GABA in pedunculo pontine tegmentum regulates spontaneous rapid eye movement sleep by acting on GABAA receptors in freely moving rats

doi:10.1016/j.neulet.2004.04.080

Neuroscience Letters

Volume 365, Issue 3, 29 July 2004, Pages 200-204

https://doi.org/10.1016/j.neulet.2004.04.080 Get rights and content

Abstract

REM-OFF and REM-ON neurons in the brainstem are reported to regulate REM sleep, however, the detailed mechanism of generation of REM sleep is unknown. The former are continuously active except during REM sleep and an inhibitory neurotransmitter, GABA, has been implicated in mediating the inhibition for the generation of REM sleep. The REM-ON neurons, on the other hand, remain inactive throughout but increase firing during REM sleep. This study was conducted to investigate if GABA in the brain area rich in cholinergic REM-ON neurons would modulate REM sleep as proposed earlier. Rats were surgically prepared for sleep–wake recording and two cannulae aiming pedunculopontine areas in the brainstem that are rich in REM-ON neurons, were implanted bilaterally. After recovery, picrotoxin, a GABA_A antagonist, was simultaneously microinjected bilaterally into the pedunculopontine area in freely moving normally behaving rats using a remote dual syringe pump and the effects were studied on electrophysiological sleep and waking parameters. The results showed that picrotoxin significantly reduced REM sleep for 6 h and the effect was due to reduction in the frequency of generation of REM sleep.

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Acknowledgements

Research funding from Indian Council of Medical Research is duly acknowledged.

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Rapid eye movement (REM) sleep plays a significant role in visuospatial learning and memory consolidation; however, its mechanism of action is unknown. Rapid eye movements (REMs), a characteristic active feature of REM sleep, is a potential correlate of neural processing for visual memory consolidation. The superior colliculus (SC) plays a central role in oculomotor control and spatial localization of objects in the visual field. We proposed that local reversible inactivation of the SC during post-learning sessions might interfere with REMs and negatively impact REM sleep associated consolidation of the visuospatial learnt task. Under gaseous anesthesia, bilateral cannulae aiming SC and electrodes for recording electrophysiological signals to classify sleep-waking were implanted. Following standard protocol, all rats were subjected to Morris water maze (MWM) training for 5 consecutive days followed by probe trial. After MWM training, on all except the probe test days, the rat SC were bilaterally infused with either vehicle (control, Group 1), Lidocaine hydrochloride a local anesthetic (Lox 2%, Group 2), or muscimol (Mus, GABA agonist, Group 3) and sleep-wakefulness recorded after day 1, 4, and post-probe learning sessions. Post-learning, compared to vehicle, Mus treated group significantly decreased REMs, phasic REM sleep, percent time spent in REM sleep and REM sleep frequency/hr. Also, during probe test, the escape latency was significantly increased, and the percentage time spent in the platform quadrant were significantly decreased in both, Mus and Lox 2% treated rats, while the number of platform location crossings was decreased in Mus treated group. The results showed that Lox 2% and Mus into SC reduced consolidation of visuospatial learning. The findings support our contention that SC mediated activation of REMs exerts a positive influence in processing and consolidation of visual learning during REM sleep. The findings explain the role of REMs during REM sleep in visual memory consolidation.
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The GABAergic neurons in the SC are essential for acute dark induction of wakefulness in nocturnal mice [21], suggesting that the SC may be critical for maintaining masking responses to light and darkness. The cholinergic and GABA-ergic role in REM sleep regulation has been well documented [22–24]. We hypothesized that manipulation of SC neurons, which contribute to saccades during wake and sleep, could modulate sleep-wake behaviour.
The superior colliculus (SC) is associated with visual attention, spatial navigation, decision making, escape and approach responses, some of which are important for defence and survival in rodents. SC helps in initiating and controlling saccadic eye movements and gaze during wakefulness. It is also activated during rapid eye movement (REM) sleep associated rapid eye movements (REMs). To investigate the contribution of SC in sleep-wake behaviour, we have demonstrated that manipulation of SC with scopolamine, carbachol, muscimol, picrotoxin and MK-801 decreased the amount of REM sleep. We observed that scopolamine and picrotoxin as well as muscimol decreased REM sleep frequency. MK-801 decreased percent amount of REM sleep, however, neither the frequency nor the duration/episode was affected. The cholinergic and GABA-ergic modulation of SC affecting REM sleep may be involved in REM sleep associated visuo-spatial learning and memory consolidation, which however, need to be confirmed. Furthermore, the results suggest involvement of efferent from SC in modulation of sleep-waking via the brainstem sleep regulating areas.
Pedunculo-pontine tegmentum cholinergic REM-ON neurons modulate ventral tegmental neurons to modulate rapid eye movement sleep in rats
2022, Neuropharmacology
Citation Excerpt :
Analysis of the data in bins of 2 h after sequential microinjection showed that the duration of REMS/episode/h (Fig. 3e) was not affected significantly in any of the 2 h bins. We have observed in this study that activation of neurons in the PPT increased REMS, which may be supported by earlier isolated, independent reports (Pal and Mallick, 2004; Van Dort et al., 2015). However, the novelty of the findings of this study is that ACh-ergic antagonist (Scop) into the VTA reduced REMS in normal rats.
The interaction among the acetylcholine (ACh)-ergic REM-ON neurons in the pedunculo-pontine area (PPT), noradrenergic REM-OFF neurons in locus coeruleus (LC) and GABA-ergic neurons in the regulation of rapid eye movement sleep (REMS) have been studied in relative details; however, many questions including the role of dopamine (DA) remain unanswered. The ventral tegmental area (VTA) is rich in DA-ergic neurons, which have been implicated with schizophrenia and depression, when REMS is significantly affected. Also, some of the symptoms of REMS and these diseases are common. As the ACh-ergic REM-ON neurons in the PPT project to VTA, we proposed that such inputs might affect REMS, dreams and hallucinations. We recorded sleep-wake-REMS in freely moving, chronically prepared rats under three controlled experimental conditions. In different sets of experiments, either the ACh-ergic inputs to the VTA were blocked by local microinjection of Scopolamine (Scop) alone, or, the PPT neurons were bilaterally stimulated by Glutamate (Glut), or, the PPT neurons were stimulated by Glut in presence of Scop into the VTA. It was observed that Glut into PPT and Scop into the VTA significantly increased and decreased REMS, respectively. Additionally, PPT stimulation induced increased REMS was prevented in the presence of Scop into the VTA. Based on these findings we propose that inputs from ACh-ergic REM-ON neurons to VTA increase REMS and it could be a possible circuitry for expressions of hallucinations and dreams.
GABA<inf>A</inf> receptors implicated in REM sleep control express a benzodiazepine binding site
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It has been reported that non-subtype-selective GABA_A receptor antagonists injected into the nucleus pontis oralis (PnO) of rats induced long-lasting increases in REM sleep. Characteristics of these REM sleep increases were identical to those resulting from injection of muscarinic cholinergic agonists. Both actions were blocked by the muscarinic antagonist, atropine. Microdialysis of GABA_A receptor antagonists into the PnO resulted in increased acetylcholine levels. These findings were consistent with GABA_A receptor antagonists disinhibiting acetylcholine release in the PnO to result in an acetylcholine-mediated REM sleep induction. Direct evidence has been lacking for localization in the PnO of the specific GABA_A receptor-subtypes mediating the REM sleep effects. Here, we demonstrated a dose-related, long-lasting increase in REM sleep following injection (60 nl) in the PnO of the inverse benzodiazepine agonist, methyl-6,7-dimethoxy-4-ethyl-β-carboline (DMCM, 10⁻² M). REM sleep increases were greater and more consistently produced than with the non-selective antagonist gabazine, and both were blocked by atropine. Fluorescence immunohistochemistry and laser scanning confocal microscopy, colocalized in PnO vesicular acetylcholine transporter, a presynaptic marker of cholinergic boutons, with the γ2 subunit of the GABA_A receptor. These data provide support for the direct action of GABA on mechanisms of acetylcholine release in the PnO. The presence of the γ2 subunit at this locus and the REM sleep induction by DMCM are consistent with binding of benzodiazepines by a GABA_A receptor-subtype in control of REM sleep.
Activation of inactivation process initiates rapid eye movement sleep
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Citation Excerpt :
To explain the mechanism it was necessary to bring in role of at least another inhibitory neurotransmitter on the REM-ON neurons receiving the NA-ergic inputs as was proposed in earlier paragraph (Mallick et al., 2001). GABA-ergic projections to the PPT, the site of REM-ON neurons (Inglis and Winn, 1995) and role of GABA in PPT for REMS regulation (Pal and Mallick, 2004; Torterolo et al., 2002) were already reported. Hence, interplay of NA and GABA in PPT for REMS regulation and projections of GABA to PPT in such regulation were investigated.
Interactions among REM-ON and REM-OFF neurons form the basic scaffold for rapid eye movement sleep (REMS) regulation; however, precise mechanism of their activation and cessation, respectively, was unclear. Locus coeruleus (LC) noradrenalin (NA)-ergic neurons are REM-OFF type and receive GABA-ergic inputs among others. GABA acts postsynaptically on the NA-ergic REM-OFF neurons in the LC and presynaptically on the latter's projection terminals and modulates NA-release on the REM-ON neurons. Normally during wakefulness and non-REMS continuous release of NA from the REM-OFF neurons, which however, is reduced during the latter phase, inhibits the REM-ON neurons and prevents REMS. At this stage GABA from substantia nigra pars reticulate acting presynaptically on NA-ergic terminals on REM-ON neurons withdraws NA-release causing the REM-ON neurons to escape inhibition and being active, may be even momentarily. A working-model showing neurochemical-map explaining activation of inactivation process, showing contribution of GABA-ergic presynaptic inhibition in withdrawing NA-release and dis-inhibition induced activation of REM-ON neurons, which in turn activates other GABA-ergic neurons and shutting-off REM-OFF neurons for the initiation of REMS-generation has been explained. Our model satisfactorily explains yet unexplained puzzles (i) why normally REMS does not appear during waking, rather, appears following non-REMS; (ii) why cessation of LC-NA-ergic-REM-OFF neurons is essential for REMS-generation; (iii) factor(s) which does not allow cessation of REM-OFF neurons causes REMS-loss; (iv) the association of changes in levels of GABA and NA in the brain during REMS and its deprivation and associated symptoms; v) why often dreams are associated with REMS.
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Citation Excerpt :
The cholinergic innervation of the pallium in birds and mammals is associated with their enrichment in muscarinic cholinergic receptors (Brann et al., 1988; Dietl et al., 1988; Kohler et al., 1995; Wächtler and Ebinger, 1989). In mammals, the basal forebrain cholinergic corticopetal cell fields receive input from the pallial amygdala, and the central and intercalated nuclei of the subpallial amygdala (Grove, 1988; Paré and Smith, 1994; Price and Amaral, 1981; Russchen, 1982; Russchen et al., 1985a,b), and the brainstem reticular formation, including the pedunculopontine nucleus (Datta and Prutzman, 2005; Pal and Mallick, 2004). In birds, it appears that the region of the NBM cholinergic neurons receives input from limbic striatum (including nucleus accumbens) and from the arcopallium–amygdaloid complex (Medina and Reiner, 1997; Veenman et al., 1995).
The subpallial region of the avian telencephalon contains neural systems whose functions are critical to the survival of individual vertebrates and their species. The subpallial neural structures can be grouped into five major functional systems, namely the dorsal somatomotor basal ganglia; ventral viscerolimbic basal ganglia; subpallial extended amygdala including the central and medial extended amygdala and bed nuclei of the stria terminalis; basal telencephalic cholinergic and non-cholinergic corticopetal systems; and septum. The paper provides an overview of the major developmental, neuroanatomical and functional characteristics of the first four of these neural systems, all of which belong to the lateral telencephalic wall. The review particularly focuses on new findings that have emerged since the identity, extent and terminology for the regions were considered by the Avian Brain Nomenclature Forum. New terminology is introduced as appropriate based on the new findings. The paper also addresses regional similarities and differences between birds and mammals, and notes areas where gaps in knowledge occur for birds.

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GABA in pedunculo pontine tegmentum regulates spontaneous rapid eye movement sleep by acting on GABAA receptors in freely moving rats

Abstract

Section snippets

Acknowledgements

Neuroscience

Neuroscience

Behav. Brain Res.

Neuroscience

Neuroscience

Neurosci. Res.

Brain Res.

Brain Res. Bull.

Brain Res.

Activity of norepinephrine containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep–waking cycle

J. Neurosci.

Norepinephrine containing neurons: changes in spontaneous discharge patterns during sleeping and waking

Science

GABA in pedunculo pontine tegmentum regulates spontaneous rapid eye movement sleep by acting on GABA_A receptors in freely moving rats