Sleep propensity varies across the day, increases after sleep deprivation (SD) or during the """"""""flu."""""""" Changes in sleep propensity reflect the degree of activation of physiological sleep mechanisms including humoral sleep mechanisms. This application is focused on the broad hypothesis that tumor necrosis factor alpha (TNFa) is a key element in the molecular network regulating sleep. Much evidence implicates TNFa in physiological sleep mechanisms and in the sleep responses occurring in many pathologies. For instance, the soluble TNF receptor (sTNFR), reduces spontaneous sleep and SD-induced sleep responses in animal models and sleepiness in insomnia patients. TNFa is, however, but one member of a molecular sleep regulatory network. The experiments in this application are focused on that network, where it acts to produce sleep and the neural circuitry involved in TNFa-enhanced sleep and EEG slow-wave activity.
Aim 1 is focused on the simultaneous measurement of multiple cytokines, all of which affect sleep, using multiplexed bead array technology. We test the hypothesis that the ratio of TNFa to other cytokines in the hypothalamus (hyp), thalamus (thal), cortex (ctx) and nucleus tractus solitarius (NTS) and plasma will dynamically change with sleep history and will predict sleep propensity.
Aim 2 focuses on the hypothesis that pathology-associated increases in systemic TNFa promote sleep via vagal afferents to the NTS. We will determine by bead array and TNF immunohistochemistry, the responses to intraperitoneal TNFa before and after vagotomy.
Aim 3 tests the hypothesis that TNFa promotes the functional state of cortical columns analogous to sleep. To test this hypothesis, cortical column functional state will be determined electrophysiologically using multi electrode arrays in conjunction with microinjection of TNFa onto the surface of columns. Functional states will be characterized by amplitudes of surface evoked potentials and several other measurements.
Aim 4 tests the hypothesis that cytokine expression changes with sleep intensity throughout the sleep regulatory axis. TNFa and/or TNF inhibitors will be unilaterally injected onto the surface of the somatosensory cortex and fos- and cytokine immunoreactivity determined in affected circuits. Preliminary data provide a rationale for each specific aim and demonstrate feasibility. Successful completion of the experiments will help integrate the biochemical, neuroanatomical and electrophysiological sleep regulatory literature.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031453-17
Application #
7754661
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Mitler, Merrill
Project Start
1993-08-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
17
Fiscal Year
2010
Total Cost
$317,914
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Zielinski, Mark R; Dunbrasky, Danielle L; Taishi, Ping et al. (2013) Vagotomy attenuates brain cytokines and sleep induced by peripherally administered tumor necrosis factor-? and lipopolysaccharide in mice. Sleep 36:1227-38, 1238A
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
Hodgson, Nicole R; Bohnet, Stewart G; Majde, Jeannine A et al. (2012) Influenza virus pathophysiology and brain invasion in mice with functional and dysfunctional Mx1 genes. Brain Behav Immun 26:83-9
Krueger, James M (2012) TRANSLATION OF BRAIN ACTIVITY INTO SLEEP. Hirosaki Igaku 63:S1-S16
Jewett, Kathryn A; Krueger, James M (2012) Humoral sleep regulation; interleukin-1 and tumor necrosis factor. Vitam Horm 89:241-57
Davis, Christopher J; Krueger, James M (2012) Sleep and Cytokines. Sleep Med Clin 7:517-527
Davis, Christopher J; Clinton, James M; Krueger, James M (2012) MicroRNA 138, let-7b, and 125a inhibitors differentially alter sleep and EEG delta-wave activity in rats. J Appl Physiol 113:1756-62
Taishi, Ping; Davis, Christopher J; Bayomy, Omar et al. (2012) Brain-specific interleukin-1 receptor accessory protein in sleep regulation. J Appl Physiol 112:1015-22
Zielinski, Mark R; Taishi, Ping; Clinton, James M et al. (2012) 5'-Ectonucleotidase-knockout mice lack non-REM sleep responses to sleep deprivation. Eur J Neurosci 35:1789-98
Krueger, James M; Majde, Jeannine A; Rector, David M (2011) Cytokines in immune function and sleep regulation. Handb Clin Neurol 98:229-40

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