Synchronization of neuronal activity within and across brain regions is a fundamental property of cortical and subcortical networks needed for normal brain functions. Synchronization of electroencephalogram (EEG) in the frequency range of 1-4 Hz, referred to as slow wave activity (SWA), is observed during slow wave sleep and is thought to be essential for the recuperative function of sleep. Recent work in our laboratory found that changes in SWA parallel the changes in the activity of neuronal nitric oxide synthase (nNOS)-immunoreactive cells in the cortex in three mammalian species. These results suggest that nNOS neurons in the cortex are part of the brain circuit that is involved in the generation of SWA. Since SWA is an established marker of the homeostatic sleep drive, the nNOS neuronal circuit is expected to be activated by homeostatic mechanisms. The proposed studies will test the following hypotheses: (1) changes in the activity of nNOS cells in the cortex correlate with SWA, (2) changes in the activity of nNOS cells in the cortex are independent of circadian input from the suprachiasmatic nucleus, (3) anatomical properties of nNOS cells are consistent with the role of these neurons in EEG synchronization, (4) nitric oxide production by nNOS is involved in SWA generation, and (5) selective ablation of nNOS cells leads to disturbances in SWA production and sleep homeostasis. This research will be a first step in characterizing newly discovered sleep-active neurons in the cortex. It will provide important information about regulation of brain activity by nNOS neurons and may advance our understanding not only of the pathophysiology of sleep disorders, but also of neurological and psychiatric diseases that involve the cerebral cortex.

Public Health Relevance

Research on the role of sleep-active neurons recently discovered in the cerebral cortex will provide new information about regulation of brain activity. An understanding of the functions and mechanisms of these neurons may lead to new approaches for treating a variety of neurological and psychiatric diseases involving the cerebral cortex, as well as for ameliorating common sleep disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
He, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Medicine
United States
Zip Code
Zielinski, Mark R; Gerashchenko, Dmitry (2017) Sleep-inducing effect of substance P-cholera toxin A subunit in mice. Neurosci Lett 659:44-47
Zielinski, Mark R; Gerashchenko, Dmitry; Karpova, Svetlana A et al. (2017) The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide. Brain Behav Immun 62:137-150
Zielinski, M R; Karpova, S A; Yang, X et al. (2015) Substance P and the neurokinin-1 receptor regulate electroencephalogram non-rapid eye movement sleep slow-wave activity locally. Neuroscience 284:260-72
Zielinski, Mark R; Kim, Youngsoo; Karpova, Svetlana A et al. (2014) Chronic sleep restriction elevates brain interleukin-1 beta and tumor necrosis factor-alpha and attenuates brain-derived neurotrophic factor expression. Neurosci Lett 580:27-31
Zielinski, M R; Kim, Y; Karpova, S A et al. (2013) Sleep active cortical neurons expressing neuronal nitric oxide synthase are active after both acute sleep deprivation and chronic sleep restriction. Neuroscience 247:35-42
Zielinski, Mark R; Gerashchenko, Ludmila; Karpova, Svetlana A et al. (2013) A novel telemetric system to measure polysomnographic biopotentials in freely moving animals. J Neurosci Methods 216:79-86
Kilduff, Thomas S; Cauli, Bruno; Gerashchenko, Dmitry (2011) Activation of cortical interneurons during sleep: an anatomical link to homeostatic sleep regulation? Trends Neurosci 34:10-9
Gerashchenko, Dmitry; Wisor, Jonathan P; Kilduff, Thomas S (2011) Sleep-active cells in the cerebral cortex and their role in slow-wave activity. Sleep Biol Rhythms 9:71-77