Bmal1 knockdown suppresses wake and increases immobility without altering orexin A, corticotrophin-releasing hormone, or glutamate decarboxylase.

OBJECTIVE: To determine the effect of Bmal1 knockdown (KD) on sleep, activity, immobility, hypothalamic levels of orexin, corticotrophin-releasing hormone (CRH), and GABAergic glutamate decarboxylase (GAD). METHODS: We used Bmal1 siRNA, or control siRNA intracerebroventricular (ICV) injection to knock down Bmal1 in C57BL/6 mice. Sleep polysomnography, wheel-running activity, and tail suspension test were performed. Polysomnographic (PSG) recordings in both groups were preceded by ICV injection made during both the light phase and the dark phase. We also measured brain orexin A and CRH using an ELISA and measured GAD using immunoblotting. RESULTS: Compared with control group, Bmal1 KD group had reduced wheel activity and increased immobility. Compared with control, the Bmal1 KD group had reduced wheel activity and increased immobility. During the first 24 hours after treatment, we observed that control siRNA induced a much greater increase in sleep during the dark phase, which was associated with lower orexin levels. However, beginning 24 hours after treatment, we observed an increase in sleep and a decrease in time spent awake during the dark phase in the Bmal1 KD group. These changes were not associated with changes in brain levels of orexin A, CRH, or GAD. CONCLUSION: Bmal1 KD led to reduced activity, increased immobility, and dramatic reduction in time spent awake as well as an increase in sleep during the dark phase. Early after injection, there was a slight change in sleep but brain levels of orexin, CRH, and GAD remain unchanged. Control siRNA also affected sleep associated with changes in orexin levels.

Gclc deficiency in mouse CNS causes mitochondrial damage and neurodegeneration.

Gamma glutamyl cysteine ligase (GCL) is the rate-limiting enzyme for intracellular glutathione (GSH) synthesis. The GSH concentration and GCL activity are declining with age in the central nervous system (CNS), and is accompanied by elevated reactive oxygen species (ROS). To study the biological effects of low GSH levels, we disrupted its synthesis both at birth by breeding a Gclc loxP mouse with a thy1-cre mouse (NEGSKO mouse) and at a later age by breeding with a CaMKII-ERT2-Cre (FIGSKO mouse). NEGSKO mice with deficiency of the Gclc in their entire CNS neuronal cells develop at 4 weeks: progressive motor neuron loss, gait problems, muscle denervation and atrophy, paralysis, and have diminished life expectancy. The observed neurodegeneration in Gclc deficiency is of more chronic rather than acute nature as demonstrated by Gclc targeted single-neuron labeling from the inducible Cre-mediated knockout (SLICK) mice. FIGSKO mice with inducible Gclc deficiency in the forebrain at 23 weeks after tamoxifen induction demonstrate profound brain atrophy, elevated astrogliosis and neurodegeneration, particularly in the hippocampus region. FIGSKO mice also develop cognitive abnormalities, i.e. learning impairment and nesting behaviors based on passive avoidance, T-Maze, and nesting behavior tests. Mechanistic studies show that impaired mitochondrial glutathione homeostasis and subsequent mitochondrial dysfunction are responsible for neuronal cell loss. This was confirmed by mitochondrial electron transporter chain activity analysis and transmission electron microscopy that demonstrate remarkable impairment of state 3 respiratory activity, impaired complex IV function, and mitochondrial swollen morphology in the hippocampus and cerebral cortex. These mouse genetic tools of oxidative stress open new insights into potential pharmacological control of apoptotic signaling pathways triggered by mitochondrial dysfunction.

Hippocampal and motor fronto-cortical neuroligin1 is increased in an animal model of depression.

Neuroligins (NLGNs) regulate synaptic excitability, neuronal signaling and sleep. We hypothesize that alteration of NLGNs is involved in the pathology of depression and tested the hypothesis in a model of depression using Wistar Kyoto (WKy) rat and its control, the Wistar (Wis) rat. We first evaluated behavioral deficits using the forced swim test and then characterized alterations of NLGN1 and NLGN2 with RT-PCR and Western Blotting in the prefrontal cortex, motor frontal cortex and hippocampus. Compared with controls of Wis rats, (1) the WKy rats had significantly shorter swim time and longer immobile time; (2) NLGN1 mRNA levels was higher in the motor frontal cortex and hippocampus in the WKy model; (3) NLGN1 protein was significantly higher in the motor frontal cortex, the prefrontal cortex and the hippocampus in the WKy model; (4) NLGN2 mRNA was significantly higher in the motor frontal cortex but significantly lower in the hippocampus in the WKy model. We concluded that NLGN1 gene and protein expression is higher in the motor frontal cortex, hippocampus and in the prefrontal cortex in the WKy rats suggesting that alterations of NLGN1 is involved in the pathology of depression but need to be further evaluated in human.

7,8-Dihydroxyflavone reduces sleep during dark phase and suppresses orexin A but not orexin B in mice.

Brain-derived neurotrophic factor (BDNF) binds to Tropomyosin-receptor-kinase B (TrkB) receptors that regulate synaptic strength and plasticity in the mammalian nervous system. 7,8-Dihydroxyflavone (DHF) is a recently identified small molecule Trk B agonist that has been reported to ameliorate depression, attenuate the fear response, improve memory consolidation, and exert neuroprotective effects. Poor and disturbed sleep remains a symptom of major depressive disorder and most current antidepressants affect sleep. Therefore, we conducted sleep/wake recordings and concomitant measurement of brain orexins, endogenous peptides that suppress sleep, in mice for this study. Baseline polysomnograph recording was performed for 24 h followed by treatment with either 5 mg/kg of DHF or vehicle at the beginning of the dark phase. Animals were sacrificed the following day, one hour after the final treatment with DHF. Orexin A and B were quantified using ELISA and radioimmunoassay, respectively. Total sleep was significantly decreased in the DHF group, 4 h after drug administration in the dark phase, when compared with vehicle-treated animals. This difference was due to a significant decrease of non-rapid eye movement sleep, but not rapid eye movement sleep. DHF increased power of alpha and sigma bands but suppressed power of gamma band during sleep in dark phase. Interestingly, hypothalamic levels of orexin A were also significantly decreased in the DHF group (97 pg/mg) when compared with the vehicle-treated group (132 pg/mg). However, no significant differences of orexin B were observed between groups. Additionally, no change was found in immobility tests.

Chromosome 1 replacement increases brain orexins and antidepressive measures without increasing locomotor activity.

Decreased orexin level has been well demonstrated in patients suffering from narcolepsy, depression accompanied with suicide attempt; obstructive sleep apnea and comorbidity were also demonstrated in these diseases. As C57BL/6J (B6) mice are more "depressed" and have lower brain orexins than A/J mice, B6 mice having chromosome 1 replacement (B6A1 mice) might have restored orexin levels and less depressive behavior. We studied the behavior of 4-6 month old B6, A/J and B6A1 mice with forced swim, tail suspension, and locomotor activity tests. The animals were then sacrificed and hypothalamus and medullas dissected from brain tissue. Orexins-A and -B were determined by radioimmunoassay. Compared with A/J mice, B6 mice displayed several signs of depression, including increased immobility, increased locomotors activity, and decreased orexin A and -B levels in both the hypothalamus and medulla. Compared to B6 mice, B6A1 mice exhibited significantly higher levels of orexins-A and -B in both brain regions. B6A1 mice also exhibited antidepressive features in most of measured variables, including decreased locomotor activity, decreased immobility and increased swim in tail suspension test; compared with B6 mice, however. B6A1 mice also reversed immobility in the early phase of the swim test. In summary, B6 mice exhibited depressive attributes compared with A/J mice, including increased locomotor activity, greater immobility, and decreased brain orexins, these were largely reversed in B6A1 mice. We conclude that orexin levels modulate these B6 behaviors, likely due to expression of A/J alleles on Chromosome 1.

Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse.

BACKGROUND: The hypothesis was that an orexin 2 receptor (OX2R) agonist would prevent sleep-related disordered breathing. METHODS: In C57BL/6J (B6) mice, body plethysmography was performed with and without EEG monitoring of state (wakefulness, NREM and REM sleep). Outcome was apnea rate/h during sleep-wake states at baseline and with an intracerebroventricular administration of vehicle, 4 nMol of agonist OB(DL), and 4 nMol of an antagonist, TCS OX2 29. RESULTS: A significant reduction (p=0.035, f=2.99) in apneas/hour occurred, especially with the agonist. Expressed as a function of the change from baseline, there was a significant difference among groups in Wake (p=0.03, f=3.8), NREM (p=0.003, f=6.98) and REM (p=0.03, f=3.92) with the agonist reducing the rate of apneas during sleep from 29.7±4.7 (M±SEM) to 7.3±2.4 during sleep (p=0.001). There was also a reduction in apneas during wakefulness. Administration of the antagonist did not increase event rate over baseline levels. CONCLUSIONS: The B6 mouse is a preclinical model of wake-and sleep-disordered breathing, and the orexin receptor agonist at a dose of 4 nMol given intracerebroventricularly will reduce events in sleep and also wakefulness.

Phospholipase D-mTOR signaling is compromised in a rat model of depression.

Depression is associated with structural and neurochemical changes in limbic structures, including the hippocampus, that control emotion and mood. Structural abnormalities such as decrease in hippocampal cell proliferation, neurogenesis and hippocampal volume, and loss of neurons and glial cells have been widely reported in physical and psychosocial stress paradigms and animal model of depression, but corresponding neurochemical changes are largely unknown. Using neonatal clomipramine (CL)-treated rats as a model to elucidate the association of phospholipase D (PLD) and mammalian target of rapamycin (mTOR) signaling with depressive pathology, we found that the hippocampus of CL-treated rats showed significantly down-regulation of PLD1 expression and attenuation of PLD activity which leads to the less formation of phosphatidic acid (PA), an activator of mTOR, and free choline, a potential biomarker for depression. With lower PA levels which could affect mTOR signaling, we further observed that the phosphorylation of p70S6 kinase, one of the downstream effectors of mTOR, was also significantly decreased in the hippocampus of CL-treated rats compared to the controls. Down-regulation of PLD1 expression, PLD activity and p70S6 phosphorylation was also found in the hypothalamus and frontal cortex with CL-treated rats. Our results indicate that PLD-mTOR signaling is associated with depressive disorder.

OX2R activation induces PKC-mediated ERK and CREB phosphorylation.

Deficiencies in brain orexins and components of mitogen activated protein kinase (MAPK) signaling pathway have been reported in either human depression or animal model of depression. Brain administration of orexins affects behaviors toward improvement of depressive symptoms. However, the documentation of endogenous linkage between orexin receptor activation and MAPK signaling pathway remains to be insufficient. In this study, we report the effects of orexin 2 receptor (OX2R) activation on cell signaling in CHO cells over-expressing OX2R and in mouse hypothalamus cell line CLU172. Short-term extracellular signal-regulated kinase (ERK) phosphorylation and long-term cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation were subsequently observed in CHO cells that over-express OX2R while 20 min of ERK phosphorylation was significantly detected in mouse adult hypothalamus neuron cell line CLU172. Orexin A, which can also activate OX2R, mediated ERK phosphorylation was as the same as orexin B in CHO cells. A MAPK inhibitor eliminated ERK phosphorylation but not CREB phosphorylation in CHO cells. Also, ERK and CREB phosphorylation was not mediated by protein kinase A (PKA) or calmodulin kinase (CaMK). However, inhibition of protein kinase C (PKC) by GF 109203X eliminated the phosphorylation of ERK and CREB in CHO cells. A significant decrease in ERK and CREB phosphorylation was observed with 1 µM GF 109203X pre-treatment indicating that the conventional and novel isoforms of PKC are responsible for CREB phosphorylation after OX2R activation. In contrast, ERK phosphorylation induced by orexin B in CLU172 cells cannot be inhibited by 1 µM of protein kinase C inhibitor. From above observation we conclude that OX2R activation by orexin B induces ERK and CREB phosphorylation and orexin A played the same role as orexin B. Several isoforms of PKC may be involved in prolonged CREB phosphorylation. Orexin B induced ERK phosphorylation in mouse hypothalamus neuron cells differs from CHO cell line and cannot be inhibited by PKC inhibitor GF 109203X. And hypothalamus neuron cells may use different downsteam pathway for orexin B induced ERK phosphorylation. This result supports findings that orexins might have anti-depressive roles.

Sleep-related epilepsy in a Long-Evans hooded rat model of depression.

INTRODUCTION: Neonatal treatment with clomipramine (CLI) has been shown to have reliable behavioral and biological changes that mimic major symptomatic and biochemical changes found in depression. This paper further explores a common feature of depression, the comorbidity of seizure activity and depressive behaviors in this mode. METHODS: Rat pups were neonatally treated with 40 mg/kg/day of CLI from postnatal day 8 through 21. In adulthood, they were instrumented with electroencephalographic (EEG) and electromyographic (EMG) electrodes for 24 h of polysomnogram (PSG) recordings. PSG data were analyzed for: (1) sleep-wake cycle; (2) spectral power; and (3) epileptiform activity, including NREM-to-REM transition (NRT) bursts. RESULTS: Neonatal treatment with CLI reliably produces enhanced levels of REM (p < 0.01) and reduced sexual activity (p < 0.05). Theta power was enhanced during NREM sleep in the CLI group (p = 0.02). CLI-treated animals experienced increased frequency at the NRT (p < 0.01), as well as additional epileptiform activity of continuous (CTS; p < 0.05) and petite-continuous (P-CTS; p < 0.01) types, across the sleep-wake cycle. There is a strong temporal correlation with increased REM sleep duration, increased frequency of NRT bursts, and increased theta power during NREM sleep in CLI-treated animals. DISCUSSION: Neonatal CLI-treated animals experienced significantly more epileptiform activity as a whole, in addition to comorbid features of depression in adulthood. Neonatal exposure to CLI will not only produce depressive phenotype but may also enhance risk for epilepsy in some individuals. This warrants further investigation into currently acceptable medicinal use in humans.

Maternal stress induces adult reduced REM sleep and melatonin level.

We have previously reported that neonatal maternal deprivation (MD) resulted in a decrease of total sleep and an increase of orexin A in adult rats. Now, we characterized features of sleep, activity, and melatonin levels in rats neonatally treated with MD and control (MC) procedures. Adult male Sprague-Dawley rats were treated with either MD or MC procedures for 10 days starting at postnatal day 4. At 3 months of age, sleep was recorded for 48 h in one set of MD and MC rats, while another set of MD and MC rats was measured for locomotor activity (under LD = 12:12). Melatonin levels in the blood, pineal gland, and hypothalamus were measured as well as clock protein level in the hypothalamus. Compared to the MC rats, REM sleep in the MD rats was significantly reduced in the light periods but not in the dark periods. Both quiet wake and total wake in the MD rats were significantly increased during the light period compared to the MC rats. The weight of the pineal gland of the MD rats was significantly smaller than in MC rats. Melatonin levels of the MD group were significantly reduced in the pineal gland and hypothalamus compared to the MC group. No significant difference was identified between groups in the expression of the clock protein in the hypothalamus. Neonatal MD resulted in reduced REM sleep and melatonin levels, without changes of circadian cycle of locomotor activity and levels of clock protein.

[Effects of CRF receptor antagonist on rem sleep in neonatal rat].

OBJECTIVE: To observe the role of NB127914, a CRF R1 receptor antagonist, in the regulation of neonatal sleep/wake cycle. METHODS: Rat pups were surgically implanted with electrodes at postnatal day(PN) 13. At PN 14, 6 hours polysomnographic recording data were continuously collected before and after administration of various doses of NBI 27914, atropine and the same amount of saline. RESULTS: Compared with baseline, rapid eye movement (REM) sleep was significantly reduced and was replaced primarily by non-REM (NREM) sleep in all groups treated with NBI, but not with dimethyl sulfoxide/saline. Atropine suppressed REM sleep significantly and increased wakefulness simultaneously. CONCLUSION: Blockage of corticotropin-releasing factor (CRF) R1 receptors deprives neonatal rat REM sleep.

Breathing and sleep: measurement methods, genetic influences, and developmental impacts.

Sleep-disordered breathing comprises alterations in respiratory rate, rhythm, and depth that present during sleep and may or may not be recognizable in breathing during wakefulness. Primary disorders include repetitive apneas, near apneas (hypopneas), or reductions in overall ventilation during sleep (hypoventilation), all of which lead to reductions in pulmonary gas exchange resulting in arousals, arrhythmia, hypercapnia, acidosis, and/or hypoxic stress responses such as pulmonary hypertension or polycythemia. Because the underlying mechanisms resulting in sleep-disordered breathing and its resulting comorbidities remain unclear, researchers use a variety of animal models to better understand the disorder. These models allow for conditioning paradigms, more detailed measurements of respiratory control, and the use of fewer preparations to provide a detailed picture of the individual components that contribute to breathing patterns. Both noninvasive and reduced methods are applicable with conditioned, inbred, and/or genetically manipulated animals to determine effect size and imply mechanisms. Research in animals has established preclinical models showing that intermediate traits of breathing pattern (e.g., responses to hypoxia, hypercapnia, and reoxygenation) vary according to genetic background and conditioning. Such findings permit new ideas about pathogenesis and prevention and form the rationale for observational and interventional studies in the human population. In this article we focus on methods of investigating respiratory control and applicable rodent models.

Alpha-melanocyte stimulating hormone and adrenocorticotropic hormone: an alternative approach when thinking about restless legs syndrome?

Alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH) possess properties suggesting that they may be involved in the pathogenesis of restless legs syndrome (RLS). We sought to determine if alpha-MSH and ACTH when administered centrally in rat recapitulate features reminiscent of RLS: increased activity, sleep fragmentation, and periodic movements during sleep. Rats were instrumented with electroencephalography, electromyography, and intracerebral cannulae and recorded for the measurement of sleep, periodic movements, and behavior following intracerebroventricular administration of alpha-MSH, ACTH, or saline. Studied behavior included grooming, locomotion, and rearing during wake and limb movements during sleep. Vigilance states included active wake (AW), quiet wake (QW), slow wave sleep I (SWSI), slow wave sleep II (SWSII), and paradoxical sleep (PS). All rats received normal saline acting as their own controls. Different rats received alpha-MSH in doses of 0.05, 0.5, 1.0, 2.0, and 6.0 microg or ACTH in doses of 0.5, 1.0, and 2.0 microg. Administered alpha-MSH caused an increase in waking behavior and prolongation of sleep latency, while ACTH stimulated waking behavior and fragmented sleep, yielding more AW and less SWSII and PS. Both hormones increased periodic movements during sleep. When administered centrally in rat, alpha-MSH and ACTH stimulate motor activity in wake, cause changes in sleep architecture, and increase periodic movements in sleep. These melanocortin hormones may play a role in the pathogenesis of RLS.

Neonatal REM sleep is regulated by corticotropin releasing factor.

Sleep/wake regulation is quite different during the neonatal and adult periods. Although cholinergic neurons have been recognized to be the major source of rapid eye movement (REM) sleep regulation in adulthood, their effect on neonatal REM sleep remains to be discovered. Current evidence suggests that corticotropin-releasing factor (CRF) may play a role in REM promotion during the neonatal period. We conducted the following study to test our hypothesis that blocking CRF R1 receptor would reduce REM sleep in developing rat pups. First, rat pups were surgically implanted with electrodes on postnatal day (PN) 13. On PN 14, six hours of polysomnographic (PSG) data were collected before and after administration of three different doses of NBI 27914 (NBI), a CRF R1 receptor antagonist. Compared with baseline, REM sleep was significantly reduced in all groups treated with NBI but not with dimethyl sulfoxide/saline. The reduction of REM sleep was dose-related and was replaced primarily by non-REM (NREM) sleep. Second, two groups of rat pups were given a single dose of either NBI or vehicle on PN 14 for quantification of ACTH and acetylcholine without PSG recording. NBI induced no change of either ACTH or acetylcholine. Third, the effect of administering atropine (6 mg/kg) on sleep/wake in two-week-old rats was investigated. Atropine suppressed REM sleep significantly and increased wakefulness simultaneously. Our data revealed that blockage of CRF R1 receptors deprives neonatal REM sleep. The mechanism for CRF in enhancing REM sleep may be associated with but not be similar to the cholinergic mechanism.

Brain orexins and wake regulation in rats exposed to maternal deprivation.

Maternal deprivation (MD) is a neonatal stressor that leads to behavioral and molecular manifestations of chronic stress in adulthood. Recent evidence has suggested that stress may impact wake regulation through corticotropin-releasing hormone (CRH) and the orexinergic system. We studied the wake/sleep features and brain levels of orexin and orexin receptors in adult rats neonatally subjected to either ten days of MD or a control procedure from postnatal day 4. At 3 months of age, one set of rats from both groups underwent 48 h of polysomnographic recording. All rats (including those that did not undergo surgery) were subsequently sacrificed for ELISA, radioimmunoassay and western blot measurement of orexins, orexin receptors and CRH in multiple brain regions. Neonatal MD induced an increase of total wake time (decreased total sleep) during the light period, which corresponds to human night time. This increase was specifically composed of quiet wake, while a small but significant decrease of active wake was observed during the dark period. At the molecular level, MD led to increased hypothalamic CRH and orexin A, and frontal cortical orexin 1 receptors (OX1R). However, hippocampal orexin B was reduced in the MD group. Our study discovered for the first time that the adult MD rat has sleep and neurobiological features of hyperarousal, which is typical in human insomnia. We concluded that neonatal MD produces adult hyperarousal in sleep physiology and neurobiology, and that the adult MD rat could be a model of insomnia with an orexinergic mechanism.

Effects of subchronic lithium treatment on levels of BDNF, Bcl-2 and phospho-CREB in the rat hippocampus.

Although it has been proposed that exposure to lithium up-regulates brain-derived neurotrophic factor (BDNF), B-cell leukaemia/lymphoma 2 protein (Bcl-2) and cyclic AMP-response element-binding protein (CREB), and these molecules are involved in the neuroplastic actions and clinical efficacy of the drug, the several lines of evidence suggest that the lithium-induced up-regulation of these molecules has not been consistently confirmed. Few studies have examined the effects of lithium exposure on the regulation of these molecules in the dentate gyrus (DG) and area CA1 in the hippocampus. We examined the effects of subchronic lithium treatment on the levels of BDNF, Bcl-2 and phosphorylated CREB in the DG and area CA1. We administered LiCl intraperitoneally (1 mEq/kg per day) to adult rats for 14 days, killed animals in 24 hr after the last administration of the drug, and determined the tissue levels of BDNF, Bcl-2 and pCREB in the DG and area CA1. Subchronic lithium treatment for 14 days did not significantly alter the levels of BDNF, Bcl-2 or phosphorylated CREB in the DG and area CA1 in the hippocampus. This study indicates that the lithium-induced up-regulation of these molecules may be various depending on the duration of lithium exposure and particular brain regions exposed to the drug.

Impairments of ERK signal transduction in the brain in a rat model of depression induced by neonatal exposure of clomipramine.

Depression is associated with deficiencies in monoaminergic transmitters and possibly neurotrophins. A common cellular response to these molecules is the activation of extracellular signal-regulated kinase (ERK). A deficiency of ERK signal transduction in depression was therefore hypothesized and was tested in a rat model of depression, produced by neonatal treatment with clomipramine (CLI). We measured sexual behaviors and brain levels of ERK, phosphorylated ERK (pERK), protein phosphatase 1 (PP1), and MAPK phosphatase-2 (MKP-2) during adulthood in control and neonatally CLI-treated rats (CLI rats). As expected, the CLI rats exhibited significantly lower sexual activities and also exhibited (1). significant decreases of pERK1/2 in the frontal cortex and pERK1 in the hippocampus, (2). slight but significant reduction of ERK2 in the frontal cortex and hippocampus, (3). no change of pERK1/2 levels in the temporal cortex, occipital cortex, parietal cortex, midbrain, and medulla, (4). significantly higher levels of PP1 in both the frontal cortex and hippocampus, (5). no change in MKP-2 in any examined region, and (6). all five measures of sexual function were significantly correlated with ERK2 and pERK2 in the frontal cortex. These findings suggest that a deficiency in the ERK signaling pathway is involved in the display of depressive behaviors.

Sleep networks and the anatomic and physiologic connections with respiratory control.

A central neuronal network regulates airway functions from the nares to the bronchioles and is an integral component of a regulatory system for brain control of breathing and airway patency during wakefulness and sleep. This network, components of which include sleep generating sites and monoaminergic neurons in particular, is characterized by reciprocal interconnections, parallel organization, and state-dependent activity patterns, which can be influenced by both genes and environment. Sleep generating neurons are interconnected with the monoaminergic containing cells to the extent that sleep-related changes in upper and lower airway patency could be due to inhibitory influences of sleep-activated neurons on serotonergic and noradrenergic producing cells. Neurochemical studies and physiologic experiments show that serotonergic and noradrenergic producing cells can make parallel pathways, directly innervating the hypoglossal motor cells regulating upper airway dilating muscles, and vagal preganglionic neurons providing cholinergic outflow to the airways. Activation of serotonergic and noradrenergic cell groups preferentially increases activity of the genioglossus muscle, but diminishes cholinergic outflow to the airways. Hence, inhibition of monoaminergic neurons during sleep may lead to a decrease in upper airway dilating forces and an elevation of cholinergic outflow to the airways. Qualitatively different responses of hypoglossal and airway-related vagal preganglionic neurons (AVPNs) occur in response to endogenously released serotonin or norepinephrine and could be related to its simultaneous action on different serotonin or norepinephrine receptor subtypes. Dysfunction of monaminergic cell groups during sleep may predispose to upper airway occlusion as well as bronchoconstriction. Pharmacological corrections of alterations of these transmitter specific converging systems might be an avenue for treatment of sleep related airway disorders such as sleep apnea and worsening of asthma.

Instrumental REM sleep deprivation in neonates leads to adult depression-like behaviors in rats.

STUDY OBJECTIVES: Previous studies have demonstrated that neonatal suppression of rapid eye movement (REM) sleep by pharmacologic agents, particularly clomipramine, produces adult depressive behavior. These findings suggest the hypothesis that REM sleep deprivation (RSD) mediates the depressogenic behaviors of neonatally administered antidepressant drugs. Drug suppression of RSD, however, was thought to be confounded by the other effects of the drugs. The current study was aimed to show the adult effect of neonatal RSD in rats by instrumental means, ie, a computer-controlled shaking method. DESIGN: Three treatment groups were studied: an instrumental RSD group, a yoked control group, and a nonshaken, maternally separated, control group. All treatments began at the age of 14 days and lasted for 7 days. Adult behavior measurements including tests of sexual activity, locomotor activity, shock-induced fighting, and sleep recording were subsequently performed. MEASUREMENTS AND RESULTS: The major findings of our investigation were that rats subjected to neonatal instrumental RSD demonstrated diminished sexual activity, decreased aggressive behavior, increased percentage of REM sleep, and decreased wake-REM sleep ratio compared with yoked control rats. These data are compatible with the findings from adult rats subjected to neonatal treatment with the REM-sleep suppressant, clomipramine, and supports the hypothesis that neonatal RSD results in adult depressive abnormalities. CONCLUSION: Neonatal RSD induced by a nondrug method results in adult depression-like changes similar to those induced by a REM-sleep suppressant drug, although the extent of these changes varies.