Saper CB, Chou TC, Scammell TE: The sleep switch: Hypothalamic control of sleep and wakefulness

Dept of Neurology, Program in Neuroscience, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Trends in Neurosciences (Impact Factor: 13.56). 01/2002; 24(12):726-31. DOI: 10.1016/S0166-2236(00)02002-6
Source: PubMed


More than 70 years ago, von Economo predicted a wake-promoting area in the posterior hypothalamus and a sleep-promoting region in the preoptic area. Recent studies have dramatically confirmed these predictions. The ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons that are active during sleep and are necessary for normal sleep. The posterior lateral hypothalamus contains orexin/hypocretin neurons that are crucial for maintaining normal wakefulness. A model is proposed in which wake- and sleep-promoting neurons inhibit each other, which results in stable wakefulness and sleep. Disruption of wake- or sleep-promoting pathways results in behavioral state instability.

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    • "The mechanism by which, for example, the DMN is segregated from other cortical regions is unclear (Greicius et al., 2003; Uddin et al., 2008). The contribution of the AAS, IL and RN to global cortical activation control is widely suspected (Steriade and McCarley, 1990; Taylor and Farrukh, 1996; Saper et al., 2001). "
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    ABSTRACT: Cortical activity exhibits persistent metastable dynamics. Assemblies of neurons transiently couple (integrate) and decouple (segregate) at multiple spatiotemporal scales; both integration and segregation are required to support metastability. Integration of distant brain regions can be achieved through long range excitatory projections, but the mechanism supporting long range segregation is not clear. We argue that the thalamocortical matrix connections, which project diffusely from the thalamus to the cortex and have long been thought to support cortical gain control, play an equally-important role in cortical segregation. We present a computational model of the diffuse thalamocortical loop, called the competitive cross-coupling (CXC) spiking network. Simulations of the model show how different levels of tonic input from the brainstem to the thalamus could control dynamical complexity in the cortex, directing transitions between sleep, wakefulness and high attention or vigilance. The model also explains how mutually-exclusive activity could arise across large portions of the cortex, such as between the default-mode and task-positive networks. It is robust to noise but does not require noise to autonomously generate metastability. We conclude that the long range segregation observed in brain activity and required for global metastable dynamics could be provided by the thalamocortical matrix, and is strongly modulated by brainstem input to the thalamus.
    Frontiers in Systems Neuroscience 08/2015; 9. DOI:10.3389/fnsys.2015.00119
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    • "Internally, the sleep–wake rhythm is centrally coordinated by an endogenous circadian clock, placed in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus (Maywood et al., 2006). The neurons of the SCN are circadian oscillators that form functional pacemakers (Saper et al., 2001; Cheng et al., 2002). The timing of their oscillations is determined by an intrinsic cellular rhythmicity, which lasts 24 h, even in the absence of external inputs (Moore et al., 2002) such as light, feeding patterns, and social environment (Mueller et al., 2013). "
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    ABSTRACT: Adult mammalian brains continuously generate new neurons, a phenomenon called neurogenesis. Both environmental stimuli and endogenous factors are important regulators of neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and neurogenesis in brain function, such as learning, memory and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on neurogenesis.
    Frontiers in Cellular Neuroscience 03/2015; 9:140. DOI:10.3389/fncel.2015.00140 · 4.29 Impact Factor
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    • "Hypersomnia or insomnia The neurophysiology of sleep and how it is changed in major depression is very complex (Mignot, 2001; Wisor et al., 2001; Zheng and Berthoud, 2007); it is, therefore, beyond the scope of this review to extensively discuss the neurobiology of sleep disturbances in the different subtypes of major depression. In general, states of arousal are regulated by the hypothalamic sleep–wake switch, which consists of sleep-promoting neurons in the ventrolateral preoptic area and wakepromoting neurons in the tuberomammillary nucleus (Saper et al., 2001). Noradrenergic and serotonergic projections from the LC and dorsal and median RN, respectively, run through the hypothalamus, where they are combined with histaminergic projections from the tuberomammillary nucleus. "
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    ABSTRACT: First line antidepressants are the so-called SSRI's (selective serotonin reuptake inhibitors), e.g. fluvoxamine, fluoxetine, sertraline, paroxetine and escitalopram. Unfortunately, these drugs mostly do not provide full symptom relief and have a slow onset of action. Therefore also other antidepressants are being prescribed that inhibit the reuptake of norepinephrine (e.g. reboxetine, desipramine) or the reuptake of both serotonin (5-HT) and norepinephrine (e.g. venlafaxine, duloxetine, milnacipran). Nevertheless, many patients encounter residual symptoms such as impaired pleasure, impaired motivation, and lack of energy. It is hypothesized that an impaired brain reward system may underlie these residual symptoms. In agreement, there is some evidence that reuptake inhibitors of both norepinephrine and dopamine (e.g. methylphenidate, bupropion, nomifensine) affect these residual symptoms. In the pipeline are new drugs that block all three monoamine transporters for the reuptake of 5-HT, norepinephrine and dopamine, the so-called triple reuptake inhibitors (TRI). The working mechanisms of the above-mentioned antidepressants are discussed, and it is speculated whether depressed patients with different symptoms, sometimes even opposite ones due to atypical or melancholic features, can be matched with the different drug treatments available. In other words, is personalized medicine for major depression an option in the near future? Copyright © 2015. Published by Elsevier B.V.
    European Journal of Pharmacology 01/2015; 753. DOI:10.1016/j.ejphar.2014.11.045 · 2.53 Impact Factor
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