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Sleepless in the laboratory
In the Literature.

Here, GNN highlights five papers about the regulation of sleep in the fruit fly and rat related to the feature Awake All Night.


Sleep restriction alters the hypothalamic-pituitary-adrenal response to stress.

Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short-lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8-day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30-min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under conditions of long total sleep deprivation but also after repeated sleep curtailment.

J Neuroendocrinol 2002 May;14(5):397-402.

Sleep deprivation in the rat: X. Integration and discussion of the findings. 1989.

The results of a series of studies on total and selective sleep deprivation in the rat are integrated and discussed. These studies showed that total sleep deprivation, paradoxical sleep deprivation, and disruption and/or deprivation of non-rapid eye movement (NREM) sleep produced a reliable syndrome that included death, debilitated appearance, skin lesions, increased food intake, weight loss, increased energy expenditure, decreased body temperature during the late stages of deprivation, increased plasma norepinephrine, and decreased plasma thyroxine. The significance of this syndrome for the function of sleep is not entirely clear, but several changes suggested that sleep may be necessary for effective thermoregulation.

Sleep 2002 Feb 1;25(1):68-87.

A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis.

In the fruit fly, Drosophila melanogaster, rest shares features with mammalian sleep, including prolonged immobility, decreased sensory responsiveness and a homeostatic rebound after deprivation. To understand the molecular regulation of sleep-like rest, we investigated the involvement of a candidate gene, cAMP response-element binding protein (CREB). The duration of rest was inversely related to cAMP signaling and CREB activity. Acutely blocking CREB activity in transgenic flies did not affect the clock, but increased rest rebound. CREB mutants also had a prolonged and increased homeostatic rebound. In wild types, in vivo CREB activity increased after rest deprivation and remained elevated for a 72-hour recovery period. These data indicate that cAMP signaling has a non-circadian role in waking and rest homeostasis in Drosophila.

Nat Neurosci 2001 Nov;4(11):1108-15.

Modulation of brain gene expression during sleep and wakefulness: a review of recent findings.

The characterization of the molecular correlates of sleep and wakefulness is essential to understand the restorative processes occurring during sleep and the cellular mechanisms underlying sleep regulation. In order to determine what molecular changes occur during the sleep-waking cycle, we have recently performed a systematic screening of gene expression in the brain of sleeping, sleep deprived, and spontaneously awake rats. Out of the approximately 10,000 genes screened so far, a small minority ( approximately 0.5%) was differentially expressed in the cerebral cortex across behavioral states. Most genes were upregulated in wakefulness and sleep deprivation relative to sleep, while only a few were upregulated in sleep relative to wakefulness and sleep deprivation. Almost all the genes upregulated in sleep, and several genes upregulated in wakefulness and sleep deprivation, did not match any known sequence. Known genes expressed at higher levels in wakefulness and sleep deprivation could be grouped into functional categories: immediate early genes/transcription factors, genes related to energy metabolism, growth factors/adhesion molecules, chaperones/heat shock proteins, vesicle and synapse-related genes, neurotransmitter/hormone receptors, neurotransmitter transporters, enzymes, and others. Although the characterization of the molecular correlates of sleep, wakefulness, and sleep deprivation is still in progress, it is already apparent that the transition from sleep to waking can affect basic cellular functions such as RNA and protein synthesis, neural plasticity, neurotransmission, and metabolism.

Neuropsychopharmacology 2001 Nov;25(5 Suppl):S28-35.

Gene expression in the brain across the sleep-waking cycle.

Sleep and waking differ significantly in terms of behavior, metabolism, and neuronal activity. Recent evidence indicates that sleep and waking also differ with respect to the expression of certain genes. To systematically investigate such changes, we used mRNA differential display and cDNA microarrays to screen approximately 10000 transcripts expressed in the cerebral cortex of rats after 8 h of sleep, spontaneous waking, or sleep deprivation. We found that 44 genes had higher mRNA levels after waking and/or sleep deprivation relative to sleep, while 10 were upregulated after sleep. Known genes that were upregulated in waking and sleep deprivation can be grouped into the following categories: immediate early genes/transcription factors (Arc, CHOP, IER5, NGFI-A, NGFI-B, N-Ras, Stat3), genes related to energy metabolism (glucose type I transporter Glut1, Vgf), growth factors/adhesion molecules (BDNF, TrkB, F3 adhesion molecule), chaperones/heat shock proteins (BiP, ERP72, GRP75, HSP60, HSP70), vesicle- and synapse-related genes (chromogranin C, synaptotagmin IV), neurotransmitter/hormone receptors (adrenergic receptor alpha(1A) and beta(2), GABA(A) receptor beta(3), glutamate NMDA receptor 2A, glutamate AMPA receptor GluR2 and GluR3, nicotinic acetylcholine receptor beta(2), thyroid hormone receptor TRbeta), neurotransmitter transporters (glutamate/aspartate transporter GLAST, Na(+)/Cl(-) transporter NTT4/Rxt1), enzymes (aryl sulfotransferase, c-jun N-terminal kinase 1, serum/glucocorticoid-induced serine/threonine kinase), and a miscellaneous group (calmodulin, cyclin D2, LMO-4, metallothionein 3). Several other genes that were upregulated in waking and all the genes upregulated in sleep, with the exception of the one coding for membrane protein E25, did not match any known sequence. Thus, significant changes in gene expression occur across behavioral states, which are likely to affect basic cellular functions such as RNA and protein synthesis, neural plasticity, neurotransmission, and metabolism.

Brain Res 2000 Dec 8;885(2):303-21.

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