Inhibition of caspase-1 in rat brain reduces spontaneous nonrapid eye movement sleep and nonrapid eye movement sleep enhancement induced by lipopolysaccharide

Evidence suggests that IL-1beta is involved in promoting physiol. nonrapid eye movement (NREM) sleep. IL-1beta has also been proposed to mediate NREM sleep enhancement induced by bacteria or their components. Mature and biologically active IL-1beta is cleaved from an inactive precursor by a cysteinyl aspartate-specific protease (caspase)-1. This study aimed to test the hypothesis that inhibition in brain of the cleavage of biol. active IL-1beta will reduce in rats both spontaneous NREM sleep and NREM sleep enhancement induced by the peripheral administration of components of the bacterial cell wall. To test this hypothesis, rats were intracerebroventricularly administered the caspase-1 inhibitor Ac-Tyr-Val-Ala-Asp chloromethyl ketone (YVAD; 3, 30, 300, and 1,500 ng) or were pretreated intracerebroventricularly with YVAD (300 ng) and then i.p. injected with the gram-neg. bacterial cell wall component LPS (250 mg/kg). Subsequent sleep-wake behavior was detd. by std. polygraphic recordings. YVAD administration at the beginning of the light phase of the light-dark cycle significantly reduced time spontaneously spent in NREM sleep during the first 12 postinjection hours. YVAD pretreatment also completely prevented NREM sleep enhancement induced by peripheral LPS administration at the beginning of the dark phase. These results, in agreement with previous evidence, support the involvement of brain IL-1beta in physiol.ogical promotion of NREM sleep and in mediating NREM sleep enhancement induced by peripheral immune challenge

Antagonism of corticotropin-releasing hormone alters serotonergic-induced changes in brain temperature, but not sleep, of rats

Serotonin is involved in many physiological processes, including the regulation of sleep and body temperature. Administration into rats of low doses (25, 50 mg/kg) of the 5-HT precursor l-5-hydroxytryptophan (5-HTP) at the beginning of the dark period of the 12:12-h light-dark cycle initially increases wakefulness. Higher doses (75, 100 mg/kg) increase nonrapid eye movement (NREM) sleep. The initial enhancement of wakefulness after low-dose 5-HTP administration may be a direct action of 5-HT in brain or due to 5-HT-induced activation of other arousal-promoting systems. One candidate arousal-promoting system is corticotropin-releasing hormone (CRH) and the hypothalamic-pituitary-adrenal axis. Serotonergic activation by 5-HTP at the beginning of the dark period also induces hypothermia. Because sleep and body temperature are influenced by circadian factors, one aim of this study was to determine responses to 5-HTP when administered at a different circadian time, the beginning of the light period. Results obtained show that all doses of 5-HTP (25-100 mg/kg) administered at light onset initially increase wakefulness; NREM sleep increases only after a long delay, during the subsequent dark period. Serotonergic activation by 5-HTP at light onset induces hypothermia, the time course of which is biphasic after higher doses (75, 100 mg/kg). Intracerebroventricular pretreatment with the CRH receptor antagonist alpha-helical CRH does not alter the impact of 5-HTP on sleep-wake behavior but potentiates the hypothermic response to 50 mg/kg 5-HTP. These data suggest that serotonergic activation by peripheral administration of 5-HTP may modulate sleep-wake behavior by mechanisms in addition to direct actions in brain and that circadian systems are important determinants of the impact of serotonergic activation on sleep and body temperature

The reciprocal link between sleep and immune responses

Good sleep is necessary for both physical and mental health; sleep and immune responses are reciprocally and closely linked. Sleep loss impairs the immune response, while, on the other hand, the immune response, activated for instance by an infection, alters sleep. Sleep alterations induced by immune activation are mediated by cytokines such as interleukin-1. In the past, it was thought that cytokines were produced only by the immune system, and active only there as signaling molecules. Today it is clear that IL-1 and other cytokines are present and active in the healthy brain, where they physiologically interact with the brain circuits and the neurotransmitter systems (for instance the serotonergic, GABAergic, and cholinergic systems) that control sleep. These interactions are altered by immune response, and, as a result, non-rapid eye move- ment (NREM) sleep is increased and fragmented, whereas rapid eye movements (REM) sleep is inhibited

Sleep, but not febrile responses of Fisher 344 rats to immune challenge are affected by aging

Sleep is altered in response to infection and immune challenge in humans and non-human animals. Although there are changes in sleep and facets of immune function with aging, sleep responses of aged subjects to immune challenge have received little, if any attention. To test the hypothesis that aging affects sleep responses to immune challenge, intracerebroventricular injections of interleukin 1 (IL-1) were given to young and aged rats and subsequent sleep-wake behavior was determined. Under basal conditions and in the absence of an immune challenge, sleep patterns of young (3 months) and aged (25\u201327 months) Fisher 344 rats did not differ. In young animals, IL-1 (2.5\ua0ng) enhanced non-rapid eye movement (NREM) sleep, inhibited rapid eye movement (REM) sleep, and induced fever. In aged animals, IL-1 administration did not alter NREM sleep, but REM sleep was inhibited and brain temperature increased to the same extent observed in young animals. These results show that alterations in sleep following immune challenge are impacted by aging, whereas febrile responses are not. Since it has been postulated that enhanced NREM sleep may facilitate recovery from microbial infection, the present results also suggest that the lack of NREM sleep responses of aged rats to immune challenge may contribute to the increased infection-induced morbidity and mortality of aged organisms