Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion.

Patients with Parkinson's disease (PD) display significant sleep disturbances and daytime sleepiness. Dopaminergic treatment dramatically improves PD motor symptoms, but its action on sleep remains controversial, suggesting a causal role of nondopaminergic lesions in these symptoms. Because the pedunculopontine nucleus (PPN) regulates sleep and arousal, and in view of the loss of its cholinergic neurons in PD, the PPN could be involved in these sleep disorders. The aims of this study were as follows: (1) to characterize sleep disorders in a monkey model of PD; (2) to investigate whether l-dopa treatment alleviates sleep disorders; and (3) to determine whether a cholinergic PPN lesion would add specific sleep alterations. To this end, long-term continuous electroencephalographic monitoring of vigilance states was performed in macaques, using an implanted miniaturized telemetry device. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment induced sleep disorders that comprised sleep episodes during daytime and sleep fragmentation and a reduction of sleep efficiency at nighttime. It also induced a reduction in time spent in rapid eye movement (REM) sleep and slow-wave sleep and an increase in muscle tone during REM and non-REM sleep episodes and in the number of awakenings and movements. l-Dopa treatment resulted in a partial but significant improvement of almost all sleep parameters. PPN lesion induced a transient decrease in REM sleep and in slow-wave sleep followed by a slight improvement of sleep quality. Our data demonstrate the efficacy of l-dopa treatment in improving sleep disorders in parkinsonian monkeys, and that adding a cholinergic PPN lesion improves sleep quality after transient sleep impairment.

Genetic association between helpless trait and depression-related phenotypes: evidence from crossbreeding studies with H/Rouen and NH/Rouen mice.

Genetic factors are believed to be involved in the aetiology of unipolar depressive disorders. We have previously described a model built up by selective breeding of mice with different responses in the tail suspension test, a screening test for potential antidepressants. In this model, helpless H/Rouen mice are essentially immobile in this test, as well as in the Porsolt forced-swim test, whereas non-helpless NH/Rouen mice show the opposite behaviour, i.e. very low immobility. However, it is unclear whether or not the other phenotypic differences (forced swim test, locomotor activity, sucrose test, sleep patterns, effect of fluoxetine) observed between H/Rouen and the NH/Rouen mice may be attributed to a genetic drift phenomenon during the selection step, rather than being related to the trait of selection. In this study we used reciprocal crossbreeding between H/Rouen and NH/Rouen mice and obtained a segregating F2 population in order to determine whether phenotypic differences between the two lines co-segregate with the trait of selection. In the segregating F2 population, we found significant and strong genetic correlations between helplessness in the tail suspension test and some phenotypical features associated with depressive disorders such as 'alterations of sleep patterns', behavioural response to fluoxetine, immobility duration in the forced swim test, and anhedonia. Our results converge with clinical observations in depressed humans. These results strengthen the validity of the H/Rouen mouse as a model of depression, notably for preclinical studies with antidepressants. In addition, this model should open the way to identifying genes related to depression-like behaviours.

[Sleep and wakefulness regulation: molecular players]. / Régulation de la veille et du sommeil: les acteurs moléculaires.

By combining brain section/lesion studies and sleep analysis, neurophysiologists have identified the brain areas responsible for regulating sleep and wakefulness during the first half of the 20th century. Identification of the phenotypic nature of the neurons underlying the regulation of vigilance, as well as their anatomical and functional connections led to a theoretical model based on mutual inhibitory interactions between sleep-on neurons (namely GABAergic neurons of the hypothalamic preoptic region) and wake-on neurons (mainly monoaminergic and cholinergic neurons). In addition to the corresponding neurotransmitters (serotonin, acetylcholine and GABA), other neuroactive molecules that play key roles in sleep and wakefulness regulation have recently been discovered, leading to an updated model. Hypocretin, also known as orexin, is a key neuropeptide involved in the sleep disorder narcolepsy. Extensive characterization of the respective roles of these neurotransmitters has led to the identification of novel therapeutic targets for the treatment of sleep disorders. For example, blockade of hypocretin receptors has hypnotic effects.

Altered sleep homeostasis after restraint stress in 5-HTT knock-out male mice: a role for hypocretins.

Restraint stress produces changes in the sleep pattern that are mainly characterized by a delayed increase in rapid eye movement sleep (REMS) amounts. Because the serotonin (5-HT) and the hypocretin (hcrt) systems that regulate REMS are interconnected, we used mutant mice deficient in the 5-HT transporter (5-HTT(-/-)) to examine the role of 5-HT and hcrt neurotransmissions in the sleep response to stress. In contrast to wild-type mice, restraint stress did not induce a delayed increase in REMS amounts in 5-HTT(-/-) mice, indicating impaired sleep homeostasis in mutants. However, pharmacological blockade of the hcrt type 1 receptor (hcrt-R1) before restraint stress restored the REMS increase in 5-HTT(-/-) mice. In line with this finding, 5-HTT(-/-) mutants displayed after restraint stress higher long-lasting activation of hypothalamic preprohcrt neurons than wild-type mice and elevated levels of the hcrt-1 peptide and the hcrt-R1 mRNA in the anterior raphe area. Thus, hypocretinergic neurotransmission was enhanced by stress in 5-HTT(-/-) mice. Furthermore, in 5-HTT(-/-) but not wild-type mice, hypothalamic levels of the 5-HT metabolite 5-hydroxyindole acetic acid significantly increased after restraint stress, indicating a marked enhancement of serotonergic neurotransmission in mutants. Altogether, our data show that increased serotonergic -and in turn hypocretinergic- neurotransmissions exert an inhibitory influence on stress-induced delayed REMS. We propose that the direct interactions between hcrt neurons in the hypothalamus and 5-HT neurons in the anterior raphe nuclei account, at least in part, for the adaptive sleep-wakefulness regulations triggered by acute stress.

Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior.

Dysfunction of the serotonin system is implicated in sleep and emotional disorders. To test whether these impairments could arise during development, we studied the impact of early-life, transient versus genetic, permanent alterations of serotonin reuptake on sleep-wakefulness patterns, depression-related behavior, and associated physiological features. Here, we show that female mice treated neonatally with a highly selective serotonin reuptake inhibitor, escitalopram, exhibited signs of depression in the form of sleep anomalies, anhedonia, increased helplessness reversed by chronic antidepressant treatment, enhanced response to acute stress, and increased serotoninergic autoinhibitory feedback. This syndrome was not reproduced by treatment in naive adults but resembled the phenotype of mutant mice lacking the serotonin transporter, except that these exhibited decreased serotonin autoreceptor sensitivity and additional anxiety-like behavior. Thus, alteration of serotonin reuptake during development, whether induced by external or genetic factors, causes a depressive syndrome lasting into adulthood. Such early-life impairments might predispose individuals to sleep and/or mood disorders.

Sleep-stabilizing effects of E-6199, compared to zopiclone, zolpidem and THIP in mice.

UNLABELLED: Gamma aminobutyric acid (GABA)A receptor modulators constitute the majority of clinically used sedative-hypnotics. These compounds have the capacity to initiate and maintain sleep, but decrease REM sleep and delta activity within NREM sleep. In order to avoid such sleep adverse effects, the development of novel compounds remains of interest. STUDY OBJECTIVES: The present study aimed at characterizing the acute effects of a novel putative hypnotic compound, E-6199, compared to zopiclone, zolpidem, and THIP on sleep-wakefulness patterns in mice. We also investigated whether repeated administration (daily injection during 10 days) of E-6199 was associated with tolerance and sleep disturbances at cessation of treatment. MEASUREMENTS AND RESULTS: Polygraphic recordings were performed during 8 h after acute treatment with the various compounds. Under such conditions, E-6199 (5-20 mg/kg i.p.), zopiclone and zolpidem (2-10 mg/kg i.p.), but not THIP (2-10 mg/kg i.p.), exerted a marked sleep-promoting effect. Furthermore, E-6199 specifically increased the duration of NREM and markedly improved sleep continuity by lengthening NREM sleep episodes and reducing short awakenings and microarousal frequency. It also intensified NREM sleep by enhancing the slow wave activity within NREM at wake-NREM transitions. These effects were sustained and became even larger during chronic administration. Finally, abrupt E-6199 withdrawal did not elicit negative sleep effects. CONCLUSIONS: Our findings demonstrate that E-6199 may be an effective hypnotic compound that promotes and improves NREMS, without producing EEG side effects, tolerance or withdrawal phenomena, when administered under chronic conditions.

Neonatal sleep, a genetically-driven rehearsal before the show: an endless encounter with Michel Jouvet.

In this short review, I would like to share some personal memories about the insights and achievements of Michel Jouvet in the field of sleep ontogeny. The first time I met Michel Jouvet was in 1972 when he accepted to chair my thesis on sleep, the research work being preformed in Howard Roffwarg's lab in New York. From then on we had many discussions together about the mechanisms and nature of neonatal Paradoxical Sleep, notably its characteristic muscular "twitches". The idea emerged of a genetically programmed pattern of motor activation responsible for this state of "seismic" sleep. Such a pattern would underlie, for example, the facial mimics displayed during sleep in early life, whose function would be to "pre-practice" a specific behavior. Later on, in the 1980's Michel Jouvet had the masterful insight to extend this role of Paradoxical Sleep to the theory of genetic programming for maintaining psychological individualism. Michel Jouvet's scientific curiosity and generosity led to his exceptional accomplishments, and he will remain as an immense figure in the culture of sleep science.

The GABAergic Gudden's dorsal tegmental nucleus: A new relay for serotonergic regulation of sleep-wake behavior in the mouse.

Serotonin (5-HT) neurons are involved in wake promotion and exert a strong inhibitory influence on rapid eye movement (REM) sleep. Such effects have been ascribed, at least in part to the action of 5-HT at post-synaptic 5-HT1A receptors (5-HT1AR) in the brainstem, a major wake/REM sleep regulatory center. However, the neuroanatomical substrate through which 5-HT1AR influence sleep remains elusive. We therefore investigated whether a brainstem structure containing a high density of 5-HT1AR mRNA, the GABAergic Gudden's dorsal tegmental nucleus (DTg), may contribute to 5-HT-mediated regulatory mechanisms of sleep-wake stages. We first found that bilateral lesions of the DTg promote wake at the expense of sleep. In addition, using local microinjections into the DTg in freely moving mice, we showed that local activation of 5-HT1AR by the prototypical agonist 8-OH-DPAT enhances wake and reduces deeply REM sleep duration. The specific involvement of 5-HT1AR in the latter effects was further demonstrated by ex vivo extracellular recordings showing that the selective 5-HT1AR antagonist WAY 100635 prevented DTg neuron inhibition by 8-OH-DPAT. We next found that GABAergic neurons of the ventral DTg exclusively targets glutamatergic neurons of the lateral mammillary nucleus (LM) in the posterior hypothalamus by means of anterograde and retrograde tracing techniques using cre driver mouse lines and a modified rabies virus. Altogether, our findings strongly support the idea that 5-HT-driven enhancement of wake results from 5-HT1AR-mediated inhibition of DTg GABAergic neurons that would in turn disinhibit glutamatergic neurons in the mammillary bodies. We therefore propose a Raphe→DTg→LM pathway as a novel regulatory circuit underlying 5-HT modulation of arousal.

Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter.

In serotonin transporter knock-out (5-HTT-/-) mice, extracellular serotonin (5-HT) levels are markedly elevated in the brain, and rapid eye movement sleep (REMS) is enhanced compared with wild-type mice. We hypothesized that such sleep impairment at adulthood results from excessive serotonergic tone during early life. Thus, we assessed whether neonatal treatment with drugs capable of limiting the impact of 5-HT on the brain could normalize sleep patterns in 5-HTT-/- mutants. We found that treatments initiated at postnatal day 5 and continued for 2 weeks with the 5-HT synthesis inhibitor para-chlorophenylalanine, or for 4 weeks with the 5-HT(1A) receptor (5-HT(1A)R) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635), induced total or partial recovery of REMS, respectively, in 5-HTT-/- mutants. Early life treatment with WAY 100635 also reversed the depression-like behavior otherwise observed in these mutants. Possible adaptive changes in 5-HT(1A)R after neonatal treatment with WAY 100635 were investigated by measuring 5-HT(1A) binding sites and 5-HT(1A) mRNA in various REMS- and/or depression-related brain areas, as well as 5-HT(1A)R-mediated hypothermia and inhibition of neuronal firing in the dorsal raphe nucleus. None of these characteristics were modified in parallel with REMS recovery, suggesting that 5-HT(1A)Rs involved in wild-type phenotype rescue in 5-HTT-/- mutants are located in other brain areas or in 5-HT(1A)R-unrelated circuits where they could be transiently expressed during development. The reversal of sleep alterations and depression-like behavior after early life blockade of 5-HT(1A)R in 5-HTT-/- mutants might open new perspectives regarding preventive care of sleep and mood disorders resulting from serotonin transporter impairments during development.

Sleep apneas are increased in mice lacking monoamine oxidase A.

STUDY OBJECTIVES: Alterations in the serotonin (5-HT) system have been suggested as a mechanism of sleep apnea in humans and rodents. The objective is to evaluate the contribution of 5-HT to this disorder. DESIGN: We studied sleep and breathing (whole-body plethysmography) in mutant mice that lack monoamine oxidase A (MAOA) and have increased concentrations of monoamines, including 5-HT. MEASUREMENTS AND RESULTS: Compared to wild-type mice, the mutants showed similar amounts of slow wave sleep (SWS) and rapid eye movement sleep (REMS), but exhibited a 3-fold increase in SWS and REMS apnea indices. Acute administration of the MAOA inhibitor clorgyline decreased REMS amounts and increased the apnea index in wild-type but not mutant mice. Parachlorophenylalanine, a 5-HT synthesis inhibitor, reduced whole brain concentrations of 5-HT in both strains, and induced a decrease in apnea index in mutant but not wild-type mice. CONCLUSION: Our results show that MAOA deficiency is associated with increased sleep apnea in mice and suggest that an acute or chronic excess of 5-HT contributes to this phenotype.

Altered sleep architecture during the first months of life in infants born to depressed mothers.

OBJECTIVE: This study investigated sleep architecture in newborn and six-month-old infants who were born to depressed mothers. METHOD: Sixty-four healthy full-term infants (32 males and 32 females) participated in the study. Of these, 32 were high-risk infants who were born to mothers diagnosed with depression, and 32 were low-risk infants born to mothers without a personal history of depression. 24-hour polysomnography was recorded at zero and six months of age (M0 and M6). Sleep macro-structural parameters (total sleep time, TST; awake time; non-rapid eye movement, NREM sleep (%); rapid eye movement, REM sleep %; arousal index; and sleep efficiency) were analysed at M0 and M6. Micro-architectural sleep features (slow-wave activity, SWA; delta sleep ratio, DSR; spindle density; and rapid eye movement density) were calculated at M6. The data between high-risk and low-risk groups were compared using Student's t-tests. RESULTS: At M0 and M6, the high-risk infants showed more awake time and fewer arousals than the low-risk infants. However, the high-risk group had less NREM% at M0 and a shorter TST as well as less REM% at M6 than the low-risk group. At M6, the high-risk group showed higher SWA, higher DSR and lower spindle density in comparison with the low-risk group. CONCLUSIONS: Altered sleep structure was observed during their first months of life in infants born from depressed mothers, thereby suggesting that the prenatal environment could enhance the depression vulnerability of the child and potentially decrease their neuroplasticity.

Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors.

Serotonin (5-hydroxytryptamine; 5-HT) plays key roles in sleep-wakefulness regulation. Evidence indicates that 5-HT2 receptors are involved mainly in non-rapid eye movement sleep (NREMS) regulation and respiratory control. Here, we investigated the relative contribution of 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptor subtypes to NREMS and breathing during sleep, using 5-HT2 subtype-selective ligands in wild-type (5-HT(2A)+/+) and knock-out (5-HT(2A)-/-) mice that do not express 5-HT(2A) receptors. Acute blockade of 5-HT(2A) receptors induced an increase in NREMS in 5-HT(2A)+/+ mice, but not 5-HT(2A)-/- mutants, which spontaneously expressed less NREMS than wild-type animals. In 5-HT(2A)+/+ mice, 5-HT(2B) receptor blockade produced a reduction of NREMS, whereas receptor activation induced an increase in this sleep stage. These effects were less pronounced in 5-HT(2A)-/- mice, indicating a lower sensitivity of 5-HT(2B) receptors in mutants, with no change in 5-HT(2B) mRNA. Blockade of 5-HT(2C) receptors had no effect on NREMS in both strains. In addition, an increase in EEG power density after sleep deprivation was observed in 5-HT(2A)+/+ mice but not in 5-HT(2A)-/- mice. Whole-body plethysmographic recordings indicated that 5-HT(2A) receptor blockade in 5-HT(2A)+/+ mice reduced NREMS apneas and bradypneas that occurred after sighs. In contrast, in 5-HT(2A)-/- mutants, NREMS apneas were not modified, and bradypnea after sighs were more pronounced. Our results demonstrate that 5-HT exerts a 5-HT(2B)-mediated facilitation of NREMS, and an influence respectively inhibitory on NREMS and facilitatory on sleep apnea generation, via 5-HT(2A) receptors. Moreover, 5-HT(2A) gene knock-out leads to functional compensations yielding adaptive changes opposite to those caused by pharmacological blockade of 5-HT(2A) receptors in 5-HT(2A)+/+ mice.

Homeostatic regulation of sleep in a genetic model of depression in the mouse: effects of muscarinic and 5-HT1A receptor activation.

In depressed patients, sleep undergoes marked alterations, especially sleep onset insomnia, sleep fragmentation, and disturbances of the Rapid Eye Movement (REM) sleep. Abnormalities of rest-activity rhythms and of hypothalamic-pituitary-adrenocortical function have also been described in these patients. In the present study, we examined the presence of such abnormalities in a recently developed line of mice (Helpless mice-H) that exhibit depression-like behaviors in validated tests, compared to the nonhelpless (NH) line derived from the same colony. Experiments were essentially carried out in females for which previous studies showed marked differences between H and NH lines. Compared to NH mice, the H line exhibited (i) lower basal locomotor activity, (ii) sleep fragmentation, shift towards lighter sleep stages, and facilitation of REM sleep reflected by increased amounts and decreased latency, (iii) larger response to the REM sleep promoting effect of muscarinic receptor stimulation (by arecoline). In contrast, H and NH mice were equally responsive to the REM sleep inhibitory effect of 5-HT1A receptor stimulation (by 8-OH-DPAT). In addition, a deficiency in delta power enhancement after sleep deprivation was observed in the H group, and acute immobilization stress in this group failed to elicit a REM sleep rebound and was associated with a long-lasting raise in serum corticosterone levels. These results further validate H mice as a depression model and suggest they might be of particular interest for investigating the neurobiological mechanisms and possibly genetic substrates underlying sleep alterations associated with depression.

Glucocorticoid receptor-dependent desensitization of 5-HT1A autoreceptors by sleep deprivation: studies in GR-i transgenic mice.

UNLABELLED: Sleep deprivation for one night induces mood improvement in depressed patients, an action that probably involves the serotonergic (5-HT) system. In animals, sleep deprivation and pharmacologic treatment with antidepressants exert similar effects on 5-HT neurotransmission, notably functional desensitization of 5-HT1A autoreceptors located on 5-HT neurons in the dorsal raphe nucleus (DRN). However, in stressful conditions, corticosterone can also induce a desensitization of these autoreceptors. STUDY OBJECTIVES: To investigate the mechanisms of this adaptation during sleep deprivation and the possible involvement of corticosterone, we studied the effects of an 18-hour sleep deprivation, by forced locomotion, on 5-HT1A receptor-mediated firing response of DRN 5-HT neurons in transgenic mice with impaired glucocorticoid-receptor expression (GR-i) and in wild-type animals. We also examined the effects of chronic treatment with the antidepressant drug fluoxetine in the same paradigm. MEASUREMENTS AND RESULTS: In both wild-type and GR-i mice, the 18-hour sleep deprivation or fluoxetine treatment had no effect on the spontaneous firing of 5-HT neurons recorded under anesthesia. However, sleep deprivation decreased the potency of the 5-HT1A agonist 8-OH-DPAT to inhibit 5-HT neuronal firing in wild-type mice, whereas it had no effect in GR-i animals. Conversely, after chronic fluoxetine treatment, the induced reduction of this 5-HT1A autoreceptor-driven response was of larger amplitude in GR-i than in wild-type mice. CONCLUSIONS: These data suggest that glucocorticoid-receptor activation by corticosterone participates in the antidepressant-like adaptive changes in 5-HT1A autoreceptors in sleep-deprived mice. On the other hand, GR-i animals exhibited enhanced 5-HT1A autoreceptor desensitization induced by fluoxetine, in line with data in other animal models of depression.

Immunocytochemical distribution of VIP and PACAP in the rat brain stem: implications for REM sleep physiology.

Recent evidence indicates that pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) might play an important role in rapid eye movement sleep (REMS) generation at the pontine level in rats. We have thus examined the immunohistochemical distribution of VIP and PACAP in the pontine and mesencephalic areas known to be involved in REMS control in rats. A dense network of VIP-immunoreactive cell bodies and fibers was found in the dorsal raphe nucleus. A large number of PACAP-positive perikarya and nerve fibers was observed in the area known as the REMS induction zone within the pontine reticular formation (PRF). The present results provide an anatomical basis to our previous functional data, and suggest that PACAPergic mechanisms within the PRF play a critical role in long-term regulation of REMS.

Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice.

For the last two decades, the involvement of 5-HT(1A) receptors in the regulation of vigilance states has been studied extensively thanks to pharmacological tools, but clear-cut conclusion has not been reached yet. By studying mutant mice that do not express this receptor type (5-HT(1A)-/-) and their wild-type 129/Sv counterparts, we herein demonstrate that 5-HT(1A) receptors play key roles in the control of spontaneous sleep-wakefulness cycles, as well as in homeostatic regulation and stress-induced adaptive changes of paradoxical sleep. Both strains of mice exhibited a diurnal sleep-wakefulness rhythm, but 5-HT(1A)-/- animals expressed higher amounts of paradoxical sleep than wild-type mice during both the light and the dark phases. In wild-type mice, pharmacological blockade of 5-HT(1A) receptors by WAY 100635 (0.5 mg/kg, i.p.) promoted paradoxical sleep, whereas the 5-HT(1A) agonist 8-OH-DPAT (0.25-1 mg/kg, s.c.) had an opposite effect. In contrast, none of the 5-HT(1A) receptor ligands affected sleep significantly in 5-HT(1A)-/- mice. However, 5-HT(1B) receptor stimulation by CP 94253 (1-3 mg/kg, i.p.) induced a reduction in paradoxical sleep in both strains, this effect being more pronounced in 5-HT(1A)-/- mutants. Finally, in contrast to wild-type mice, 5-HT(1A)-/- mutants did not exhibit any rebound of paradoxical sleep after either a 9 hr instrumental paradoxical sleep deprivation or a 90 min immobilization stress. Altogether, these data indicate that, in the mouse, 5-HT(1A) receptors participate in the spontaneous and homeostatic regulation, as well as in stress-induced adaptive changes of paradoxical sleep.

Beta2-containing nicotinic receptors contribute to the organization of sleep and regulate putative micro-arousals in mice.

The cholinergic system is involved in arousal and in rapid eye movement sleep (REMS). To evaluate the contribution of nicotinic acetylcholine receptors (nAChRs) to these functions, we studied with polygraphic recordings the regulation of sleep in mice lacking the beta2 subunit gene of the nAChRs, a major component of high-affinity nicotine binding sites in the brain. Nicotine (1-2 mg/kg, i.p.) increased wakefulness in wild-type but not knock-out animals, indicating that beta2-containing nAChRs mediate the arousing properties of nicotine. Under normal conditions, the beta2-/- mice displayed the same amounts of waking, non-REM sleep (NREMS) and REMS as their wild-type counterparts. However, they exhibited longer REMS episodes and a reduced fragmentation of NREMS by events characterized notably by a transient drop in EEG power and frequently associated with EMG activation, tentatively referred to as micro-arousals. Respiration monitoring showed that these events were accompanied with, but not caused by, breathing irregularities. Sleep deprivation of beta2-/- mice resulted in a normal increase in REMS episode duration and NREMS delta power but yielded a reduction of the number of micro-arousals in NREMS. In contrast, in beta2-/- mice, a 1 hr immobilization stress failed to produce the normal rebound in REMS in the following 12 hr and, instead, was associated with increased NREMS fragmentation and sustained corticosterone levels. Our results show that the beta2-containing nAChRs contribute to the organization of sleep by regulating the transient phasic activity in NREMS, the REMS onset and duration, and the REMS-promoting effect of stress.

Sleep of preterm neonates under developmental care or regular environmental conditions.

UNLABELLED: Sleep is the main behavioral state of the premature infant. In adult intensive care units, sleep deprivation has been reported as one of the major stressors. Developmental care (DC) aims to decrease stressful events in neonatal intensive care unit and support well-being. AIM: To assess whether DC is accompanied by changes in sleep in preterm neonates. METHODS: A prospective cross-over study included 33 preterm neonates [mean (S.D.): gestational age: 29.3 (1.8) weeks; birth weight: 1245 (336) g]. Polysomnography was performed in two randomly ordered 3-h periods with and without DC. A blinded electrophysiologist analyzed sleep. The total sleep time (TST) was the primary outcome, duration of active (AS), quiet (QS) and indeterminate sleep, and latency before sleep were the secondary outcomes. Non-parametric Wilcoxon tests and ANOVA were used. RESULTS: In DC condition vs. control: TST increased [in minutes, mean (S.E.M.): 156.2 (2.9) vs. 139.2 (4.6), p=0.002], with increase in AS [86.6 (3.7) vs. 77.0 (4.2), p=0.024] and in QS [47.1 (4.1) vs. 36.9 (4.2), p=0.015], and sleeping latency decreased (2.1 (0.7) vs. 10.5 (2.0), p=0.0005]. CONCLUSION: DC promoted sleep in our study. The impact of DC on the neuro-behavioral outcome needs futures studies.

Effect of melatonin on sleep disorders in a monkey model of Parkinson's disease.

OBJECTIVES: To evaluate and compare the effects of melatonin and levodopa (L-dopa) on sleep disorders in a monkey model of Parkinson's disease. MATERIALS AND METHODS: The daytime and nighttime sleep patterns of four macaques that were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were recorded using polysomnography in four conditions: at baseline, during the parkinsonian condition; after administration of L-dopa, and after administration of a combination of melatonin with L-dopa. RESULTS: It was confirmed that MPTP intoxication induces sleep disorders, with sleep episodes during daytime and sleep fragmentation at nighttime. L-dopa treatment significantly reduced the awake time during the night and tended to improve all other sleep parameters, albeit not significantly. In comparison to the parkinsonian condition, combined treatment with melatonin and L-dopa significantly increased total sleep time and sleep efficiency, and reduced the time spent awake during the night in all animals. A significant decrease in sleep latencies was also observed in three out of four animals. Compared with L-dopa alone, combined treatment with melatonin and L-dopa significantly improved all these sleep parameters in two animals. On the other hand, combined treatment had no effect on sleep architecture and daytime sleep. CONCLUSION: These data demonstrated, for the first time, objective improvement on sleep parameters of melatonin treatment in MPTP-intoxicated monkeys, showing that melatonin treatment has a real therapeutic potential to treat sleep disturbances in people with Parkinson's disease.

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype.

Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT2B mutant (Htr2B(-/-)) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr2B(-/-) mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr2B(-/-) mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT2B receptors in the neurobiology of psychotic disorders.