TRIB1 constitutes a molecular link between regulation of sleep and lipid metabolism in humans

Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N=6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P=8.92^*10⁻⁵, Bonferroni corrected P=0.0053, β=0.081 h per allele; rs2954029, P=0.00025, corrected P=0.015, β=0.076; P<0.001 for both variants after adjusting for blood lipid levels or body mass index). The finding was replicated in the twin sample (rs17321515, P=0.022, β=0.063; meta-analysis of both samples P=8.1^*10⁻⁶, β=0.073). After the experimentally induced sleep restriction period TRIB1 expression increased 1.6-fold and decreased in recovery phase (P=0.006). In addition, a negative correlation between TRIB1 expression and slow wave sleep was observed in recovery from sleep restriction. These results show that allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. The findings give evidence for the pleiotropic nature of TRIB1 and may reflect the shared roots of sleep and metabolism. The shared genetic background may at least partially explain the mechanism behind the well-established connection between diseases with disrupted metabolism and sleep.     

Orexin neuronal circuitry: role in the regulation of sleep and wakefulness

Orexin A and orexin B were initially identified as endogenous ligands for two orphan G protein-coupled receptors [104]. They were initially recognized as regulators of feeding behavior in view of their exclusive production in the lateral hypothalamic area (LHA), a region known as the feeding center, and their pharmacological activity [104,30,49,107]. Subsequently, the finding that orexin deficiency causes narcolepsy in humans and animals suggested that these hypothalamic neuropeptides play a critical role in regulating sleep/wake cycle [22,46,71,95,117]. These peptides activate waking-active monoaminergic and cholinergic neurons in the hypothalamus/brain stem regions to maintain a long, consolidated awake period. Recent studies on efferent and afferent systems of orexin neurons, and phenotypic characterization of genetically modified mice in the orexin system further suggested roles of orexin in the coordination of emotion, energy homeostasis, reward system, and arousal [3,80,106,137]. A link between the limbic system and orexin neurons might be important for increasing vigilance during emotional stimuli. Orexin neurons are also regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose, suggesting that they might have important roles as a link between energy homeostasis and vigilance states [137]. Recent research has also implicated orexins in reward systems and the mechanisms of drug addiction [13,48,91]. These observations suggest that orexin neurons sense the outer and inner environment of the body, and maintain proper wakefulness of animals for survival. This review discusses the mechanism by which orexins maintain sleep/wakefulness states, and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis.     

Hypocretin/orexin and sleep: implications for the pathophysiology and diagnosis of narcolepsy

PURPOSE OF REVIEW: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy. The discovery that the majority of human patients lack the hypothalamic neuropeptide hypocretin-1 has initiated a large body of new research. RECENT FINDINGS: Several studies on cerebrospinal fluid hypocretin-1 levels in narcolepsy and in various other sleep disorders have shown that hypocretin deficiency is both highly sensitive and specific for narcolepsy/cataplexy. Importantly, 15% of narcoleptic patients show low hypocretin levels, despite a negative multiple sleep latency test. Besides regulating sleep, the hypocretin system is involved in the regulation of energy balance, autonomic function and several neuroendocrine ensembles. Consequently, up to one-third of patients are obese (body mass index > 30). Furthermore, serum leptin levels are decreased in both nonoverweight and obese patients. The new rodent models for narcolepsy may aid in the further characterization of these endocrinological abnormalities. Finally, there is increasing insight into the physiological role of the hypocretin system in the regulation of sleep and wakefulness. SUMMARY: Hypocretin measurements may now be applied as a new diagnostic tool, providing the results are interpreted within the clinical context. In the clinical care of narcoleptic patients, attention should be paid to the obesity that frequently accompanies the disorder. In the future, hypocretin agonists may become available. Further characterization of animal models for narcolepsy will undoubtedly increase our insight into the pathophysiology of the disorder.     

星形胶质细胞与睡眠的研究进展

星形胶质细胞(AS)不仅仅对神经元起支持填充作用,而且可以通过神经递质的释放与神经元进行对话,调节神经元功能,在突触形成和突触可塑性中起重要作用。AS通过脂肪酸结合蛋白7(Fabp7)、腺苷(adenosine)、肿瘤坏死因子(TNF)、白细胞介素-1(IL-1)和神经生长因子(NGF)的释放参与睡眠-觉醒周期的调节;通过ATP、肝糖原(glycogen)以及AS-神经元乳酸盐穿梭机制参与睡眠时的能量代谢,进而调节睡眠。本文简单回顾了AS的功能和睡眠调节机制,重点对AS和睡眠调节的关系作一综述,以供参考。     

Telomere length as a marker of sleep loss and sleep disturbances: a potential link between sleep and cellular senescence

The identification of biological markers that allow the early diagnosis, or even the prevention of age-related diseases, is an important goal that is being actively pursued in the research community. Sleep is one of the physiological processes that is most affected by aging, and there is a strong relationship between age-related sleep alterations and diseases. Changes in cellular senescence and the linked changes in telomere length might be potential markers of age-related sleep changes. In this review, we present some of the most recent evidence showing that telomere length has been associated with sleep loss and sleep disturbances in cross-sectional and case–control studies. We also present insights into the cellular senescence mechanisms relating to changes in telomere length, and we suggest that this field lacks basic and clinical research studies, especially long-term longitudinal studies, which may bring opportunities to sleep researchers to investigate this relationship in more depth.     

The link between sleep and depression: The effects of antidepressants on EEG sleep

The assumption that sleep dysregulation is more than a mere epiphenomenon of depression is based on several observations: sleep disturbances are strongly associated with the depressive state; a number of sleep manipulations can alleviate symptoms of depression in some patients; and the majority of antidepressants bring about remarkable changes in sleep polygraphic variables. An obvious question is whether changes in sleep physiological processes are intimately involved in the pathogenesis and recovery from depression. One way to elucidate the link between sleep and depression is to examine whether the influence of antidepressants on sleep is related to clinical improvement in depressives. For that purpose, the effects of antidepressants on EEG sleep and their importance for the treatment of depression are summarized against the background of two existing hypotheses concerning the link between sleep and depression: one hypothesis concerning the role of REM; the other concerning the role of non-REM sleep. EEG sleep studies on the use of antidepressants in depressives have not produced clear evidence of the involvement of REM sleep or non-REM sleep in the mechanisms underlying clinical change. Furthermore, the role of sleep physiological mechanisms during treatment with antidepressants is still unclear. To interpret the effects of antidepressants on EEG sleep in terms of sleep physiological processes more fundamental sleep research is necessary. Also, more comparative studies of antidepressants with similar therapeutic effects but different pharmacological profiles are needed in both healthy and depressed subjects to further quantify the impact of EEG sleep modification in the recovery from depression and to differentiate between pharmacological and sleep-related aspects.     

ADHD, psychostimulants, and sleep disorders: Is there a link?

Sleep difficulties occur in a high percentage of children and adults with attention-deficit/hyperactivity disorder (ADHD). Poor sleep worsens cognitive difficulties; ADHD children who sleep poorly have increased school absenteeism, and their caregivers are more often late for work. This article will review new findings in ADHD sleep disorder studies and the impact of psychostimulant treatment on sleep-related problems. Insomnia is frequently reported as a side effect when stimulants are initiated but is usually mild to moderate in severity and improves during the first week of treatment. Polysomnography shows improvement in sleep latency and overall sleep efficiency when ADHD adults are treated with methylphenidate twice a day. A large clinical trial in ADHD children found no difference in overall sleep parameters between placebo and sustained-release methylphenidate. Similarly, an adult lisdexamfetamine trial found no change in overall sleep efficiency with significant improvement in daytime function.     

Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis

The finding of orexin (hypocretin) deficiency in patients with narcolepsy suggests that this hypothalamic neuropeptide plays a crucial role in regulating and maintaining sleep/wakefulness states and energy homeostasis. Orexin might be especially important for stabilization of behavioral states, because the major symptom in narcolepsy is instability of each behavioral state, which results in sleep/wakefulness fragmentation. The efferent and afferent systems of orexin neurons suggest interactions between these cells and arousal/sleep-wakefulness centers in the brainstem as well as important feeding centers in the hypothalamus. Electrophysiological studies have shown that orexin neurons are regulated by monoamines and acetylcholine as well as metabolic cues, including leptin, glucose, and ghrelin. Thus, orexin neurons have the requisite functional interactions with hypothalamic feeding pathways and monoaminergic/cholinergic centers, and provide a critical link between peripheral energy balance and the central mechanisms that coordinate sleep/wakefulness and motivated behavior such as food seeking.     

Probable causal link between epilepsy and sleep apnea: case report

Patients with epilepsy were reported to have concomitant sleep apnea, but it has been rarely linked to the epilepsy itself. We present a case of a 28-year-old, obese man with secondary medically resistant partial complex epilepsy due to a brain trauma, with progressive snoring, and sleep agitation, apneas, and important daytime somnolence. It was noticed in the polysomnographic study that he had several sleep respiratory events, probably due both to the epileptic seizures and the sleep apnea syndrome as a co-morbidity. Apnea and epilepsy will be discussed. A careful video-EEG-polysomnography study is important in evaluating refractory epileptic patients and/or epileptic patients with snoring.     

Immunomodulators and feeding regulation: a humoral link between the immune and nervous systems

Cells of the nervous and immune systems have specific receptors for humoral substances that originate in both systems. These elements establish a bidirectional information exchange network between the nervous and immune systems. In particular, neuroregulators (neurotransmitters and neuromodulators) can modulate specific immune system function(s) and immunoregulators (immunomodulators) can modulate specific nervous system function(s). Modulation of immune functions by neuroregulators has been receiving considerable attention; however, modulation of nervous system functions by immunomodulators has been little studied. The presence of immunomodulators in the brain and cerebrospinal fluid may represent local synthesis by astrocytes, microglia, endothelial cells, intrinsic macrophages and blood-derived lymphocytes which cross the blood-brain barrier, or the concentration of substances derived from the peripheral blood. Acute and chronic inflammatory processes, malignancy, and immunological reactions stimulate the synthesis and release of immunomodulators in various cell systems. These immunomodulators have pivotal roles in the coordination of the host defense mechanisms and repair and induce a series of endocrine, metabolic, and neurologic responses. This paper focuses on the effects of immunomodulators (interleukins, tumor necrosis factor, tuftsin, platelet activating factor, and others) on the central nervous system (CNS), in particular, on feeding regulation. It is proposed that an immunomodulatory system regulates food intake by a direct action in the CNS through a specific neuro-immuno interaction. This regulatory system may be operative during acute and chronic disease.     

Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats

BackgroundThe orexin (hypocretin) system is important for reward-driven motivation but has not been implicated in the expression of a multiphenotype addicted state.MethodsRats were assessed for economic demand for cocaine before and after 14 days of short access, long access, or intermittent access (IntA) to cocaine. Rats were also assessed for a number of other DSM-5–relevant addiction criteria following differential access conditions. Orexin system function was assessed by quantification of numbers and activity of orexin cells, pharmacological blockade of the orexin-1 receptor, and subregion-specific knockdown of orexin cell populations.ResultsIntA produced a cluster of addiction-like behaviors that closely recapitulate key diagnostic criteria for addiction to a greater extent than long access or short access. IntA was accompanied by an increase in number and activity of orexin-expressing neurons within the lateral hypothalamic subregion. This increase in orexin cell number and activity persisted during protracted withdrawal from cocaine for at least 150 days and was accompanied by enhanced incubation of craving in the same rats. Selective knockdown of lateral hypothalamic orexin neurons reduced motivation for cocaine, and orexin-1 receptor signaling played a larger role in drug seeking after IntA.ConclusionsWe provide the first evidence that lateral hypothalamic orexin system function extends beyond general reward seeking to play a critical role in expression of a multiphenotype addiction-like state. Thus, the orexin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addiction-like behavior in rats.     

Hypocretin (orexin) and melatonin values in a narcoleptic-like sleep disorder after pinealectomy

Narcolepsy secondary to other neurologic processes has been recently associated with hypocretin (orexin) deficiency. We present a patient who developed a narcoleptic-like sleep disorder after receiving treatment for a choroid plexus carcinoma of the pineal gland. She underwent a pinealectomy, chemotherapy, and radiation treatment. The primary features of this condition were excessive daytime sleepiness, sleep paralysis and hypnagogic hallucinations. Increased percentage of rapid eye movement (REM) sleep and sleep onset REM periods were seen during the multiple sleep latency test. Circadian rhythmicity was preserved for melatonin and cortisol. She was negative for human leukocyte antigen DQB1*0602 and had a detectable cerebrospinal fluid hypocretin level (518 pg/ml). We emphasize that the narcoleptic-like disorder likely resulted from the surgical intervention or radiation therapy. Her symptoms are caused by an unknown mechanism unrelated to hypocretin depletion which merits more research.     

The link between emotion regulation,social functioning,and depression in boys with ASD

PurposeSymptoms of depression are common in children and adolescents with an autism spectrum disorder (ASD), but information about underlying developmental factors is limited. Depression is often linked to aspects of emotional functioning such as coping strategies, but in children with ASD difficulties with social interactions are also a likely contributor to depressive symptoms.MethodologyWe examined several aspects of emotional coping (approach, avoidant, maladaptive) and social functioning (victimization, negative friendship interactions) and their relation to depression symptoms in children with ASD (N = 63) and typically developing (TD) peers (N = 57). Children completed a battery of self-report questionnaires.ResultsLess approach and avoidant, but more maladaptive coping strategies, and poor social functioning were uniquely associated with more symptoms of depression in children with ASD. Only less approach and more maladaptive coping were uniquely associated with depression severity in TD boys.ConclusionsUnlike TD boys, boys with ASD who report using avoidant strategies to deal with stressful situations report fewer symptoms of depression, suggesting that this may be an adaptive emotion regulation strategy. However, understanding the role of over-arousal in this process, inferences about long-term effects of this strategy, its causality and direction of effects will require additional research.