A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity
- Stephen R. Morairty1,
- Lars Dittrich1,
- Ravi K. Pasumarthi1,
- Daniel Valladao,
- Jaime E. Heiss,
- Dmitry Gerashchenko2, and
- Thomas S. Kilduff3
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Edited* by Masashi Yanagisawa, University of Texas Southwestern Medical Center, Dallas, TX, and approved October 11, 2013 (received for review August 10, 2013)
Significance
Sleep is a homeostatically regulated process. Slow wave sleep is characterized by slow waves detectable from the cerebral cortex by EEG. When homeostatic sleep “drive” is manipulated by varying durations of sleep deprivation, the intensity of EEG slow waves proportionally increases. The neural circuitry underlying this homeostatic response is little understood. In this study we describe a systematic relationship between homeostatic sleep drive and activation of cortical neurons that express neuronal nitric oxide synthase (nNOS). We also find that transgenic mice lacking nNOS have a greatly diminished response to sleep deprivation. We conclude that cortical nNOS neurons and nNOS enzymatic activity are likely involved in the homeostatic regulation of slow wave sleep.
Abstract
Although the neural circuitry underlying homeostatic sleep regulation is little understood, cortical neurons immunoreactive for neuronal nitric oxide synthase (nNOS) and the neurokinin-1 receptor (NK1) have been proposed to be involved in this physiological process. By systematically manipulating the durations of sleep deprivation and subsequent recovery sleep, we show that activation of cortical nNOS/NK1 neurons is directly related to non-rapid eye movement (NREM) sleep time, NREM bout duration, and EEG δ power during NREM sleep, an index of preexisting homeostatic sleep drive. Conversely, nNOS knockout mice show reduced NREM sleep time, shorter NREM bouts, and decreased power in the low δ range during NREM sleep, despite constitutively elevated sleep drive. Cortical NK1 neurons are still activated in response to sleep deprivation in these mice but, in the absence of nNOS, they are unable to up-regulate NREM δ power appropriately. These findings support the hypothesis that cortical nNOS/NK1 neurons translate homeostatic sleep drive into up-regulation of NREM δ power through an NO-dependent mechanism.
Footnotes
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↵1S.R.M., L.D., and R.K.P. contributed equally to this work.
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↵2Present address: Harvard Medical School/VA Medical Center, West Roxbury, MA 02132.
- ↵3To whom correspondence should be addressed. E-mail: thomas.kilduff{at}sri.com.
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Author contributions: S.R.M., D.G., and T.S.K. designed research; S.R.M., L.D., R.K.P., and D.G. performed research; S.R.M., L.D., D.V., J.E.H., D.G., and T.S.K. analyzed data; and L.D. and T.S.K. wrote the paper.
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The authors declare no conflict of interest.
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↵*This Direct Submission article had a prearranged editor.
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See Commentary on page 19982.
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This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1314762110/-/DCSupplemental.
