohort of n = 23 ASD and n = 20 TD participants, we collected macro/micro sleep architecture with overnight home polysomnogram and daytime behavior scores with Child Behavior Checklist (CBCL) scores.
Results:
Controlling for non-verbal IQ and medication use, ASD and TD children have similar REM and NREM sleep architecture. Only ASD children show positive relationships between REM%, REM theta power and REM beta power with internalizing scores. Only TD participants showed an inverse relationship between NREM SWA and externalizing scores.
Conclusion:
REM sleep measures reflect concerning internalizing behaviours in ASD and could serve as a biomarker for mood disorders in this population. While improving deep sleep may help externalizing behaviours in TD, we do not find evidence of this relationship in ASD.
... In contrast, carbachol injection into the cat PPT induces a state of active wake characterized by hallucination with contralateral circling [72], and, at a higher dose, repetitive hissing and growling [74]. Carbachol-induced W can be followed by a longlasting enhancement of PS, particularly when carbachol is injected into the caudolateral PPT [75]. ...
... Decreasing theta power within REM sleep matches well with decreased PGO wave amplitude. Some interventions that increase REM sleep time also increase PGO wave activity (Denlinger, Patarca et al. 1988;Datta, Calvo et al. 1991;Simon-Arceo, Ramirez-Salado et al. 2003). Our results combined with Bowker's 1985 study would indicate that these increased PGO waves should be clustered toward the beginning of those long REM bouts and/or their amplitudes decrease steadily across the bout. ...
The theta rhythm during waking has been associated with voluntary motor activity and learning processes involving the hippocampus. Theta also occurs continuously during rapid eye movement (REM) sleep where it likely serves memory consolidation. Theta amplitude builds across wakefulness and is the best indicator of the homeostatic need for non-REM (NREM) sleep. Although REM sleep is homeostatically regulated independently of NREM sleep, the drivers of REM sleep regulation are under debate. The dynamics of theta within REM sleep bouts have not been thoroughly explored. We equipped 20 male rats with sleep instrumentation and hippocampal electrodes to measure theta across normal sleep/waking periods over the first 4 h of the sleep phase on two consecutive days. We found that theta power decreased by a third, on average, within individual REM sleep bouts, but recovered between bouts. Thus, there was no general decline in theta power across the duration of the recording period or between days. The time constant of theta power decline within a REM sleep bout was the same whether the bout was short, midlength, or long, and did not predict the behavioral state immediately following the REM sleep bout. Interestingly, the more time spent in NREM sleep prior to REM sleep, the larger the decline in theta power during REM sleep, indicating that REM sleep theta may be homeostatically driven by NREM sleep just as NREM delta power is driven by the length of prior waking and by waking theta. Potential causes and implications for this phenomenon are discussed.
... Studies have shown that changes in the central DA-ergic synaptic transmission have been associated with several neurodegenerative and psychiatric disorders, including PD, schizophrenia, depression (Carlsson 1987;Greenwood et al. 2006;Lima 2013). Subsequently SN neurons were shown to increase firing during REMS as compared to NREMS and waking states (Datta et al. 1991;Maloney et al. 2002;Dahan et al. 2007). The extracellular levels of DA in different brain areas remained significantly elevated during waking (Feenstra et al. 2000) as well as during REMS (Lena et al. 2005). ...
The dopamine (DA)-ergic neurons are primarily localized in the substantia nigra (SN) and ventral tegmental area (VTA) of the brainstem. These neurons are involved in diverse functions including control of movements, reward, sleep-wakefulness and rapid eye movement sleep (REMS). Loss of these DA-ergic neurons is associated with different behavioral disorders, including Parkinson’s disease, depression, REMS behavior disorder (RBD) and notably in all these disorders sleep including REMS is affected. These neurons receive projections from the locus coeruleus (REM-OFF) and laterodorsal/pedunculopontinetegmentum (REM-ON), neurons, and these modulate REMS. However, how these DA-ergic neurons regulate REMS largely remains unknown. Relevant literatures suggest that the DA-ergic neurons may have an indirect modulatory role, which however needs confirmation.
... Nevertheless, REM sleep without muscle atonia has never been reported before in non-human primates. As described previously by different authors [Baghdoyan et al., 1993;Datta et al., 1991Datta et al., , 1992Datta & Siwek, 1997;Hernández-Peón et al., 1962;Jouvet, 1962;Vanderwolf, 1988], mammalian brainstem cholinergic systems are highly active during REM sleep. Likewise, hypothalamic and basal forebrain sleep-on cells, as well as glutamatergic cells in the sublocus coeruleus (SLC REM-on neurons), increase their activity during REM sleep [Siegel & Rogawski, 1988]. ...
The normal sleep patterns of the spider monkey (Ateles geoffroyi) have not been described yet. The objective of this study was to characterize the electrophysiological patterns, sleeping postures, and sleep-wake cycle in semi-restricted spider monkeys. Continuous 24-hr polysomnographic (PSG) recordings, involving simultaneous recording of non-invasive electroencephalographic (EEG), electro-oculographic (EOG), and electromyographic (EMG) activities, were carried out in captive monkeys living in outdoor rainforest enclosures. Electrode placement was done according to the human international 10–20 system. Specific behaviors displayed by monkeys during the sleep-wake cycles were correlated with the PSG recordings. The nycthemeral distribution of the sleep-wake cycle was also calculated. The results show that electrophysiological N-REM sleep patterns in spider monkeys are similar to those observed in other primates, including human beings. Furthermore, a vertical semi-fetal posture was observed during N-REM and REM sleep phases. The amount of nocturnal sleep was significantly higher than that of the diurnal period, showing that the spider monkey is a diurnal primate. An outstanding finding was the absence of muscular atonia during the spider monkey's REM sleep, which suggests that arboreal primates have developed a neuromuscular mechanism specialized for sleeping in a vertical posture. Am. J. Primatol. © 2014 Wiley Periodicals, Inc.
... However, data in animals and in humans relate to roles that each of these sleep stages may play in this inhibitory process. REM sleep was initiated by administration of cholinergic agonists into pons [355,356]. Sleep related seizures in partial epilepsy occurred more than 20 times as frequently in non-REM (NREM) as opposed to REM sleep [357] and interictal epileptiform discharges in patients with epilepsy are more common in NREM than in REM sleep [358]. These results suggest that REM sleep may be considered neuroprotective and supports a role it may play in inhibiting phantosmia in these patients. ...
Olfactory hallucinations without subsequent myoclonic activity have not been well characterized or understood. Herein we describe, in a retrospective study, two major forms of olfactory hallucinations labeled phantosmias: one, unirhinal, the other, birhinal. To describe these disorders we performed several procedures to elucidate similarities and differences between these processes. From 1272, patients evaluated for taste and smell dysfunction at The Taste and Smell Clinic, Washington, DC with clinical history, neurological and otolaryngological examinations, evaluations of taste and smell function, EEG and neuroradiological studies 40 exhibited cyclic unirhinal phantosmia (CUP) usually without hyposmia whereas 88 exhibited non-cyclic birhinal phantosmia with associated symptomology (BPAS) with hyposmia. Patients with CUP developed phantosmia spontaneously or after laughing, coughing or shouting initially with spontaneous inhibition and subsequently with Valsalva maneuvers, sleep or nasal water inhalation; they had frequent EEG changes usually ipsilateral sharp waves. Patients with BPAS developed phantosmia secondary to several clinical events usually after hyposmia onset with few EEG changes; their phantosmia could not be initiated or inhibited by any physiological maneuver. CUP is uncommonly encountered and represents a newly defined clinical syndrome. BPAS is commonly encountered, has been observed previously but has not been clearly defined. Mechanisms responsible for phantosmia in each group were related to decreased gamma-aminobutyric acid (GABA) activity in specific brain regions. Treatment which activated brain GABA inhibited phantosmia in both groups.
... The PGO system appears to contain a significant cholinergic dimension. Injection of the cholinergic agonist carbachol stimulates an increase in REM and PGO activity when injected into the brainstem and the amygdala (Calvo, Simon-Arceo, & Fernandez-Mas, 1996;Datta, Calvo, Quattrochi, & Hobson, 1991). Acetylcholine release in the hippocampus of rats and cats is highest during REM sleep and is positively correlated with both frequency and power of theta waves (Keita, Frankel-Kohn, Bertrand, Lecanu, & Monmaur, 2000;Marrosu et al., 1995). ...
This paper reviews scientific literature on four subjective states: the dream state, the dreamy state of temporal lobe epilepsy and temporal lobe stimulation, the acute psychotic state, and the psychedelic state. Evidence is cited showing that underlying the emergence of dreamlike phenomena in all four states is the occurrence of high-voltage bursts of theta and slow-wave activity (2–8 Hz) in the medial temporal lobes. The medial temporal regions are recognized to play an important role in memory and emotion. In the dream state, medial temporal lobe bursts are tightly correlated with PGO waves. It has been widely speculated that PGO waves are direct neuro-physiological correlates of dreaming. On a phenomenological level, the dream state, the dreamy state, the acute psychotic state, and the psychedelic state have all been viewed as conducive to the emergence of unconscious material into consciousness. An argument is made that bursts of electrical activity spreading from the medial temporal lobes to the association cortices are the primary functional correlate of discharging psychical energies, experienced on a subjective level as the emergence of unconscious material into consciousness. The implications of these findings for the scientific legitimacy of the psychodynamic model are discussed.
... As reviewed here and elsewhere in this symposium, acetylcholine, in conjunction with other neurotransmitter systems, plays a very important role in the regulation of circadian and sleepwake states. To briefly recapitulate, several current basic concepts about the regulation of sleepwake states include: (a) REM sleep, or at least its phasic events (eye movements and PGO spikes), are promoted by cholinergic neurons originating within the peribrachial regions [LDTPPT] (Mitani et al., 1988;Shiromani et al., 1988;Datta et al., 1991;Shouse and Siegel, 1992); (b) REM sleep may be inhibited by noradrenergic and serotonergic neurons in the locus coeruleus and dorsal raphe, respectively (Siegel, 1989;Steriade and McCarley, 1990;Jones, 1991); (c) stages 3 and 4 (Delta) sleep are inhibited by cholinergic terminals from basal forebrain to cortex (Buzsaki et al., 1988) and from LDT/PPT to thalamus (Steriade and McCarley, 1990;Steriade et al., 1991); (d) Delta sleep is modulated by complex serotonergic mechanisms; for example, it is increased by pharmacological antagonists of 5HT, receptors (Declerck et al., 1987;Dugovic et al., 1989;Benson et al., 1991), although the mechanism and neuroanatomical site at which this effect occurs is unknown. ...
Some aspects of the function of hypothalamus related to sleep are described through the activity of adenosine. Adenosine (AD) bas several roles as a neurotransmitter, that may link metabolic as well as excitatory functions in the central nervous System. AD is produced mainly as a metabolic output in brain activity and tends to accumulate in the intracellular space during wake time; this is most notorious when the subject is sleep deprived. At the same time, extra cellular adenosine h reduced during prolonged episode of sleep. Two types of adenosine receptors, A1 et A2A, seem to be relevant to the sleep function, A1 and A2A, Caffeine is an antagonist of adenosine receptors and it was used as a tool for some of the studies that are presented. Possible changes in adenosine functioning due to the aging process were observed in animal models and also some abnormalities in adenosine system which could explain primary insomnia or the reduced amount of delta sleep and increase sensitivity to caffeine substances that some subjects presented. The new discoveries of the role of the hypothalamus in sleep physiology as well as in the pathophysiology of some sleep disorders, bring us new opportunities to understand and deal better with some sleep disturbances.
... Regarding the long-lasting effect of 2-AG on REM sleep, although interesting, we do not have an explanation at present. We dare not to speculate about the mechanisms, but we can mention that such a long-lasting effect has been caused by other pharmacological approaches, such as carbachol administration into the gigantocellular tegmental field (FTG) in cats, which increased REMS for 6 days (Datta et al., 1991) or into the central nucleus of the amygdala increasing REMS for 5 days in cats (Calvo et al., 1996), or pituitary adenylyl cyclase-activating polypeptide (PACAP) administration into the oral pontine reticular nucleus (PnO) increasing REMS for 11 days in rats (Ahnaou et al., 1999). Likewise, since it has been shown that both AEA and 2-AG inhibit the production of proinflammatory cytokines in the human eye (Krishnan and Chatterjee, 2012) and also it has been shown that the administration of the proinflammatory cytokine interleukin-1 (IL-1) into the LDT of rats reduces REMS about 50% (Brambilla et al., 2010), another possibility that arises in our study is that 2-AG might be inducing and inhibition of IL-1, or other proinflammatory cytokines in the brain, in order to facilitate this REMS long-lasting effect, but this possibility requires to be determined. ...
... Therefore in the absence of aminergic modulation, the brain is unable to adequately organize or record the events in a dream. Second, there is evidence that phasic activity such as eye movements and PGO spikes that occur during REM sleep are triggered by cholinergic neurons (Datta, Calvo, Quattrochi, & Hobson, 1991). Mamelak and Hobson (1989) suggest that such cholinergically mediated activity contributes significantly to changes in thought or scene shifts during a dream. ...
Dreaming is a statistically robust cognitive correlate of REM sleep, but all of its formal features may occur in other states of sleep and even in waking, especially during fantasy. In order to test the hypothesis that the brain basis of such cognitive features as dream bizarreness is to be found in REM sleep neurophysiology, it is critical to quantify bizarreness in dreams and other mental states and to analyze the data with respect to both the magnitude and the kind of bizarreness so measured. Any differences in the cognitive dimensions are candidate correlates of REM sleep neurophysiology. Sixty pairs of home-based dream and fantasy reports were collected from 12 subjects and scored for bizarreness using a two-stage scoring system adapted from Hobson, Hoffman, Helfand, and Kostner (1987). Our results show that bizarreness was twice as prevalent in dream reports as in wake-state fantasy reports of the same subjects. Further analysis of the reports also showed differences in other features including the number of persona and remoteness of time and place.
... PPT plays an important role in rapid eye movement (REM) sleep and REM sleep-related phenomena, including EEG activation, hippocampal theta rhythm and pontine-waves (p-waves) (Datta and Hobson, 1995;Garcia-Rill, 1991;Rye, 1997;Shouse and Siegel, 1992;Steriade and McCarley, 1990;Vertes et al., 1993). Injection of glutamate into the PPT increases REM sleep and wakefulness for hours in unanesthetized rats (Datta et al., 2001a and b) and injection of carbachol increases REM sleep for days in cats (Calvo et al., 1992;Datta et al., 1991;) and rats (Carley and Radulovacki, 1999). Lesions or pharmacological blockade of the PPT diminishes wakefulness and eliminates or alters expression of the tonic and phasic components REM sleep, including p-waves and rapid eye movements (Shouse and Siegel, 1992). ...
Functionally distinct areas were mapped within the pedunculopontine tegmentum (PPT) of 42 ketamine/xylazine anesthetized rats using local stimulation by glutamate microinjection (10 mM, 5-12 nl). Functional responses were classified as: (1) apnea; (2) tachypnea; (3) hypertension (HTN); (4) sinus tachycardia; (5) genioglossus electromyogram activation or (6) pontine-waves (p-waves) activation.We found that short latency apneas were predominantly elicited by stimulation in the lateral portion of the PPT, in close proximity to cholinergic neurons. Tachypneic responses were elicited from ventral regions of the PPT and HTN predominated in the ventral portion of the antero-medial PPT. We observed sinus tachycardia after stimulation of the most ventral part of the medial PPT at the boundary with nucleus reticularis pontis oralis, whereas p-waves were registered predominantly following stimulation in the dorso-caudal portion of the PPT. Genioglossus EMG activation was evoked from the medial PPT. Our results support the existence of the functionally distinct areas within the PPT affecting respiration, cardiovascular function, EEG and genioglossus EMG.
... Neuroanatomical studies have revealed that the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT) send projections to the LSd and the LSi, and spared the LSv (Satoh and Fibiger, 1986;Hallanger and Wainer, 1988;Staiger and Nurnberger, 1991). Since the LDT/PPT have a crucial role in regulating REM sleep and the cholinergic neurons in these nuclei are active during REM sleep (Gnadt and Pergam, 1986;Datta et al., 1991;Sakai and Koyama, 1996), the efferent projections from the LDT/PPT to the LSd and the LSi would be of potential significance for the generation of erections during REM sleep. ...
The effects of electrical stimulation to the septum on penile erections in rats were examined to clarify the mechanisms for regulation of erectile responses during different states of vigilance. Penile responses were assessed by changes in pressure in the corpus spongiosum of penis (CSP) and electromyography (EMG) of the bulbospongiosus (BS) muscle. In anesthetized and un-anesthetized rats, stimulation in and around the septum induced three erectile patterns; 1) a Normal type response, which was indistinguishable from a spontaneous erection, characterized by a slow increase in CSP pressure with sharp CSP pressure peaks associated with BS muscle bursts, 2) Mixed type response, in which high frequency CSP pressure peaks were followed by a Normal type response, and 3) a Prolonged type response, evoked only in the anesthetized rat, consisting of a single sharp CSP peak followed by a slow increase in CSP pressure and a return to baseline with multiple subsequent events repeated for up to 960 s. In addition, a Micturition type response was also observed involving high frequency CSP pressure oscillations similar to the pressure pattern seen during spontaneous micturition. We found that erections were induced after stimulation to the lateral septum (LS), but not from the medial septum (MS). In anesthetized rats, a few responses were also obtained following stimulation of the horizontal limb of diagonal band (HDB). In un-anesthetized rats, responses were also induced from the HDB and the ventral limb of diagonal band (VDB) and the adjoining areas. The effective sites for eliciting erection during rapid eye movement (REM) sleep were located in the dorsal and intermediate parts of the LS, whereas the ventral part of the LS was the most effective site for eliciting erections during wakefulness. These results suggest a functional role for penile erection in the septum, and further suggest that subdivisions of the LS may have different roles in the regulation of penile erection during wakefulness and REM sleep.
... 38 If the cholinergic agonist is injected into the paramedian pontine brain stem, the effect is immediate and short-lived (four to six hours), if injected into the far lateral peribrachial pons the effect is delayed and prolonged (eight to 10 days). 23,37,38,40 The relationship between these REM induction sites and PGO burst cells are shown in Figure. 4. ...
State-dependent aspects of consciousness are explored with particular attention to waking and dreaming. First, those phenomenological differences between waking and dreaming that have been established through subjective reports are reviewed. These differences are robustly expressed in most aspects of consciousness including perception, attention, memory, emotion, orientation, and thought. Next, the roles of high frequency neuronal oscillation and neuromodulation are explored in waking and rapid eye movement sleep, the stage of sleep with which the most intense dreaming is associated. The high frequency neuronal oscillations serve similar functions in the wake and rapid eye movement states sleep but neuromodulation is very different in the two states. The collective high frequency oscillatory activity gives coherence to spatially separate neurons but, because of the different neuromodulation, the binding of sensory input in the wake state is very different from the binding of internally perceived input during rapid eye movement sleep. An explanatory model is presented which states that neuromodulation, as well as input source and brain activation level differentiate states of the brain, while the self-organized collective neuronal oscillations unify consciousness via long range correlations.
... Multiple lines of evidence are consistent with the possibility that protein phosphorylation plays a key role in sleep cycle control. REM sleep can be enhanced for many hours (7) and for days (13,23) following the administration of microgram quantities of cholinomimetics into the pons or amygdala. The probability that mPRF levels of cAMP and PKA modulate cholinergic REM sleep enhancement also is supported by the finding that microinjection of the PKA inhibitor Rp-cAMP[S] did not alter cholinergic REM sleep generation (Figs. 3 and 5B). ...
Cholinergic neurotransmission in the medial pontine reticular formation (mPRF) modulates rapid eye movement (REM) sleep generation. Microinjection of cholinergic agonists and acetylcholinesterase inhibitors into the mPRF induces a REM sleep-like state, and microdialysis data reveal increased mPRF levels of acetylcholine during REM sleep. Muscarinic cholinergic receptors (mAChRs) participate in REM sleep generation, and data suggest that mAChRs of a non-M1 subtype modulate REM sleep generation. The signal transduction pathway activated by m2 and m4 mAChRs involves a pertussis toxin-sensitive G protein, adenylate cyclase (AC), adenosine 3',5'-cyclic monophosphate (cAMP), and protein kinase A (PKA). Therefore, the present study tested the hypothesis that cAMP and PKA within the mPRF modulate the carbachol-induced REM sleep-like state. To test this hypothesis, the mPRF was microinjected with compounds known to facilitate the effects of cAMP (dibutyryl cAMP and 8-bromo-cAMP), stimulate PKA (Sp-cAMP[S]), and inhibit PKA (Rp-cAMP[S]). The results showed that compounds that fostered the intracellular effects of cAMP significantly decreased cholinergic REM sleep, while having no effect on spontaneously occurring REM sleep. These data are consistent with the recent finding that within the mPRF, AC and a pertussis toxin-sensitive G protein modulate cholinergic REM sleep generation. These new data suggest a modulatory role for pontine cAMP and PKA in cholinergic REM sleep regulation.
... Induction of REM sleep like EEG, EMG, and EOG activity in rats after injection of carbachol at the pons is also in accordance with the earlier reports [2,5,8,22]. Carbachol-induced REM sleep-like changes in electrophysiological signals have been reported in other species also [1,3,6,15,16,18,23,24]. In the carbachol-induced REM sleep, SREs were totally absent. ...
This study was undertaken to find out whether sleep-related penile erections occur in the carbachol-induced rapid eye movement sleep model in rats. Bulbospongiosus EMG, as a measure of penile erection, was recorded along with EEG, EMG, and EOG during normal sleep-wakefulness. These parameters were again recorded after injection of carbachol into the pontine tegmentum. Carbachol-induced rapid eye movement sleep was not accompanied by penile erections.
... For example, in freely moving rats, carbachol injection to PPT led to increased REM sleep and respiratory pattern variability [35] . Further, it has been shown that glutamatergic stimulation of the PPT alters the expression of REM and wake- fulness [16] , and that cholinergic manipulations of the brainstem network for REM regulation in anesthetized animals can produce REM-like states [25,37383940. The aim of this study was to test the hypothesis that respiratory modulation by the PPT can be independent of other signs of behavioral state change, including induction of REM-sleep-related phenomena. ...
The pedunculopontine tegmental nucleus (PPT) has been shown to have important functions relevant to the regulation of behavioral states and various motor control systems, including breathing control. Our previous work has shown that the activation of neurons within the PPT, a structure that is typically active during rapid eye movement (REM) sleep, can produce respiratory disturbances in freely moving and anesthetized rats. The aim of this study was to test the hypothesis that respiratory modulation by the PPT in anesthetized rats can be evoked in the absence of other signs of an REM-sleep-like state. We characterized electroencephalogram (EEG) and electromyogram (EMG) changes during respiratory disturbances induced by glutamatergic stimulation of the PPT in spontaneously breathing, adult male Sprague-Dawley rats anesthetized with a ketamine/xylazine combination or with nembutal. Respiratory movements were monitored by a piezoelectric strain gauge. Two-barrel glass pipettes were used to pressure inject glutamate, to probe for respiratory effective sites within the PPT, and to inject oil red dye at the end of the experiments for histological verification of the injection sites. The EEGs were recorded from the sensorimotor cortex, hippocampus, and from the pons contralateral from the injection site. The EMGs were recorded from the genioglossus muscle. The initial response to glutamate injection into the respiratory modulating region of the PPT was always a respiratory pattern disturbance. Subsequent activation of EMG and EEG often occurred in ketamine/xylazine-anesthetized rats, but REM-sleep-like patterns were not observed. Respiratory pattern and EMG power changes in nembutal-anesthetized rats were similar, but EEG activation was never observed. Thus, we conclude that respiratory suppression produced by the local activation of PPT neurons may not necessarily be accompanied by an REM-sleep-like cortical state in this anesthetized model.
We spend so much of our lives sleeping, yet its precise function is unclear, in spite of our increasing understanding of the processes generating and maintaining sleep. We now know that sleep can be accompanied by periods of intense cerebral activity, yet only recently has experimental data started to provide us with some insights into the type of processing taking place in the brain as we sleep. There is now strong evidence that sleep plays a crucial role in learning and in the consolidation of memories. Once the preserve of psychoanalysts, ‘dreaming’ is now a topic of increasing interest amongst scientists. With research into sleep growing, this book presents a unique study of the relationship between sleep, learning, and memory. It brings together a team of international scientists researching sleep in both human and animal subjects.
This chapter describes the biochemical pharmacology of sleep. Various theoretical models have been proposed to account for the regulation of sleep and wakefulness. One model that takes into account both circadian and homeostatic considerations is the two-process model developed by Borbely and associates. The first, process S, is a homeostatic process—the longer the organism is awake, the greater will be its propensity to sleep and to have more intense sleep. The second, process C, reflects an oscillatory process that determines the threshold of sensitivity to the homeostatic factor and thus affects the propensity for sleep and waking. Process C is hypothesized to entrain or be entrained with other oscillators responsible for biologic rhythms, such as temperature, cortisol secretion, and rapid eye movement (REM) sleep. The current widely accepted paradigm is that REM sleep is promoted by cholinergic neurons that originate in the brain stem, most probably the lateral dorsal tegmental nucleus and pedunculopontine tegmental group, and that it is inhibited by noradrenergic and serotonergic neurons located in the locus ceruleus and dorsal raphe, respectively. Cholinergic neurons exert a widespread and crucial role in the orchestration of REM sleep, through their projections to medial pontine reticular formation, medulla, and forebrain areas in the thalamus and basal forebrain.
The data outlined in this chapter provides evidence to support a concept that the activation of pontine-wave (P-wave) generating neurons plays a critical role in long-term memory formation. The P-wave, generated by the phasic activation of glutamatergic neurons in the pons, is one of the most prominent phasic events of REM sleep. These P-wave generating neurons project to the hippocampus, amygdala, entorhinal cortex and many other regions of the brain known to be involved in cognitive processing. These P-wave generating glutamatergic neurons remain silent during wakefulness and slow-wave sleep (SWS), but during the transition from SWS to REM sleep and throughout REM sleep these neurons discharge high-frequency spike bursts in the background of tonically increased firing rates. Activation of these P-wave generating neurons increases glutamate release and activates postsynaptic N-methyl-D-aspartic acid (NMDA) receptors in the dorsal hippocampus. Activation of P-wave generating neurons increases phosphorylation of transcription factor cAMP response element binding protein (CREB) in the dorsal hippocampus and amygdala by activating intracellular protein kinase A (PKA). The P-wave generating neurons activation-dependent PKA-CREB phosphorylation increases the expression of activity-regulated cytoskeletal-associated protein (Arc), brain-derived neurotrophic factor (BDNF), and early growth response-1 (Egr-1) genes in the dorsal hippocampus and amygdala. The P-wave generator activation-induced increased activation of PKA and expression of pCREB, Arc, BDNF, and Egr-1 in the dorsal hippocampus is shown to be necessary for REM sleep-dependent memory processing. Continued research on P-wave generation and its functions may provide new advances in understanding memory and treating its disorders.
¡Todo mundo duerme! El sueño es tan familiar para cada uno de nosotros y, aún así, es un fenómeno envuelto en el misterio de sus funciones. Con tremendos y significativos avances como el descubrimiento del electroencefalograma en 1929, de la descripción del sueño de
movimientos oculares rápidos en 1953, de la descripción de la existencia del reloj endógeno circadiano en 1972, de la localización del sitio relacionado con la disfunción del sueño en el caso del síndrome de la apnea obstructiva en 1965, del tratamiento no invasivo denominado CPAP (por sus siglas en ingles: Continuous Positive Airway Pressure) para el síndrome de la apnea del
sueño en 1981 y del descubrimiento del gen relacionado con ritmos denominado CLOCK en la mosca de la fruta Drosophila en 1990, todavía continuamos preguntándonos ¿qué es el sueño?
¿Para qué dormimos? Es gratificante observar cómo la medicina del sueño va ganando espacios en la sociedad y se le otorga la importancia que merece, en especial cuando se relaciona con trastornos del dormir. Dicho interés se debe al creciente número de artículos vinculados con el tema del sueño
los cuales han sido publicados en diferentes medios de comunicación, tanto de divulgación científica como de difusión social.
El presente trabajo es el resultado del esfuerzo conjunto de científicos expertos en el área del estudio del ciclo sueño-vigilia que han contribuido con conocimientos actuales y avanzados relacionados con el tema. El propósito del libro es favorecer la comprensión sobre aspectos básicos y clínicos del sueño con una aproximación adecuada. Espero que el presente trabajo tenga
una gran aceptación entre estudiantes, profesores e investigadores y cumpla con las expectativas de todo lector.
A number of theories have proposed the involvement of different brain structures and neurotransmitters in order to explain the regulation of the sleep–wake cycle. However, there is no clear consensus as to the mechanisms through which the brain structures and their various neurotransmitters interact to produce theses phases.
Perhaps the problem is related to the fact sleep is a very fragile state, easily modified or influenced by a variety of substances or experimental manipulations.
In this paper, we describe the evidence of two different groups of factors that induce important changes on the sleep–wake cycle.
The endogenous factors: neurotransmitters; hormone; peptides; and some substances of lipidic nature and exogenous factors: stress, food intake, learning, sleep deprivation, sensorial stimulation, exercise and temperature on the regulation the sleep–wake cycle.
Likewise, we propose a hypothesis which attempts to reconcile the fact that endogenous and exogenous factors have similar effects.
Posttraumatic stress disorder (PTSD) patients with comorbid panic disorder (PD) may express additive symptoms of central fear system disturbance. They endorse elevated levels of sleep and nightmare disturbance [Leskin GA, et al., J Psychiatr Res 2002;36:449–452], and demonstrate movement suppression during laboratory sleep [Woodward SH, et al., Sleep 2002;25:681–688]. We estimated respiratory rate and rate variability separately for rapid-eye movement (REM) and non-rapid-eye movement (NREM) sleep. Subjects were 49 Vietnam combat-related PTSD inpatients (11 with comorbid PD and 38 without) and 15 controls. Computer-based estimates of respiratory rate and variability were derived from 10 to 18 hr of baseline sleep collected over two or three nights. Neither rate nor rate variability distinguished PTSD patients with comorbid PD from those without, or PTSD patients from controls; however, PTSD patients failed to exhibit the expected differences between REM and NREM respiratory rates. Moreover, the difference between REM and NREM respiratory rate was inversely related to a continuous measure of PTSD severity. PTSD patients with trauma-related nightmare complaint exhibited higher sleep respiration rates over both REM and NREM sleep. Conversely, in addition to slowed respiration, nightmare-free patients exhibited reduced respiratory rate variability in REM relative to NREM sleep, which was a reversal of the normal pattern. These finding are discussed in light of known telencephalic regulatory influences upon respiration rate. Depression and Anxiety 18:198–204, 2003 © 2003 Wiley-Liss, Inc.
Rapid eye movement sleep is a unique paradoxical state within sleep period. Normally it follows deep sleep, is maintained for varying duration and may terminate in either sleep or wake state. During REM sleep some neurons increase firing, the REM-ON neurons, while some others cease firing, the REM-OFF neurons. Although the mechanism is not completely known, these REM sleep -related neurons are likely to play a significant role in the initiation and maintenance of REM sleep. It was proposed that GABA may be involved in the cessation of REM-OFF neurons and the classical sleep and waking areas in the brain stem are likely to modulate the REM-ON and REM-OFF neurons for the regulation of REM sleep.
Results from our single neuronal activity experiments in freely behaving animals confirmed that the brain stem area, which induce wakefulness inhibit the REM-ON neurons but stimulate the REM-OFF neurons. Microinjection studies revealed that the increase in REM sleep by the cholinergic input (possibly from REM-ON neurons) to the locus coeruleus (where REM-OFF neurons are located) is mediated through GABA. Thus, it is proposed that during wakefulness the REM-ON neurons are inhibited while the REM-OFF neurons are active. During sleep gradually the awake-related neurons slow down withdrawing their effects on REM sleep related neurons. This causes an increase in the REM-ON neuronal activity inducing release of acetylcholine on the GABA-ergic neurons in the locus coeruleus. GABA then inhibits the REM-OFF neurons resulting in the initiation of REM sleep. The presence of GABA in optimum concentration maintains the duration of REM sleep episode.
A single microinjection of the cholinergic agonist carbachol into the feline caudolateral parabrachial nucleus produces an immediate increase in state-independent ipsilateral ponto-geniculooccipital waves, followed by a long-term rapid eye movement sleep enhancement lasting 7-10 days. Using retrogradely-transported fluorescent carbachol-conjugated nanospheres and choline acetyltransferase immunohistochemistry, afferent projections to this injection site for long-term rapid eye movement sleep enhancement were mapped and quantified. Six regions in the brain stem contained retrogradely-labelled cells: the raphe nuclei, locus coeruleus, laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus, parabrachial nucleus, and the pontine reticular formation. The retrogradely-labelled (rhodamine+) cells in the pontine reticular formation and pedunculopontine tegmental nucleus contributed the predominant input to the parabrachial nucleus injection site (34.3 +/- 5.3% and 28.4 +/- 5.6%, respectively), compared to the laterodorsal tegmental nucleus (5.8 +/- 3.8%), parabrachial nucleus (13.5 +/- 3.1%), raphe nuclei (12.9 +/- 2.7%), and locus coeruleus (5.1 +/- 2.4%). By comparison with findings of afferent input to the induction site for short-latency rapid eye movement sleep in the anterodorsal pontine reticular formation, the parabrachial nucleus injection site is characterized by a similar proportion of afferents, except that the raphe nuclei were found to provide more than a two-fold greater input. Retrogradely-labelled neurons quantified in these nuclear regions consisted of 21.5% double-labelled (rhodamine+/choline acetyltransferase+) cholinergic and 78.5% noncholinergic (rhodamine+/choline acetyltransferase-) cells. The pedunculopontine tegmental nucleus contributed the predominant (51.7 +/- 8.2%) cholinergic input, compared to laterodorsal tegmental nucleus (20.7 +/- 10.2%), parabrachial nucleus (23.1 +/- 7.5%), and pontine reticular formation (4.4 +/- 2.1%). A comparative analysis of the total retrogradely-labelled cells within each nuclear region which were also double-labelled showed the highest proportion in the laterodorsal tegmental nucleus (76.2 +/- 7.5%) compared to pedunculopontine tegmental nucleus (39.4 +/- 3.6%), parabrachial nucleus (37.3 +/- 2.8%), and pontine reticular formation (3.2 +/- 2.1%). These data indicate that while pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus neurons exert a powerful cholinergic influence on the injection site for long-term rapid eye movement enhancement, a major component of the afferent circuitry is non-cholinergic. Since the non-cholinergic input includes contributions from the locus coeruleus and raphe nuclei, it is probable that the caudolateral parabrachial nucleus contains cholinergic and aminergic afferent systems that participate in the long-term enhancement of rapid eye movement sleep.
The most important recent work on the neurobiology of sleep has focused on the precise cellular and biochemical mechanisms of rapid eye movement sleep mediation. Direct and indirect evidence implicates acetylcholine-containing neurons in the peribrachial pons as critical in the triggering and maintenance of rapid eye movement sleep. Other new studies provide support for the hypothesis that the cholinergic generator system is gated during waking by serotonergic and noradrenergic influences. A growing consensus regarding the basic neurobiology has stimulated new thinking about the brain basis of consciousness during waking and dreaming.
The aim of this study was to examine the afferents to the rat locus coeruleus by means of retrograde and anterograde tracing experiments using cholera-toxin B subunit and phaseolus leucoagglutinin. To obtain reliable injections of cholera-toxin B in the locus coeruleus, electrophysiological recordings were made through glass micropipettes containing the tracer and the noradrenergic neurons of the locus coeruleus were identified by their characteristic discharge properties. After iontophoretic injections of cholera-toxin B into the nuclear core of the locus coeruleus, we observed a substantial number of retrogradely labeled cells in the lateral paragigantocellular nucleus and the dorsomedial rostral medulla (ventromedial prepositus hypoglossi and dorsal paragigantocellular nuclei) as previously described. We also saw a substantial number of retrogradely labeled neurons in (1) the preoptic area dorsal to the supraoptic nucleus, (2) areas of the posterior hypothalamus, (3) the Kölliker-Fuse nucleus, (4) mesencephalic reticular formation. Fewer labeled cells were also observed in other regions including the hypothalamic paraventricular nucleus, dorsal raphe nucleus, median raphe nucleus, dorsal part of the periaqueductal gray, the area of the noradrenergic A5 group, the lateral parabrachial nucleus and the caudoventrolateral reticular nucleus. No or only occasional cells were found in the cortex, the central nucleus of the amygdala, the lateral part of the bed nucleus of the stria terminalis, the vestibular nuclei, the nucleus of the solitary tract or the spinal cord, structures which were previously reported as inputs to the locus coeruleus. Control injections of cholera-toxin B were made in areas surrounding the locus coeruleus, including (1) Barrington's nucleus, (2) the mesencephalic trigeminal nucleus, (3) a previously undefined area immediately rostral to the locus coeruleus and medial to the mesencephalic trigeminal nucleus that we named the peri-mesencephalic trigeminal nucleus, and (4) the medial vestibular nucleus lateral to the caudal tip of the locus coeruleus. These injections yielded patterns of retrograde labeling that differed from one another and also from that obtained with cholera-toxin B injection sites in the locus coeruleus. These results indicate that the area surrounding the locus coeruleus is divided into individual nuclei with distinct afferents. These results were confirmed and extended with anterograde transport of cholera-toxin B or phaseolus leucoagglutinin. Injections of these tracers in the lateral paragigantocellular nucleus, preoptic area dorsal to the supraoptic nucleus, the ventrolateral part of the periaqueductal gray, the Kölliker-Fuse nucleus yielded a substantial to large number of labeled fibers in the nuclear core of the locus coeruleus.(ABSTRACT TRUNCATED AT 400 WORDS)
Extensive studies have ascribed a role to the brainstem cholinergic system in the generation of rapid eye movement (REM) sleep and ponto-geniculo-occipital (PGO) waves. Much of this work stems from systemic and central cholinergic drug administration studies. The brainstem cholinergic system is also implicated in cortical activation via basal forebrain, thalamic, and hypothalamic relay neurons. This cholinergic ascending reticular activating hypothesis has also been suggested by in vivo experiments under anesthetics and by in vitro studies using cholinergic agonists in thalamic and hypothalamic slices. During the last ten years, brainstem cholinergic neurons have been discovered to be in the peribrachial area (PBL). With the discovery of PBL cholinergic neurons, many studies were devoted to the examination of PBL neuronal activity and their connectivity. This article reviews PBL neuronal activity in behaving animals and the anatomical features of these neurons in relation to behavioral state control. The role of the PBL in the generation of REM sleep, PGO waves, and the ascending reticular activating system (ARAS) has been evaluated at the cellular and neurochemical level. Based on recent literature, tentative mechanisms of REM sleep generation, PGO waves generation, and the cortical activation process are also outlined.
Cholinergic neurons in the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei are implicated in the generation of rapid eye movement sleep (REM) and ponto-geniculo-occipital (PGO) waves. Serotonin (5-HT) has a role in sleep-wake regulation and appears to inhibit PGO wave generation. We studied the effects of the central infusion of the relatively specific 5-HT1A receptor agonist 8-hydroxy-2-(n-dipropylamino)tetralin (DPAT) and the less specific 5-HT1 receptor agonist 1(3-chlorophenyl)piperazine (mCPP) on the regulation of REM and on PGO wave generation. DPAT (0.0, 0.002, 0.01, 0.08, and 0.8 microgram/0.5 microliter normal saline) and mCPP (0.0, 0.02, 0.2, 2.0, and 20.0 micrograms/0.5 microliter normal saline) were infused unilaterally into the peribrachial region of PPT (PB) in cats. Additionally, DPAT (0.01 microgram/0.5 microliter) was infused bilaterally into PB in a separate experiment. Low dosages of DPAT (unilateral or bilateral) decreased successful entrances into REM (0.01 microgram) and time spent asleep (0.002 microgram and 0.01 microgram) without affecting outward behavior. No dosage of mCPP significantly decreased the number of REM episodes, and neither drug decreased REM episode duration once REM had been entered. Neither drug affected the rate of PGO waves independently of modulating behavioral state. We propose that 5-HT1A receptor mechanisms have an inhibitory role in actual REM initiation, possibly by facilitating endogenously generated excitation of brainstem startle mechanisms at the onset of REM.
One of the major conceptual and empirical challenges confronting behavioral neurobiology is to develop theoretical models and experimental paradigms that will help to understand how single cells and their specific chemical signals come to be organized at the level of population ensembles in order to determine the global behavioral states of waking and sleep. To help meet this challenge, recent discoveries suggesting a role for acetylcholine containing neurons in both the triggering and long-term regulation of REM sleep offer inviting and instructive opportunities. It is the main purpose of this chapter to provide a detailed review of a recent and unexpected discovery: the long-term potentiation of REM sleep following the micro-injection of the cholinergic agonist carbachol into the cholinergic neuronal population of the peribrachial pontine tegmentum. Following a brief summary of the background of the cholinergic hypothesis of REM sleep generation and the current concept of the cellular nature of the REM sleep generator network, this chapter discusses the general neurobiology of the peribrachial area, and focus on its cholinergic neuronal sub-population as a prelude to a detailed account of the long-term REM sleep enhancement that follows the microinjection of carbachol into this zone. It discusses this finding in terms of a new, “cholinergic priming” hypothesis, which attributes the surprisingly long duration of the response to the setting in motion of an endogenous metabolic mechanism.
This study examined the hypothesis that cholinergic receptor mechanisms within the gigantocellular tegmental field (FTG) of the medial pontine reticular formation can cause state-dependent changes in the firing rates of parabrachial nuclear complex (PBNC) neurons. Using intact, unanesthetized cats, long-term recordings were obtained from single PBNC neurons following FTG administration of cholinergic agonists and antagonists. We show that the state-dependent decrease in PBNC cell discharge reported in this study can be attributed to muscarinic mechanisms within the FTG. Our pharmacological blocking results further suggest that diminished PBNC discharge was mediated by non-M1 muscarinic receptors in the FTG. This study demonstrates the usefulness of combining long-term neuronal recordings in the PBNC with multiple pharmacological manipulations within the FTG.
A newly synthesized agent S-12024-2 was shown to improve some aspects of cognitive processes such as memory consolidation. The relationships between sleep and memory lead us to investigate the effects of the intraperitoneal administration of three different doses (1, 3, and 10 mg/kg) of S-12024-2 on sleep variables in the rat. The results showed that S-12024-2 (10 mg/kg) increased slow wave sleep (SWS) and decreased wakefulness during the light period of the first 24 h of sleep recording. During day 1 of sleep recording, S-12024-2 tended to increase paradoxical sleep (PS) with a maximal effect observed with 3 mg/kg. Four days after administration of S-12024-2 (3 mg/kg), PS remained significantly high. These data suggest an active role for S-12024-2 on SWS and PS, compatible with its favourable effects on memory.
Considerable evidence suggests that brain stem pedunculopontine tegmentum (PPT) cholinergic cells are critically involved in the normal regulation of wakefulness and rapid eye movement (REM) sleep. However, much of this evidence comes from indirect studies. Thus, although involvement of PPT cholinergic neurons has been suggested by numerous investigations, the excitation of PPT cholinergic neurons causal to the behavioral state of wakefulness and REM sleep has never been directly demonstrated. In the present study we examined the effects of three different levels of activation of PPT cholinergic cells in wakefulness and sleep behavior. The effects of glutamate on the activity of PPT cholinergic cells were studied by microinjection of one of the three different doses of L-glutamate (0.3, 1.0, and 3.0 microg) or saline (vehicle control) into the PPT cholinergic cell compartment while quantifying the effects on wakefulness and sleep in free moving chronically instrumented cats. All microinjections were made during wakefulness and were followed by 4 h of recording. Polygraphic records were scored for wakefulness, slow-wave sleep states 1 and 2, slow-wave sleep with pontogeniculooccipital waves, and REM sleep. Dependent variables quantified after each microinjection included the percentage of recording time spent in each state, the latency to onset of REM sleep, the number of episodes per hour for REM sleep, and the duration of each REM sleep episode. A total of 48 microinjections was made into 12 PPT sites in six cats. Microinjection of 0.3- and 1.0-microg doses of L-glutamate into the cholinergic cell compartment of the PPT increased the total amount of REM sleep in a dose-dependent manner. Both doses of L-glutamate increased REM sleep at the expense of slow-wave sleep but not wakefulness. Microinjection of 3.0 microg L-glutamate kept animals awake for 2-3 h by eliminating slow-wave and REM sleep. The results show that the microinjection of the excitatory amino acid L-glutamate into the PPT cholinergic cell compartments can increase wakefulness and/or REM sleep depending on the L-glutamate dosage. These findings unambiguously confirm the hypothesis that the excitation of the PPT cholinergic cells is causal to the generation of wakefulness and REM sleep.
Rapid eye movement sleep can be elicited in the rat by microinjection of the cholinergic agonist carbachol into the oral pontine reticular nucleus. Intracerebroventricular administration, during the light period, of vasoactive intestinal peptide enhances rapid eye movement sleep in several species. Since this peptide is co-localized with acetylcholine in many neurons in the central nervous system, it was assumed that the oral pontine tegmentum could also be one target for vasoactive intestinal peptide to induce rapid eye movement sleep. This hypothesis was tested by recording the sleep-wakefulness cycle in freely-moving rats injected with vasoactive intestinal peptide or its fragments (1-12 and 10-28) directly into the oral pontine reticular nucleus. when administered into the posterior part of this nucleus, vasoactive intestinal peptide at 1 and 10 ng (in 0.1 microliter of saline), but not its fragments, induced a 2-fold enhancement of rapid eye movement sleep during 4 h, at the expense of wakefulness. At the dose of 10 ng, a significant increase in rapid eye movement sleep persisted for up to 8 h. Moreover, when the peptide was injected into the centre of the positive zone, rapid eye movement sleep was enhanced during three to eight consecutive days. These data provide the first evidence that rapid eye movement sleep can be elicited at both short- and long-term by a single intracerebral microinjection of vasoactive intestinal peptide. Peptidergic mechanisms, possibly in association with cholinergic mechanisms, within the caudal part of the oral pontine reticular nucleus may play a critical role in the long-term regulation of rapid eye movement sleep in rats.
A number of experimental and theoretical reports have suggested that the ponto-geniculo-occipital (PGO) wave-generating cells are involved in the generation of rapid eye movement (REM) sleep and REM sleep dependent cognitive functions. No studies to date have examined anatomical projections from PGO-generating cells to those brain structures involved in REM sleep generation and cognitive functions. In the present study, pontine PGO wave-generating sites were mapped by microinjecting carbachol in 74 sites of the rat brainstem. Those microinjections elicited PGO waves only when made in the dorsal part of the nucleus subcoeruleus of the pons. In six rats, the anterograde tracer biotinylated dextran amine (BDA) was microinjected into the physiologically identified cholinoceptive pontine PGO-generating site to identify brain structures receiving efferent projections from those PGO-generating sites. In all cases, small volume injections of BDA in the cholinoceptive pontine PGO-generating sites resulted in anterograde labeling of fibers and terminals in many regions of the brain. The most important output structures of those PGO-generating cells were the occipital cortex, entorhinal cortex, piriform cortex, amygdala, hippocampus, and many other thalamic, hypothalamic, and brainstem nuclei that participate in the generation of REM sleep. These findings provide anatomical evidence for the hypothesis that the PGO-generating cells in the pons could be involved in the generation of REM sleep. Since PGO-generating cells project to the entorhinal cortex, piriform cortex, amygdala, and hippocampus, these PGO-generating cells could also be involved in the modulation of cognitive functions.
A number of theories have proposed the involvement of different brain structures and neurotransmitters in order to explain the regulation of the sleep wake cycle. However, there is no clear consensus as to the mechanisms through which the brain structures and their various neurotransmitters interact to produce theses phases. Perhaps the problem is related to the fact sleep is a very fragile state, easily modified or influenced by a variety of substances or experimental manipulations. In this paper, we describe the evidence of two different groups of factors that induce important changes on the sleep wake cycle. The endogenous factors: neurotransmitters; hormone; peptides; and some substances of lipidic nature and exogenous factors: stress, food intake, learning, sleep deprivation, sensorial stimulation, exercise and temperature on the regulation the sleep-wake cycle. Likewise, we propose a hypothesis which attempts to reconcile the fact that endogenous and exogenous factors have similar effects.
Acetylcholine clearly plays a role in regulating sleep. This influence may involve nicotinic systems because several studies have demonstrated that nicotine treatment alters sleep. However, the literature that suggests an effect of nicotine treatment on sleep is contradictory, perhaps because different doses and routes of administration were used.
The studies reported here evaluated the effects of several doses of nicotine on REM sleep in the rat.
Male Wistar rats were prepared with a set of sleep recording electrodes and, following habituation to the test chamber, were used in one of three studies: a) a dose-response analysis of an acute dose of nicotine on REM sleep measured during the first 4 h after injection; b) a chronic treatment experiment; or c) a mecamylamine blockade experiment.
Acute nicotine administration decreased REM sleep in a dose-dependent fashion; significant effects were observed following injection with the 0.5 and 1.0 mg/kg doses. A decrease in slow wave sleep and an increase in wakefulness were also observed. Mecamylamine by itself did not affect REM sleep, but it blocked the effects on sleep produced by nicotine when given 30 min before a 1 mg/kg dose of nicotine. Rats that had been injected once daily with a 0.1 mg/kg dose of nicotine showed an increase in REM sleep after the third injection, whereas rats that had been chronically treated with a higher dose (0.5 mg/kg) displayed a reduction in REM and total sleep time.
These findings argue that the effects of both acute and chronic nicotine treatment on sleep are influenced by the dose of nicotine used.
This study presents new findings of carbachol-induced long-term ponto-geniculo-occipital (PGO) enhancement lasting five days, but without REM sleep enhancement. A quantitative analysis of the number and types of bilateral PGO wave events during slow wave sleep with PGO activity (SP) and REM was performed in each of four cats over a period of six days following a single unilateral microinjection of carbachol nanospheres into the caudolateral peribrachial area. The results demonstrate increases in the summed total of all PGO wave events to continue for five days postcarbachol reaching a peak sixfold increase on day three in SP and REM. The tendency of PGO waves to occur in clusters of greater than three waves increased sevenfold on day three in SP and fourfold during REM. These findings indicate a dissociation of long-term PGO enhancement from long-term REM enhancement, and suggest that even a sixfold increase in PGO activity alone is not, in itself, sufficient to produce the cholinergic orchestration of REM sleep enhancement.
The aim of this study was to test the hypothesis that supplementary activation of the phasic pontine wave (P-wave) generator during rapid eye movement (REM) sleep enhances consolidation and integration of memories, resulting in improved learning. To test this hypothesis, two groups of rats were trained on a two-way active avoidance learning task in the morning. Immediately after training, one group of rats received a carbachol microinjection into the P-wave generator and the other group was microinjected with control saline into the same target area. After training trials and microinjections, rats were allowed a 6-h period of undisturbed sleep in the polygraphic recording chamber. At the end of 6 h of undisturbed sleep-wake recordings, rats were retested in a session of avoidance learning trials. After learning trials, the total percentage of time spent in REM sleep was significantly increased in both saline (15.36%)- and carbachol (17.70%)-microinjected rats. After learning trials, REM sleep P-wave density was significantly greater throughout the 6-h period of recordings in carbachol treated rats than in the saline treated rats. In the retrial session, the improvement in learning task performance was 22.75% higher in the carbachol-microinjected rats than in the saline-microinjected rats. These findings show that the consolidation and integration of memories create a homeostatic demand for P-waves. In addition, these findings provide experimental evidence, for the first time, that activation of the P-wave generator may enhance consolidation and integration of memories, resulting in improved performance on a recently learned task.
Pharmacological, lesion and single-unit recording techniques in several animal species have identified a region of the pontine reticular formation (subcoeruleus, SubC) just ventral to the locus coeruleus as critically involved in the generation of rapid-eye-movement (REM) sleep. However, the intrinsic membrane properties and responses of SubC neurons to neurotransmitters important in REM sleep control, such as acetylcholine and orexins/hypocretins, have not previously been examined in any animal species and thus were targeted in this study.
Cyclic nucleotides are thought to act as second messengers of neurotransmission inside central neurons, and cyclic guanosine monophosphate (cGMP) has been postulated to act as a messenger for muscarinic, cholinergic transmission. Nonetheless, the action of cGMP has not yet been established in identified cortical neurons. We injected cGMP and horseradish peroxidase (HRP) intracellularly in neurons of the motor cortex of awake cats. Fifty-four percent of injected cells responded to cGMP and HRP with an increase in input resistance within 30 s after injection. None of a control group of cells injected with HRP without cGMP so responded. In cells receiving intracellular depolarizing current sufficient to produce repeated spike discharge at the time of injection, the increase in input resistance after cGMP persisted for as long as the cells could be held. There was no significant increase in firing rate after injection of cGMP. Cells responding to cGMP with an increased input resistance were identified as pyramidal cells of layer V. One inverted pyramidal cell of layer VI also showed an increase in input resistance in response to cGMP. Previous studies have suggested that muscarinic cholinergic agents produce an increased input resistance (thought to reflect a decreased potassium conductance) underlying an increased rate of discharge in neocortical neurons. Our results favor a dual action of muscarinic cholinergic transmission in mammalian cortical neurons--the increase in input resistance in layer V pyramidal cells mediated by cGMP, and the increase in rate of discharge mediated by other means.