Role of the dorsal paragigantocellular reticular nucleus in paradoxical (rapid eye movement) sleep generation: a combined electrophysiological and anatomical study in the rat

doi:10.1016/j.neuroscience.2007.12.014

Neuroscience

Volume 152, Issue 3, 27 March 2008, Pages 849-857

https://doi.org/10.1016/j.neuroscience.2007.12.014 Get rights and content

Abstract

It is well known that noradrenergic locus coeruleus neurons decrease their activity during slow wave sleep and are quiescent during paradoxical sleep. It was recently proposed that their inactivation during paradoxical sleep is due to a tonic GABAergic inhibition arising from neurons located into the dorsal paragigantocellular reticular nucleus (DPGi). However, the discharge profile of DPGi neurons across the sleep–waking cycle as well as their connections with brain areas involved in paradoxical sleep regulation remain to be described.

Here we show, for the first time in the unanesthetized rat that the DPGi contained a subtype of neurons with a tonic and sustained firing activation specifically during paradoxical sleep (PS-on neurons). Noteworthy, their firing rate increase anticipated for few seconds the beginning of the paradoxical sleep bout. By using anterograde tract-tracing, we further showed that the DPGi, in addition to locus coeruleus, directly projected to other areas containing wake-promoting neurons such as the serotonergic neurons of the dorsal raphe nucleus and hypocretinergic neurons of the posterior hypothalamus. Finally, the DPGi sent efferents to the ventrolateral part of the periaqueductal gray matter known to contain paradoxical sleep-suppressing neurons.

Taken together, our original results suggest that the PS-on neurons of the DPGi may have their major role in simultaneous inhibitory control over the wake-promoting neurons and the permissive ventrolateral part of the periaqueductal gray matter as a means of influencing vigilance states and especially PS generation.

Section snippets

The head-restrained rat method

The procedure (fixation of the head-restraining system and chronic implantation for the polygraphic recordings) has been previously described in detail (Boissard et al 2002, Gervasoni et al 1998). All experiments were conducted in agreement with the Guide for the Care and Use of Laboratory Animals (NIH Publication 80-23; authorization no. 03-505 of the French Ministry of Agriculture) and every effort was made to minimize the number of animals used and their suffering. Briefly, male

Classification of neurons by their behavior

The localization of each recorded neuron was estimated postmortem by assessing on brainstem sections the location of PSB or PHA-L deposit loci, corresponding to the area where cells were recorded. In this context, a sample of 41 neurons was recorded in the DPGi (n=9 rats, three PHA-L and six PSB injection sites) during at least one complete sleep–waking cycle (with W, SWS and PS). Neurons recorded outside the DPGi, i.e. in the vestibular nucleus or the gigantocellular reticular nucleus ventral

Discussion

We show for the first time that the DPGi contains neurons selectively activated during PS (tonic PS-on neurons). Moreover, using anterograde tract-tracing, we demonstrated that neurons of the DPGi simultaneously project to the main structures known to be involved in PS regulation, including the wake-promoting areas and the vlPAG. These original results highlight the role of the DPGi in PS regulation.

Noradrenergic neurons of the LC are silent during PS, due to a tonic GABAergic inhibition (

Conclusion

We highlighted here for the first time that the DPGi contains a population of PS-on neurons that may play a key role in the executive processes of PS generation, by inhibiting simultaneously the wake-promoting neurons and the vlPAG, two permissive systems for PS onset. Additional studies, such as the confirmation of the GABAergic phenotype of the PS-on neurons or the effects on PS of DPGi lesion, are necessary to test our hypothesis and to determine the mechanisms of activation of DPGi neurons

Acknowledgments

This work was supported by CNRS (FRE2469 and UMR5167) and Université C. Bernard Lyon I. R. Goutagny received a PhD grant from the “Région Rhône-Alpes” and the “Fondation pour la Recherche Médicale.” We thank S. Williams for his critical reading of the manuscript and R. Boissard and L. Leger for their help.

References (44)

E.E. Abrahamson et al.
The posterior hypothalamic area: chemoarchitecture and afferent connections
Brain Res
(2001)
Y. Koyama et al.
In vivo electrophysiological distinction of histochemically-identified cholinergic neurons using extracellular recording and labelling in rat laterodorsal tegmental nucleus
Neuroscience
(1998)
P.H. Luppi et al.
Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin
Neuroscience
(1995)
B.Y. Mileykovskiy et al.
Behavioral correlates of activity in identified hypocretin/orexin neurons
Neuron
(2005)
A.K. Moschovakis et al.
The microscopic anatomy and physiology of the mammalian saccadic system
Prog Neurobiol
(1996)
D. Nitz et al.
GABA release in the locus coeruleus as a function of sleep/wake state
Neuroscience
(1997)
T. Ohtake
Ascending projections from the gigantocellular reticular and dorsal paragigantocellular nuclei of the medulla oblongata in the rat: an anterograde PHA-L tracing study
Neurosci Res
(1992)
C.B. Saper et al.
The sleep switch: hypothalamic control of sleep and wakefulness
Trends Neurosci
(2001)
J.P. Sastre et al.
Importance of the ventrolateral region of the periaqueductal gray and adjacent tegmentum in the control of paradoxical sleep as studied by muscimol microinjections in the cat
Neuroscience
(1996)
M.N. Alam et al.
GABA-mediated control of hypocretin- but not melanin-concentrating hormone-immunoreactive neurones during sleep in rats
J Physiol
(2005)

E. Aserinsky et al.

Regularly occurring periods of eye motility and concomitant phenomena during sleep

Science

(1953)

G. Aston-Jones et al.

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

J Neurosci

(1981)

G. Aston-Jones et al.

The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network

Science

(1986)

R. Boissard et al.

Localization of the GABAergic and non-GABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset

Eur J Neurosci

(2003)

R. Boissard et al.

The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study

Eur J Neurosci

(2002)

M. Ennis et al.

GABA-mediated inhibition of locus coeruleus from the dorsomedial rostral medulla

J Neurosci

(1989)

P. Fort et al.

In vitro identification of the presumed sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO)

T. Gallopin et al.

Identification of sleep-promoting neurons in vitro

Nature

(2000)

D. Gervasoni et al.

Electrophysiological evidence that noradrenergic neurons of the rat locus coeruleus are tonically inhibited by GABA during sleep

Eur J Neurosci

(1998)

D. Gervasoni et al.

Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons

J Neurosci

(2000)

R. Goutagny et al.

GABAergic control of hypothalamic melanin-concentrating hormone-containing neurons across the sleep-waking cycle

Neuroreport

(2005)

J.A. Hobson et al.

Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups

Science

(1975)

Cited by (65)

Which structure generates paradoxical (REM) sleep: The brainstem, the hypothalamus, the amygdala or the cortex?
2024, Sleep Medicine Reviews
Paradoxical or Rapid eye movement (REM) sleep (PS) is a state characterized by REMs, EEG activation and muscle atonia. In this review, we discuss the contribution of brainstem, hypothalamic, amygdalar and cortical structures in PS genesis. We propose that muscle atonia during PS is due to activation of glutamatergic neurons localized in the pontine sublaterodorsal tegmental nucleus (SLD) projecting to glycinergic/GABAergic pre-motoneurons localized in the ventro-medial medulla (vmM). The SLD PS-on neurons are inactivated during wakefulness and slow-wave sleep by PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray (vPAG) and the adjacent deep mesencephalic reticular nucleus. Melanin concentrating hormone (MCH) and GABAergic PS-on neurons localized in the posterior hypothalamus would inhibit these PS-off neurons to initiate the state. Finally, the activation of a few limbic cortical structures during PS by the claustrum and the supramammillary nucleus as well as that of the basolateral amygdala would also contribute to PS expression. Accumulating evidence indicates that the activation of these limbic structures plays a role in memory consolidation and would communicate to the PS-generating structures the need for PS to process memory. In summary, PS generation is controlled by structures distributed from the cortex to the medullary level of the brain.
REM sleep
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
The key brain structure for generating REM sleep is the pons and adjacent portions of the midbrain. These areas and the hypothalamus contain cells that are maximally active in REM sleep, called REM-on cells, and cells that are minimally active in REM sleep, called REM-off cells. Subgroups of REM-on cells use the transmitter gamma-aminobutyric acid (GABA), acetylcholine, glutamate, or glycine. Subgroups of REM-off cells use the transmitter norepinephrine, epinephrine, serotonin, histamine and GABA. Destruction of large regions within the midbrain and pons can prevent the occurrence of REM sleep. Damage to portions of the brainstem can cause abnormalities in certain aspects of REM sleep. Hypocretin neurons have an important role in the regulation of REM sleep and other sleep–wake phenomena.
Regulation of REM sleep by inhibitory neurons in the dorsomedial medulla
2022, Current Biology
Citation Excerpt :
Pharmacological inhibition of the LC suppressed the extension of REMs episodes elicited by electrical stimulation of the PH, suggesting that this projection contributes to REMs maintenance.16,38 As previous studies also demonstrated the importance of the DPGi in regulating REMs,13,15,19 it would be interesting to similarly test the specific role of DPGi inhibitory neurons using projection targets preferentially innervated by these neurons or by identifying specific molecular markers for these neurons.39,40 Stimulation of dmM GAD2 neurons strongly promoted θ oscillations during NREMs, indicating that these neurons directly or indirectly interact with circuits involved in generating hippocampal θ oscillations.
The two major stages of mammalian sleep—rapid eye movement sleep (REMs) and non-REM sleep (NREMs)—are characterized by distinct brain rhythms ranging from millisecond to minute-long (infraslow) oscillations. The mechanisms controlling transitions between sleep stages and how they are synchronized with infraslow rhythms remain poorly understood. Using opto- and chemogenetic manipulation in mice, we show that GABAergic neurons in the dorsomedial medulla (dmM) promote the initiation and maintenance of REMs, in part through their projections to the dorsal and median raphe nuclei. Fiber photometry revealed that their activity is strongly increased during REMs and fluctuates during NREMs in close synchrony with infraslow oscillations in the sleep spindle band of the electroencephalogram. The phase of this rhythm influenced the latency and probability with which dmM activation induced REMs. Thus, dmM inhibitory neurons strongly promote REMs, and their slow activity fluctuations may coordinate the timing of REMs episodes with infraslow brain rhythms.
Physiology of Sleep From Infancy to Old Age
2021, Encyclopedia of Respiratory Medicine, Second Edition
In this chapter, we summarize the neurophysiology of sleep and discuss the impact of sleep on the respiratory, cardiovascular and endocrine/metabolic systems, highlighting the differences across the age spectrum. The aim of this chapter is to provide an up to date review of the normal physiology, enabling a better understanding of the pathophysiology behind the various types of sleep disordered breathing detailed in the subsequent chapters. It emphasizes that sleep, in particular REM sleep, is a potential state of vulnerability for the respiratory system, due to its effects on the control of ventilation and the upper airway and respiratory musculature.
Neurochemistry and pharmacology of sleep
2019, The Behavioral, Molecular, Pharmacological, and Clinical Basis of the Sleep-Wake Cycle
In the last several decades, there has been a substantial increase in the knowledge of the anatomy, electrophysiology, and neurochemistry of the neuronal networks that generate wakefulness, nonrapid eye movement, and rapid eye movement sleep. These neuronal networks interact to generate the sleep–wakefulness cycle. In addition, they are modulated by the circadian rhythm pacemaker that is located in the suprachiasmatic nucleus, determining that all diurnal animals (including humans) present their main waking period during daytime. Finally, several substances such as adenosine, melatonin, cytokines, nitric oxide, and endocannabinoids modulate this cycle.
The knowledge of the neurochemical basis of these systems is critical to understanding the physiology of the sleep–wakefulness cycle, the pathophysiology of diseases that affect sleep, and to generate pharmacological approaches to treat them. In this chapter, we reviewed the crucial concepts of the neurochemical foundation of sleep and wakefulness, and the neurobiological strategies behind the main pharmacological approaches to treat paradigmatic sleep disturbances.
Neuroanatomical and Neurochemical Systems Involved in Paradoxical Sleep (PS) Generation
2019, Handbook of Behavioral Neuroscience
Rapid eye movement sleep (REM or paradoxical sleep (PS)) is a state of sleep characterized by REMs, EEG activation, and muscle atony. In the present review, we present the most recent results on the neuronal network responsible for PS generation. We propose that muscle atony during PS is due to the activation of PS-on glutamatergic neurons localized in the caudal pontine sublaterodorsal tegmental nucleus (SLD) and the glycinergic/GABAergic premotoneurons localized in the medullary ventral reticular nuclei. The SLD neurons are inactivated during waking and slow-wave sleep by PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray and the adjacent deep mesencephalic reticular nucleus. PS onset and maintenance is due to the inhibition of these PS-off neurons by PS-on GABAergic neurons localized in the posterior hypothalamus, the ventrolateral periaqueductal gray, and the lateral and dorsal paragigantocellular reticular nuclei.

View all citing articles on Scopus

View full text

Systems neuroscienceRole of the dorsal paragigantocellular reticular nucleus in paradoxical (rapid eye movement) sleep generation: a combined electrophysiological and anatomical study in the rat

Abstract

Section snippets

The head-restrained rat method

Classification of neurons by their behavior

Discussion

Conclusion

Acknowledgments

Brain Res

Neuroscience

Neuroscience

Neuron

Prog Neurobiol

Neuroscience

Neurosci Res

Trends Neurosci

Neuroscience

GABA-mediated control of hypocretin- but not melanin-concentrating hormone-immunoreactive neurones during sleep in rats

J Physiol

Regularly occurring periods of eye motility and concomitant phenomena during sleep

Science

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

J Neurosci

The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network

Science

Localization of the GABAergic and non-GABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset

Eur J Neurosci

The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study

Eur J Neurosci

GABA-mediated inhibition of locus coeruleus from the dorsomedial rostral medulla

J Neurosci

In vitro identification of the presumed sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO)

Identification of sleep-promoting neurons in vitro

Nature

Electrophysiological evidence that noradrenergic neurons of the rat locus coeruleus are tonically inhibited by GABA during sleep

Eur J Neurosci

Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons

J Neurosci

GABAergic control of hypothalamic melanin-concentrating hormone-containing neurons across the sleep-waking cycle

Neuroreport

Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups

Science

Systems neuroscience
Role of the dorsal paragigantocellular reticular nucleus in paradoxical (rapid eye movement) sleep generation: a combined electrophysiological and anatomical study in the rat