Activation of inactivation process initiates rapid eye movement sleep

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Abstract

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.

Highlights

► Wake and NREMS-related neurons are reciprocally connected; they exert opposite influence on REM-OFF and REM-ON neurons. ► During waking and NREMS, LC-REM-OFF neurons are active, which inhibit REM-ON neurons and prevent appearance of REMS. ► GABA acting pre-synaptically on REM-OFF terminals stops NA release, resulting dis-inhibition/activation of REM-ON neurons. ► Active REM-ON neurons trigger GABA-induced cessation of REM-OFF neurons initiating REMS—A neural network has been modelled. ► Model satisfactorily explains mechanism of simultaneous cessation of REM-OFF and activation of REM-ON neurons during REMS.

Introduction

Sleep and waking are expressed in animals relatively higher in evolution. The closest analogous states in animals lower in evolution are rest and activity. By and large, although animals have species-specific sleeping posture(s), experimental studies towards our understanding on the brain regulation of sleep could systematically progress only after these states could be objectively defined and quantified by the presence or absence of associated electrophysiological signals recorded from the brain, the electroencephalogram (EEG), eye movements, electrooculogram (EOG) and muscle tone, electromyogram (EMG). These electrophysiological recordings have finally helped us to set aside the earlier belief that sleep is a homogenous state and paved the way towards our present understanding that sleep is an active, non-homogenous state. Based on such objective electrophysiological criteria sleep has been broadly classified into rapid eye movement sleep (REMS) and non-REMS (NREMS); the REMS has also been referred to as active sleep, paradoxical sleep, desynchronized sleep or dream state of sleep.

Based on the electrophysiological criteria, although REMS has been objectively characterized since 1953 (Aserinsky and Kleitman, 1953), behaviourally, dream state of sleep has been known to humans since ancient times. Different states of consciousness and sleep including those of dream stage of sleep are mentioned in the oldest philosophical scripts associated to the original inhabitants of the Indus valley civilization of the Indian peninsula, the Vedic and the Upanishadic literatures written between 11th and 16th century BC (Datta and Maclean, 2007), in Chinese and Greek literatures (Barbera, 2008, Shapiro et al., 2009) as well as in other relatively lesser ancient documents, stories, paintings, etc. (Shapiro et al., 2009). However, very few attempts have been made to offer neuro-physio-anatomo-pharmacological correlation of those older philosophical concepts in light of the present knowledge especially based on experimentally derived neuro-biological data (Mallick and Mukhopadhyay, 2011).

Our understanding on the neurobiological mechanism of REMS regulation also has undergone significant revisions and modifications. In this review we will focus on the control and responses of locus coeruleus (LC) noradrenalin (NA)-ergic neurons for REMS-regulation. In brief, it will be shown that the NA-ergic neurons in the LC normally continue firing during all states except REMS, and they continue firing upon REMS deprivation (REMSD). Any factor, that would keep these neurons active or essentially would not allow them to cease activity, would prevent appearance of REMS and result in associated increased level of NA. Furthermore, this elevated level of NA is a primary factor responsible for underlying cellular changes inducing expression of REMS loss-associated signs and symptoms and patho-physio-behavioural changes.

Section snippets

REMS—an overview

Based on classical characteristic electrophysiological parameters until now REMS in some form has been detected at least in birds and mammals (www.bu.edu/phylogeny). Since EEG desynchronization during sleep is one of the most important characteristic features for objective identification of REMS, it can be observed only in species higher in evolution with a phylogenetically evolved and ontogenetically developed brain. Therefore, based on the existing criteria our definition will be limited and

Early studies to localize brain region responsible for REMS regulation

During sleep simultaneous presence of desynchronized EEG, rapid eye movements and muscle atonia characterize REMS. By the time REMS was formally and objectively classified (Aserinsky and Kleitman, 1953), it was already known that brain stem neurons modulate the EEG, EOG and EMG, the characteristic features which define REMS (Lindsley et al., 1949, Lindsley et al., 1950, Moruzzi, 1972, Moruzzi and Magoun, 1949). Therefore, it was reasonable to explore the brain stem to localize site(s)

LC-NA-ergic neurons and REMS

According to Maeda (2000) the locus coeruleus in the dorsolateral tegmentum of the pons has been so named (Wenzel and Wenzel, 1812) for its dark bluish colour in man and primates. It is unique in neurochemical anatomy because most of NA-ergic neurons in the brain are concentrated at this site and they supply NA throughout the brain. In cats, depending on size of the neurons and their organization LC has been classified into LC-principal, peri-LC and sub-coeruleus (Sakai et al., 1981). In rats

Neurochemical modulation of LC neurons for the regulation of REMS

The effects of microinjections of agonists and antagonists of various neurotransmitter receptors into the LC and the surrounding area on REMS have been studied independently by various groups (Table 2). ACh-ergic perfusion of the LC neurons has been reported to decrease REMS (Masserano and King, 1982a). The same authors reported that infusion of NA into the LC of cats decreased, while phentolamine, an adrenergic antagonist, increased REMS (Masserano and King, 1982b). The NA level in different

A working model for REMS generation

The knowledge gathered so far has been collated and integrated to synthesize a model (detailed below) explaining the neural mechanism of REMS regulation. The highlight is that GABA acts postsynaptically at the LC, while presynaptically at the PPT to trigger REMS.

Physiological validity of the neuro-chemo-anatomical working model described above

We have discussed above isolated independent studies showing inputs from known NREMS- and wakefulness-inducing brain areas on LC-NA-ergic REM-OFF and ACh-ergic REM-ON neurons, interactions among those REMS-related neurons and role of GABA-ergic interneurons as well as presynaptic inputs on neural regulation of REMS. Based on these connections we have constructed a neuro-chemo-anatomical working model (Fig. 5). However, since most of those studies were conducted independently and in isolation,

Summary

Interaction between REM-ON and REM-OFF neurons controls REMS. In general, the neurons in the waking areas stimulate the REM-OFF neurons and inhibit the REM-ON neurons, whereas the neurons in the sleep inducing areas have opposite influences on those neurons. The activities of those REM-ON and REM-OFF neurons depend on relative levels of various neurotransmitters on them. Activation of GABA-ergic input acting presynaptically on inhibitory NA terminals of REM-OFF neurons projecting on REM-ON

Acknowledgements

We thank Prof. Adrian R. Morrison, Pennsylvania and Dr. Noor Alam, UCLA for their editorial suggestions on a previous version of this manuscript. Research funding from Indian agencies, viz. Council of Scientific and Industrial Research; Department of Biotechnology; Department of Science and Technology; Indian Council of Medical Research; J. C. Bose fellowship and University Grants Commission (Capacity Build Up, UPOE and Network programme) to BNM are acknowledged.

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