Work conducted in my laboratory has demonstrated that microbial infections induced by numerous pathogenic agents cause alterations in normal sleep patterns, and that facets of the immune response to microbial challenge are likely to mediate these behavioral effects. Identifying the factors that cause fatigue and excessive or disturbed sleep during microbial infections and developing effective interventions for these disabling symptoms could improve the economic well-being and quality of life of many individuals. My long-term goal is to define the genetic and inflammatory mechanisms that mediate fatigue and altered sleep propensity during infectious disease. To that end, I recently completed an analysis of genetic contributions to altered sleep patterns in influenza-infected mice. My preliminary data indicate that a discrete subset of genes is likely to account for large and consistent differences in influenza-induced sleep in different strains of inbred mice. This application proposes to build on that work by identifying the genetic and pathologic mechanisms that mediate sleep responses to other types of microbial challenges and by integrating the new data with our previous findings. A genome-wide approach to identifying candidate genes will be applied in the proposed aims. As the critical first step in identifying genes that regulate infection-induced alterations in sleep, we will characterize the sleep patterns of prototypic strains of mice after specific microbial challenges. We will use those data to select the most efficient strategies for mapping quantitative trait loci for infection-related sleep phenotypes using recombinant inbred mice. Identifying the genes that modulate infection-induced sleep is an important step toward discovering gene products that influence disease susceptibility and symptomatology. Studying the mechanisms by which genes and their products modulate sleep will ultimately improve our understanding of processes that control normal sleep and contribute to sleep disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040220-04
Application #
6394463
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Program Officer
Nichols, Paul L
Project Start
1999-09-30
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$218,636
Indirect Cost
Name
Southern Illinois University Carbondale
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939007555
City
Carbondale
State
IL
Country
United States
Zip Code
62901
Toth, Linda A; Trammell, Rita A; Williams, Robert W (2014) Mapping complex traits using families of recombinant inbred strains: an overview and example of mapping susceptibility to Candida albicans induced illness phenotypes. Pathog Dis 71:234-48
Trammell, Rita A; Cox, Lisa; Pikora, Joshua et al. (2012) Evaluation of an extract of North American ginseng (Panax quinquefolius L.) in Candida albicans-infected complement-deficient mice. J Ethnopharmacol 139:414-21
Trammell, Rita A; Toth, Linda A (2011) Markers for predicting death as an outcome for mice used in infectious disease research. Comp Med 61:492-8
Turner, Jeremy; Hughes, Larry F; Toth, Linda A (2010) Sleep, activity, temperature and arousal responses of mice deficient for muscarinic receptor M2 or M4. Life Sci 86:158-69
Ding, Ming; Arnold, Jennifer; Turner, Jeremy et al. (2010) Lack of association of a spontaneous mutation of the Chrm2 gene with behavioral and physiologic phenotypic differences in inbred mice. Comp Med 60:272-81
Johnston, Nancy A; Bosgraaf, Christine; Cox, Lisa et al. (2007) Strategies for refinement of abdominal device implantation in mice: strain, carboxymethylcellulose, thermal support, and atipamezole. J Am Assoc Lab Anim Sci 46:46-53
Ding, Ming; Toth, Linda A (2006) mRNA expression in mouse hypothalamus and basal forebrain during influenza infection: a novel model for sleep regulation. Physiol Genomics 24:225-34
Toth, Linda A; Hughes, Larry F (2006) Sleep and temperature responses of inbred mice with Candida albicans-induced pyelonephritis. Comp Med 56:252-61
Toth, Linda A; Hughes, Larry F; Rehg, Jerold E (2005) Sleep during concanavalin-A-induced hepatitis and peritonitis in inbred mice. Sleep 28:571-82
Toth, Linda A; Hughes, Larry F (2004) Macrophage participation in influenza-induced sleep enhancement in C57BL/6J mice. Brain Behav Immun 18:375-89

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