Sleep presents a conundrum for neurobiology: we do not know what function(s) sleep serves for the brain (or the body). We do know, however, that adequate sleep is essential for physical and mental health. In addition to effects on cognition and performance, lack of sleep, or sleep disruption due to sleep disorders may be a contributing factor to multiple pathologies, including but not limited to hypertension, coronary artery disease, cerebrovascular disease, and hyperglycemia. Numerous studies demonstrate that sleep loss impairs immune function and that immune activation from infection alters sleep. Responsiveness to infection varies widely: in the extreme, some will live and others will die in response to the same pathogen(s). Numerous systematic pre- clinical studies demonstrate infection-induced alterations in sleep. Most infections increase non-rapid eye movements sleep (NREMS) and decrease rapid eye movements sleep (REMS). Our functional hypothesis is that the manner in which sleep is altered during infection is a critical determinant of clinical outcome. Indeed, one retrospective study demonstrates that specific sleep patterns of rabbits are associated with survival from infection. To further our understanding of central nervous system responses that result in good clinical outcome, we focus on the cytokine interleukin (IL)-1 as one mediator of altered sleep during immune activation. Data indicate IL-1 increases NREMS and suppresses REMS. We propose in this application to focus effort on IL-1-induced suppression of REMS, an effect that has been universally ignored. IL-1 inhibits ACh synthesis and release. Cholinergic neurons of the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei are involved in EEG desynchronization and thalamocortical activation during REMS. REMS- generating structures are under GABAergic inhibition: IL-1 enhances GABA inhibitory effects at multiple levels. Studies proposed in this application will test the mechanistic hypothesis that IL-1 suppresses REMS by opposed, yet complementary actions on brainstem cholinergic and GABAergic systems. Our preliminary data indicate: IL-1 microinjected into the LDT reduces REMS of rats;IL-1 reduces firing rates of cholinergic neurons in LDT slice preparations;and IL-1 increases the number of c-Fos+ neurons in the ventrolateral periaqueductal grey (vlPAG), a GABA-rich area that projects to the pontine reticular formation and the LDT. In this application, we propose to determine: 1) the impact on sleep of IL-1 microinjection into brainstem cholinergic/cholinoceptive nuclei, 2) in vitro effects of IL-1 on electrophysiological properties of cholinergic neurons, and 3) the impact of IL-1 on REMS-relevant brainstem nuclei and neurotransmitter systems using immuno- fluorescence techniques. Successful completion of these aims will provide novel data critical for our understanding of mechanisms by which REMS is suppressed during infection. Determination of whether alterations in sleep contribute to good clinical outcome will only be possible when the neuroanatomic and neurochemical substrates targeted by immune responses to infection are clearly understood.

Public Health Relevance

Some individuals live and others die in response to infections. Sleep is dramatically altered during infection. Evidence suggests the manner in which sleep is altered may contribute to survival. This project will determine effects of immune activation on brain systems responsible for regulating one phase of sleep that is suppressed during sickness. Once we understand how (by what means) sleep is altered during infection, we will be able to study why sleep is altered during infection, i.e., does altered sleep facilitate recovery?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biological Rhythms and Sleep Study Section (BRS)
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Desmond, Nancy L
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University of Washington
Schools of Medicine
United States
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Imeri, Luca; Opp, Mark R (2009) How (and why) the immune system makes us sleep. Nat Rev Neurosci 10:199-210
Opp, Mark R (2009) Sleeping to fuel the immune system: mammalian sleep and resistance to parasites. BMC Evol Biol 9:8
Morrow, Jonathan D; Vikraman, Sundeep; Imeri, Luca et al. (2008) Effects of serotonergic activation by 5-hydroxytryptophan on sleep and body temperature of C57BL/6J and interleukin-6-deficient mice are dose and time related. Sleep 31:21-33
Olivadoti, M D; Opp, M R (2008) Effects of i.c.v. administration of interleukin-1 on sleep and body temperature of interleukin-6-deficient mice. Neuroscience 153:338-48
Imeri, Luca; Bianchi, Susanna; Opp, Mark R (2006) Inhibition of caspase-1 in rat brain reduces spontaneous nonrapid eye movement sleep and nonrapid eye movement sleep enhancement induced by lipopolysaccharide. Am J Physiol Regul Integr Comp Physiol 291:R197-204
Opp, Mark R (2006) Sleep and psychoneuroimmunology. Neurol Clin 24:493-506
Opp, Mark R (2005) Cytokines and sleep. Sleep Med Rev 9:355-64
Imeri, Luca; Bianchi, Susanna; Opp, Mark R (2005) Antagonism of corticotropin-releasing hormone alters serotonergic-induced changes in brain temperature, but not sleep, of rats. Am J Physiol Regul Integr Comp Physiol 289:R1116-23
Kapsimalis, Fotis; Richardson, Gary; Opp, Mark R et al. (2005) Cytokines and normal sleep. Curr Opin Pulm Med 11:481-4
Morrow, Jonathan D; Opp, Mark R (2005) Diurnal variation of lipopolysaccharide-induced alterations in sleep and body temperature of interleukin-6-deficient mice. Brain Behav Immun 19:40-51

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