Cytomorphometric changes in the dorsal raphe neurons after rapid eye movement sleep deprivation are mediated by noradrenalin in rats

<p>Abstract</p> <p>Objectives</p> <p>This study was carried out to investigate the effect of rapid eye movement sleep (REMS) deprivation (REMSD) on the cytomorphology of the dorsal raphe (DR) neurons and to evaluate the possible role of REMSD-induced increased noradrenalin (NA) in mediating such effects.</p> <p>Methods</p> <p>Rats were REMS deprived by the flowerpot method; free moving normal home cage rats, large platform and post REMS-deprived recovered rats were used as controls. Further, to evaluate if the effects were induced by NA, separate sets of experimental rats were treated (i.p.) with α1-adrenoceptor antagonist, prazosin (PRZ). Histomorphometric analysis of DR neurons in stained brain sections were performed in experimental and control rats; neurons in inferior colliculus (IC) served as anatomical control.</p> <p>Results</p> <p>The mean size of DR neurons was larger in REMSD group compared to controls, whereas, neurons in the recovered group of rats did not significantly differ than those in the control animals. Further, mean cell size in the post-REMSD PRZ-treated animals was comparable to those in the control groups. IC neurons were not affected by REMSD.</p> <p>Conclusions</p> <p>REMS loss has been reported to impair several physiological, behavioral and cellular processes. The mean size of the DR neurons was larger in the REMS deprived group of rats than those in the control groups; however, in the REMS deprived and prazosin treated rats the size was comparable to the normal rats. These results showed that REMSD induced increase in DR neuronal size was mediated by NA acting on α1-adrenoceptor. The findings suggest that the sizes of DR neurons are sensitive to REMSD, which if not compensated could lead to neurodegeneration and associated disorders including memory loss and Alzheimer's disease.</p

Role of norepinephrine in the regulation of rapid eye movement sleep

Sleep and wakefulness are instinctive behaviours that are present across the animal species. Rapid eye movement (REM) sleep is a unique biological phenomenon expressed during sleep. It evolved about 300 million years ago and is noticed in the more evolved animal species. Although it has been objectively identified in its present characteristic form about half a century ago, the mechanics of how REM is generated, and what happens upon its loss are not known. Nevertheless, extensive research has shown that norepinephrine plays a crucial role in its regulation. The present knowledge that has been reviewed in this manuscript suggests that neurons in the brain stem are responsible for controlling this state and presence of excess norepinephrine in the brain does not allow its generation. Furthermore, REM sleep loss increases levels of norepinephrine in the brain that affects several factors including an increase in Na-K ATPase activity. It has been argued that such increased norepinephrine is ultimately responsible for REM sleep deprivation, associated disturbances in at least some of the physiological conditions leading to alteration in behavioural expression and settling into pathological conditions

REM sleep loss increases brain excitability: role of noradrenalin and its mechanism of action

Ever since the discovery of rapid eye movement sleep (REMS), studies have been undertaken to understand its necessity, function and mechanism of action on normal physiological processes as well as in pathological conditions. In this review, first, we briefly surveyed the literature which led us to hypothesise REMS maintains brain excitability. Thereafter, we present evidence from in vivo and in vitro studies tracing behavioural to cellular to molecular pathways showing REMS deprivation (REMSD) increases noradrenalin level in the brain, which stimulates neuronal Na-K ATPase, the key factor for maintaining neuronal excitability, the fundamental property of a neuron for executing brain functions; we also show for the first time the role of glia in maintaining ionic homeostasis in the brain. As REMSD exerts a global effect on most of the physiological processes regulated by the brain, we propose that REMS possibly serves a housekeeping function in the brain. Finally, subject to confirmation from clinical studies, based on the results reviewed here, it is being proposed that the subjects suffering from REMS loss may be effectively treated by reducing either noradrenalin level or Na-K ATPase activity in the brain

Influence of hypnogenic brain areas on wakefulness- and rapid-eye-movement sleep-related neurons in the brainstem of freely moving Cats

Rapid-eye-movement (REM) sleep is normally preceded by non-REM sleep; however, every non-REM sleep episode is not followed by REM sleep. It has been proposed that, for the regulation of REM sleep, the brain areas modulating waking and non-REM sleep are likely to communicate with neurons promoting REM sleep. The former has been reported earlier, and in this study the latter has been investigated. Under surgical anaesthesia, cats were prepared for electrophysiological recording of sleep-wakefulness and electrical stimulation of caudal brainstem as well as preopticoanterior hypothalamic hypnogenic areas. Insulated microwires of 25-32 μm were used to record 52 single neuronal activities from the brainstem along with bipolar electroencephalogram, electromyogram, electrooculogram, and pontogeniculooccipital waves in freely moving, normally behaving cats. The neurons were classified into five groups based on changes in firing rates associated with different sleep-waking states compared with quiet wakefulness. Thereafter, the responses of these neurons to 1-Hz stimulation of the two non-REM sleep-promoting areas were studied. At the end of experiment, the stimulating and recording sites were histologically identified. It was observed that, among the affected neurons, the caudal brainstem non-REM sleep-promoting area excited more REM-on neurons, whereas the preopticoanterior hypothalamus hypnogenic area inhibited more awake-active neurons. Thus, the results suggest that, at the single neuronal level, the caudal brainstem non-REM sleep-modulating area, rather than the preopticoanterior hypothalamic hypnogenic area in the brain, plays a modulatory role in triggering REM sleep initiation at a certain depth of sleep

In silico modeling of 1A-adrenoceptor: interaction of its normal and mutated active sites with noradrenaline as well as its agonist and antagonist

Noradrenaline, like most other neurotransmitters, acts through various adrenoceptor subtypes. The structure and active site of adrenoceptors for the binding of noradrenaline were unknown, however, such information are crucial for understanding the molecular mechanism of action of neurotransmitters, including noradrenaline, in health and disease as well as for drug designing. In this in silico study, we modeled the α1A-adrenoceptor; a G protein coupled receptor and defined its active site. Further, molecular docking and interaction of noradrenaline and its agonist as well as antagonist with the so defined active site of the receptor was studied before and after in silico site directed mutation of several amino acid residues forming the active site. Our results indicate that the ARG166 is the most crucial residue for binding of noradrenaline and methoxamine to α1A-adrenoceptor and ILE178 is the most important residue for binding of prazosin to it. Thus, the observations provide new insights into the structure function relationship of α 1A-adrenoceptor. A significant finding of this study is that the same residue of the active site may not be necessary for binding of a receptor with its natural ligand and its pharmacologically active known agonist and antagonist

Role of wake inducing brain stem area on rapid eye movement sleep regulation in freely moving Cats

Some of the characteristic symptoms associated with rapid eye movement (REM) sleep are opposite to, while some apparently resemble, those of wakefulness. Therefore, it was hypothesised that the neurons present in the wakefulness inducing area(s) in the brain are likely to communicate with the REM sleep related neurons. Brain stem neurons were classified based on their firing rates in relation to electrophysiological correlates associated with spontaneous sleep and wakefulness recorded from freely moving, normally behaving cats. Thereafter, the responses of those classified neurons to stimulation of brain stem reticular wakefulness inducing area were studied. Results from 63 neurons showed that the wake inducing area affected 62% of the neurons. Fifty-eight percent of the neurons which increased firing during wakefulness, including the REM-OFF neurons, were excited, while 70% of the neurons which decreased firing during wakefulness, including the REM-ON neurons, were inhibited. These observations support our hypothesis and, along with their physiological significance, are discussed

Adrenergic and cholinergic modulation of spontaneous and brain stem reticular formation stimulation induced desynchronization of the cortical EEG in freely moving behaving Cats

The brain stem reticular formation is responsible for EEG desynchronization.It bears,among others,adrenergic and cholinergic neurons.Neurons of this area project directly or indirectly to the cortex.Isolated studies have shown that both the adrenergic as well as the cholinergic inputs may induce and modulate cortical EEG desynchronization,however,their relative role was unknown.In this study,the differential influence of adrenergic and cholinergic inputs in cortical EEG desynchronization during spontaneous and brain stem reticular formation stimulation induced wakefulness was investigated in freely moving chronically prepared cats.The cats were chronically prepared for standard electrophysiologcial sleep- wakefulness recording and also with stimulating electrode in the midbrain reticular formation. After recovery,baseline recording of sleep-wakefulness was done.Thereafter,either adrenergic . 1-adrenoceptor antagonist,prazosin (1 mg/Kg),. 2-adrenoceptor agonist, clonidine (25 μg/Kg),. 2-adrenoceptor antagonist,yohimbine (1 mg/Kg),. -adrenoceptor antagonist,propranolol (10 mg/kg)or,cholinergic muscarinic receptor antagonist, scopolamine (0.5 mg/Kg)was injected i.p.and the effect on spontaneous as well as midbrain reticular formation stimulation induced EEG desynchronization investigated.It was found that desynchronization of the EEG was modulated significantly by both,the cholinergic as well as by the adrenergic systems.The cholinergic action was mediated through the muscarinic receptor while the adrenergic through the . 1-adrenoceptor.The effect of the former was relatively long lasting and it reduced the high frequency waves while the latter was more effective in increasing the rhythmicity of the EEG waves in the power spectrum record.These differences possibly have relevance in EEG desynchronization during wakefulness and REM sleep

GABA in locus coeruleus regulates spontaneous rapid eye movement sleep by acting on GABA<SUB>A</SUB> receptors in freely moving Rats

The aminergic neurons in the locus coeruleus are known to cease firing during rapid eye movement sleep. Since electrical stimulation of locus coeruleus reduced, while carbachol stimulation increased rapid eye movement sleep and γ-aminobutyric acid (GABA) neurons as well as terminals are present in the locus coeruleus, we hypothesized that GABA may be involved for cessation of locus coeruleus neuronal firing during rapid eye movement sleep. Under surgical anaesthesia male Wistar rats (250-300 g) with bilateral guide cannulae targeting locus coeruleus were prepared for chronic sleep-wakefulness recording. Electroencephalogram (EEG), electrooculogram (EOG), electromyogram (EMG) were recorded in normal, after 250 nl saline and after picrotoxin (250 ng in 250 nl) injection bilaterally into the locus coeruleus. The results showed that mean duration per episode of rapid eye movement sleep was significantly reduced, although its frequency of generation/h was not significantly affected. This study suggests that GABA in locus coeruleus is involved in tonic regulation of rapid eye movement sleep and the action is mediated through GABA<SUB>A</SUB> receptor

Rapid eye movement sleep and significance of its deprivation studies - a review

Rapid eye movement (REM) sleep is a unique phenomenon within sleep-wakefulness cycle. It is associated with increased activity in certain group of neurons and decreased activity in certain other group of neurons and dreaming. It is likely to have evolved about 140 million years ago. Although mention of this stage can be traced back to as early as 11 century BC in the Hindu Vedic literature, the Upanishads, it has been defined in its present form in the mid-twentieth century. So far, neurobiology of its genesis, physiology and functional significance are not known satisfactorily and mostly remains hypothetical. Nevertheless, more and more studies have increasingly convinced us to accept that it is an important physiological phenomenon which cannot be ignored as a vestigial phenomenon. Although there are articles where different aspects of REM sleep have been dealt with, a review where the knowledge gathered by REM sleep deprivation studies to un-derstand its significance is lacking. There is a need for such a review because a major portion of the knowledge about various aspects of REM sleep, specially its functional significance, has been acquired mostly from the REM sleep deprivation studies. Hence, in this review the knowledge gathered by REM sleep deprivation studies have been cola-ted along with their importance so that it may be useful and referred to for information as well as while designing future studies

Uncompetitive stimulation of rat brain Na-K ATPase activity by rapid eye movement sleep deprivation

Rapid eye movement sleep deprivation is associated with an increase in Na-K ATPase activity. In order to understand the possible biochemical mechanism of this increase, the kinetics of Na-K ATPase was studied. Although the enzyme activity increased after the deprivation, the catalytic efficiency of the enzyme remained unaltered. The rapid eye movement sleep deprivation increased both the V<SUB>max</SUB> and the K<SUB>m</SUB> suggesting an uncompetitive stimulation of the enzyme. While increase in norepinephrine resulted in an increased V<SUB>max</SUB>, that of calcium increased the K<SUB>m</SUB>. Since an increase in norepinephrine has been suggested after deprivation, the increased V<SUB>max</SUB> is attributed to increased norepinephrine level following deprivation. However, since rapid eye movement sleep deprivation is reported to be associated with a decrease in calcium levels, the increase in K<SUB>m</SUB> following deprivation may be attributed to changes in factor(s) other than calcium