Excitation of the Brain Stem Pedunculopontine Tegmentum Cholinergic Cells Induces Wakefulness and REM Sleep

Datta, Subimal and Donald F. Siwek. Excitation of the brain stem pedunculopontine tegmentum cholinergic cells induces wakefulness and REM sleep. J. Neurophysiol. 77: 2975–2988, 1997. 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 μg) 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-μg 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 μg 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.

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Evidence That REM Sleep Is Controlled by the Activation of Brain Stem Pedunculopontine Tegmental Kainate Receptor

Journal of Neurophysiology ◽

10.1152/jn.00763.2001 ◽

2002 ◽

Vol 87 (4) ◽

pp. 1790-1798 ◽

Cited By ~ 61

Author(s):

Subimal Datta

Keyword(s):

Brain Stem ◽

Rem Sleep ◽

Kainate Receptors ◽

Specific Receptor ◽

Cell Compartment ◽

Pharmacological Blockade ◽

Specific Receptors ◽

Cholinergic Cell ◽

First Time ◽

The Brain

Glutamate, the neurotransmitter, enhances rapid-eye-movement (REM) sleep when microinjected into the brain stem pedunculopontine tegmentum (PPT) of the cat and rat. Glutamate and its various receptors are normally present in the PPT cholinergic cell compartment. The aim of this study was to identify which specific receptor(s) in the cholinergic cell compartment of the PPT are involved in glutamate-induced-REM sleep. To identify these glutamate-induced REM-sleep-generating receptor(s) in the PPT cholinergic cell compartment, specific receptors were pharmacologically blocked differentially by localized pretreatment of specific glutamate receptor antagonists; glutamate was then microinjected into the PPT cholinergic cell compartment while quantifying the effects on REM sleep in freely moving chronically instrumented rats. The results demonstrate that when kainate receptors were blocked by pretreatment with a kainate-specific receptor antagonist, microinjection of glutamate was unable to induce REM sleep. Pharmacological blockade of specific N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors was unable to block glutamate-microinjection-induced-REM sleep. These findings suggest, for the first time, that the activation of kainate receptors within the cholinergic cell compartment of the PPT is an essential portion of the mechanism for the generation of glutamate-induced REM sleep in the rat.

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Spontaneous REM Sleep Is Modulated By the Activation of the Pedunculopontine Tegmental GABAB Receptors in the Freely Moving Rat

Journal of Neurophysiology ◽

10.1152/jn.01104.2003 ◽

2004 ◽

Vol 91 (4) ◽

pp. 1822-1831 ◽

Cited By ~ 38

Author(s):

Jagadish Ulloor ◽

Vijayakumar Mavanji ◽

Subhash Saha ◽

Donald F. Siwek ◽

Subimal Datta

Keyword(s):

Rem Sleep ◽

Gabab Receptors ◽

Optimum Dose ◽

Dependent Manner ◽

Specific Receptors ◽

Cholinergic Cell ◽

Freely Moving ◽

Dose Dependent ◽

The Brain

Considerable evidence suggests that the neurotransmitter γ-aminobutyric acid (GABA)-ergic system and pedunculopontine tegmentum (PPT) in the brain stem are critically involved in the regulation of rapid-eye-movement (REM) sleep. GABA and its various receptors are normally present in the PPT cholinergic cell compartment. The aim of this study was to identify the role of GABA and its receptors in the regulation of REM sleep. To achieve this aim, specific receptors were activated differentially by local microinjection of selective GABA receptor agonists into the PPT while quantifying its effects on REM sleep in freely moving chronically instrumented rats ( n = 21). The results demonstrated that when GABAB receptors were activated by local microinjection of a GABAB receptor selective agonist, baclofen, spontaneous REM sleep was suppressed in a dose-dependent manner. The optimum dose for REM sleep reduction was 1.5 nmol. In contrast, when GABAA and GABAC receptors were activated by microinjecting their receptor selective agonists, isoguvacine (ISGV) and cis-4-aminocrotonic acid (CACA), respectively, the total percentages of REM sleep did not change compared with the control values. In another eight freely moving rats, effects of baclofen application was tested on firing rates of REM-on cells ( n = 12). Of those 12 neurons, 11 stopped firing immediately after application of baclofen [latency: 50 ± 14 s (SD)] and remained almost silent for 130 ± 12 min. Findings of the present study provide direct evidence that the PPT GABAB receptors and REM-on cells are involved in the regulation of REM sleep.

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Brain stem gigantocellular neurons: patterns of activity during behavior and sleep in the freely moving rat

Journal of Neurophysiology ◽

10.1152/jn.1979.42.1.214 ◽

1979 ◽

Vol 42 (1) ◽

pp. 214-228 ◽

Cited By ~ 133

Author(s):

R. P. Vertes

Keyword(s):

Brain Stem ◽

Eye Movement ◽

Cell Population ◽

Slow Wave ◽

Rem Sleep ◽

Theta Rhythm ◽

Slow Wave Sleep ◽

The Other ◽

Rapid Eye Movement ◽

Freely Moving

1. The activity of 44 single brain stem gigantocellular neurons was recorded in the freely moving rat during the following four states: quiet waking (W), waking with movement (W-M), slow-wave sleep (SWS), and rapid eye movement (REM) sleep. 2. Cells were classified into three groups on the basis of the states in which they maintained their highest rate of discharge. The three cell categories were: movement-REM (MOV-REM), movement (MOV), and quiet waking (QW) neurons. The MOV-REM neurons, comprising 68% of the cell population, discharged significantly more during waking-movement and REM sleep than during either W or SWS. The MOV neurons, 16% of the cells, showed significant increases in activity only when the rat moved. The QW neurons, also 16% of the cells, typically maintained high rates of discharge in the absence of movement. 3. The MOV-REM neurons were further divided into two subclasses of cells--phasically and tonically discharging neurons. The phasic MOV-REM cells appeared to participate in phasic motor events of REM sleep and corresponding movements during waking. The pattern of activity of the tonic MOV-REM neurons suggested that they may be involved in the generation and maintenance of the theta rhythm of the hippocampus during waking-movement and REM sleep. 4. No cells were found to discharge significantly more in REM sleep or SWS sleep than in the other states, (i.e., no REM or SWS selective cells were seen).

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Faculty Opinions recommendation of Learning-dependent, transient increase of activity in noradrenergic neurons of locus coeruleus during slow wave sleep in the rat: brain stem-cortex interplay for memory consolidation?

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1103341.559379 ◽

2008 ◽

Author(s):

Mark Mayford

Keyword(s):

Locus Coeruleus ◽

Brain Stem ◽

Rat Brain ◽

Slow Wave ◽

Memory Consolidation ◽

Slow Wave Sleep ◽

Transient Increase ◽

Noradrenergic Neurons

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Serotonin elicits long-lasting enhancement of rhythmic respiratory activity in turtle brain stems in vitro

Journal of Applied Physiology ◽

10.1152/jappl.2001.91.6.2703 ◽

2001 ◽

Vol 91 (6) ◽

pp. 2703-2712 ◽

Cited By ~ 21

Author(s):

Stephen M. Johnson ◽

Julia E. R. Wilkerson ◽

Daniel R. Henderson ◽

Michael R. Wenninger ◽

Gordon S. Mitchell

Keyword(s):

Brain Stem ◽

Respiratory Activity ◽

Dependent Manner ◽

Frequency Increase ◽

Burst Frequency ◽

Bath Application ◽

Burst Amplitude ◽

Dose Dependent ◽

The Brain

Brain stem preparations from adult turtles were used to determine how bath-applied serotonin (5-HT) alters respiration-related hypoglossal activity in a mature vertebrate. 5-HT (5–20 μM) reversibly decreased integrated burst amplitude by ∼45% ( P < 0.05); burst frequency decreased in a dose-dependent manner with 20 μM abolishing bursts in 9 of 13 preparations ( P < 0.05). These 5-HT-dependent effects were mimicked by application of a 5-HT1A agonist, but not a 5-HT1B agonist, and were abolished by the broad-spectrum 5-HT antagonist, methiothepin. During 5-HT (20 μM) washout, frequency rebounded to levels above the original baseline for 40 min ( P < 0.05) and remained above baseline for 2 h. A 5-HT3 antagonist (tropesitron) blocked the post-5-HT rebound and persistent frequency increase. A 5-HT3 agonist (phenylbiguanide) increased frequency during and after bath application ( P < 0.05). When phenylbiguanide was applied to the brain stem of brain stem/spinal cord preparations, there was a persistent frequency increase ( P < 0.05), but neither spinal-expiratory nor -inspiratory burst amplitude were altered. The 5-HT3receptor-dependent persistent frequency increase represents a unique model of plasticity in vertebrate rhythm generation.

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Neostriatal administration of somatostatin: differential effect of small and large doses on behavior and motor control

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y77-034 ◽

1977 ◽

Vol 55 (2) ◽

pp. 234-242 ◽

Cited By ~ 49

Author(s):

M. Rezek ◽

V. Havlicek ◽

L. Leybin ◽

C. Pinsky ◽

E. A. Kroeger ◽

...

Keyword(s):

Motor Control ◽

Eye Movements ◽

Slow Wave ◽

Rem Sleep ◽

Differential Effect ◽

Slow Wave Sleep ◽

Small Doses ◽

Freely Moving ◽

Behavioral Excitation ◽

Higher Doses

The administration of small doses of somatostatin (SRIF) (0.01 and 0.1 μg) into the neostriatal complex of unrestrained, freely moving rats induced general behavioral excitation associated with a variety of stereotyped movements, tremors, and a reduction of rapid eye movements (REM) and deep slow wave sleep (SWS). In contrast, the higher doses of SRIF (1.0 and 10.0 μg) caused movements to be uncoordinated and frequently induced more severe difficulties in motor control such as contralateral hemiplegia-in-extension which restricted or completely prevented the expression of normal behavioral patterns. As a result, the animals appeared drowsy and inhibited. Analysis of the sleep-waking cycle revealed prolonged periods of a shallow SWS while REM sleep and deep SWS were markedly reduced; electroencephalogram recordings revealed periods of dissociation from behavior. The administration of endocrinologically inactive as well as the active analogues of SRIF failed to induce effects comparable with those observed after the administration of the same dose of the native hormone (10.0 μg).

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Insights into paradoxical (REM) sleep homeostatic regulation in mice using an innovative automated sleep deprivation method

SLEEP ◽

10.1093/sleep/zsaa003 ◽

2020 ◽

Vol 43 (7) ◽

Cited By ~ 3

Author(s):

Sébastien Arthaud ◽

Paul-Antoine Libourel ◽

Pierre-Hervé Luppi ◽

Christelle Peyron

Keyword(s):

Slow Wave ◽

Rem Sleep ◽

High Efficiency ◽

Environmental Changes ◽

Slow Wave Sleep ◽

Paradoxical Sleep ◽

Corticosterone Level ◽

Plasma Corticosterone ◽

Homeostatic Regulation ◽

External Modulation

Abstract Identifying the precise neuronal networks activated during paradoxical sleep (PS, also called REM sleep) has been a challenge since its discovery. Similarly, our understanding of the homeostatic mechanisms regulating PS, whether through external modulation by circadian and ultradian drives or via intrinsic homeostatic regulation, is still limited, largely due to interfering factors rendering the investigation difficult. Indeed, none of the studies published so far were able to manipulate PS without significantly altering slow-wave sleep and/or stress level, thus introducing a potential bias in the analyses. With the aim of achieving a better understanding of PS homeostasis, we developed a new method based on automated scoring of vigilance states—using electroencephalogram and electromyogram features—and which involves closed-loop PS deprivation through the induction of cage floor movements when PS is detected. Vigilance states were analyzed during 6 and 48 h of PS deprivation as well as their following recovery periods. Using this new automated methodology, we were able to deprive mice of PS with high efficiency and specificity, for short or longer periods of time, observing no sign of stress (as evaluated by plasma corticosterone level and sleep latency) and requiring no human intervention or environmental changes. We show here that PS can be homeostatically modulated and regulated while no significant changes are induced on slow-wave sleep and wakefulness, with a PS rebound duration depending on the amount of prior PS deficit. We also show that PS interval duration is not correlated with prior PS episode duration in the context of recovery from PS deprivation.

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Each distinct type of mental state is supported by specific brain functions

Behavioral and Brain Sciences ◽

10.1017/s0140525x00434023 ◽

2000 ◽

Vol 23 (6) ◽

pp. 941-943 ◽

Cited By ~ 5

Author(s):

Claude Gottesmann

Keyword(s):

Slow Wave ◽

Mental State ◽

Rem Sleep ◽

Psychological Functioning ◽

Slow Wave Sleep ◽

Mental Content ◽

Distinct Type ◽

Inhibitory Processes ◽

Brain Functions

Reflective waking mentation is supported by cortical activating and inhibitory processes. The thought-like mental content of slow wave sleep appears with lower levels of both kinds of influence. During REM sleep, the equation: activation + disinhibition + dopamine may explain the often psychotic-like mode of psychological functioning.[Hobson et al.; Nielsen; Revonsuo; Solms; Vertes & Eastman]

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