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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064193-04
Application #
8445274
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
He, Janet
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$266,244
Indirect Cost
$59,372
Name
Harvard University
Department
Neurology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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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