Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Cytokine and neurotransmitter interactions in sleep regulation

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Sleep as a complex behavior presents a conundrum for neurobiology: we do not know what function(s) sleep serves for the brain. We do know, however, that adequate sleep is essential for physical and mental health. Interactions between sleep and the immune system are bidirectional: activation of the immune system alters sleep, whereas sleep loss impairs immune function. During the previous funding period we focused our studies on interactions between one cytokine, interleukin-1 (IL-1), and the serotonergic system. Data indicate IL-1 increases NREMS. We demonstrated that interactions between IL-1 and the serotonergic system are of functional relevance to NREMS. We propose in this application to focus effort on one aspect of IL-1 effects on sleep that has been universally ignored, suppression of REMS. 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 overall 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 positive neurons in the ventrolateral periaqueductal grey (vlPAG), a GABA-rich area that projects to the pontine reticular formation, and in the LDT, brain stem regions implicated in REMS. In this application, we propose to: 1) determine the impact on sleep of IL-1 microinjection into brainstem cholinergic/cholinoceptive nuclei, 2) determine in vitro effects of IL-1 on electrophysiol-ogical properties of brainstem cholinergic neurons, and 3) localize brain stem sites of action for IL-1 using immunohistochemical techniques. Successful completion of these aims will provide novel data about potential mechanisms whereby IL-1 suppresses REMS. Such information is critical for our understanding of the functional consequences of infection-induced alterations in sleep. Knowledge of mechanisms by which IL-1 alters REMS will further our understanding of mental disorders characterised by disruptions to REMS and by cytokine dysregulation, such as major depressive disorders.
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