The central nervous system (CNS) and immune system engage in reciprocal communication. Sleep is a fundamental CNS process that is regulated by neurotransmitters and responds to immune challenge, as evidenced by changes in sleep that occur when we are sick. In this application we focus on interactions in brain between serotonin (5-hydroxytryptamine; 5-HT) and interleukin-1 (IL-1) as representatives of neurotransmitters and immune-active molecules that are involved in sleep regulation. We previously investigated IL-1 effects on 5-HT and showed that sleep responses to IL-1 are altered if the 5-HT system is antagonized. Studies proposed in this application focus on the reciprocal interaction, i.e., 5-HT effects on IL-1. Our central hypothesis is that, serotonergic activation stimulates the somnogenic cytokine IL-1, which may be one of the factors through which 5-HT exerts its effects on sleep. This central hypothesis will be addressed within the framework of the following questions. 1) Does serotonergic activation alter the brain IL-1 system? 2) Are 5-HT effects on sleep altered when the brain IL-1 system is antagonized? 3) Is the preoptic area/anterior hypothalamus (POA) an important site for these interactions? These questions will be addressed using behavioral, electrophysiological, and molecular approaches. Our preliminary data from the rat indicate that serotonergic activation increases NREM sleep, IL-1 mRNA expression, and c-fos activity in the hypothalamus. These new results and those of previous studies indicate that interactions between these two systems are functionally relevant to sleep. 5-HT and IL-1 are involved in the regulation in the regulation of a number of physiological functions and behaviors in addition to sleep. As such, although our focus remains firmly on sleep, the integrated experimental approach we propose will result in information relevant to several fields of basic and clinical neuroscience.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064843-05
Application #
6864857
Study Section
Special Emphasis Panel (ZRG1-IFCN-3 (01))
Program Officer
Winsky, Lois M
Project Start
2001-03-15
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2007-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$252,590
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Febinger, Heidi Y; George, Amrita; Priestley, Jill et al. (2014) Effects of housing condition and cage change on characteristics of sleep in mice. J Am Assoc Lab Anim Sci 53:29-37
Ingiosi, Ashley M; Opp, Mark R; Krueger, James M (2013) Sleep and immune function: glial contributions and consequences of aging. Curr Opin Neurobiol 23:806-11
Brambilla, Dario; Barajon, Isabella; Bianchi, Susanna et al. (2010) Interleukin-1 inhibits putative cholinergic neurons in vitro and REM sleep when microinjected into the rat laterodorsal tegmental nucleus. Sleep 33:919-29
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) Sleep and psychoneuroimmunology. Immunol Allergy Clin North Am 29:295-307
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

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