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 (1) member of a large 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.
Specific 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.
Specific 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, the responses to intraperitoneal TNFa before and after, vagotomy and blocking NTS-TNFa production.
Specific Aim 3 tests the hypothesis that reticular thalamic changes in cytokines help regulate non-REM sleep intensity as evidenced by EEG 8 power.
This aim uses the model of TNFa-induced unihemispheric state-dependent enhanced EEG 8 power we developed. We will inject TNFa and/or blockers of TNFa such as nuclear factor kappa B inhibitory peptide, into the perireticular area adjacent to the reticular thalamus and determine subsequent EEG asymmetries and thereby determine functional neural and molecular anatomies of the cytokine-sleep network.
Specific Aim 4 tests the hypothesis that cytokine expression changes with sleep intensity throughout the CNS autonomic sleep regulatory axis. TNFa and/or TNF inhibitors will be unilaterally injected into the somatosensory cortex and fos- and cytokine immunoreactvity determined. Preliminary data provides 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.
| 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 |
| 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 (2012) TRANSLATION OF BRAIN ACTIVITY INTO SLEEP. Hirosaki Igaku 63:S1-S16 |
| 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 |
| 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 |
| Krueger, James M; Tononi, Giulio (2011) Local use-dependent sleep; synthesis of the new paradigm. Curr Top Med Chem 11:2490-2 |
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