The PI's and other recent studies with the immediate-early gene, c-fos, have shown that this gene is expressed differentially in discrete brain regions in response to sleep and wakefulness. These findings have led to the speculation that c-fos is involved in sleep. If this cascade is compromised, as with the application of c-fos antisense (which blocks new c-Fos protein synthesis), or in animals lacking the c-fos gene (null c-fos), then there should be less sleep. Recent findings using c-fos antisense is consistent with this hypothesis. Our own preliminary data with null c-fos mice also supports this hypothesis. Specifically, we find that null c-fos mice have a 30% reduction in SWS; REM sleep is intact. We have now discovered that another gene, fos-B, that shares 70% homology with c-fos is involved in REM sleep. Mice lacking fos-B (either heterozygote or homozygote with respect to fos-B deletion) have a 40% reduction in REM sleep; wakefulness and SWS are unchanged. These findings suggest that wakefulness, SWS or REM sleep can be influenced by specific genes.
Four specific aims will mechanistically test the overall hypothesis that deletion of specific genes affects specific sleep states.
Specific aim 1 will test the hypothesis that null c-fos (homozygous, -/-) mice have less SWS, compared to siblings with one (heterozygotes, +/-) or both alleles of the gene (c-fos +/+).
Specific aim 2 will test the hypothesis that null c-fos mice sleep less even when the pressure to sleep is increased.
Specific aim 3 will determine whether the reduced sleep in null c-fos mice is due to reductions in levels or sensitivity to known somnogens.
Specific aim 4 will test the hypothesis that adenosine, a known somnogen, induces c-fos expression and resultant AP-1 binding in the basal forebrain and VLPO of WT but not null c-fos mice. The finding that sleep could be affected at the level of inducible genes is a novel one. This approach is consistent with emerging evidence that certain behaviors are governed by a cascade of cellular events that involve transcription factors. Clearly, a defect in a gene could result in a malformed protein which could result in abnormal sleep, as has been found in fatal familial insomnia, a prion disease. Our findings are applicable to narcolepsy, an inherited sleep disorder characterized by excessive daytime sleepiness, sleep attacks, cataplexy and hypnagogic hallucinations. The PI's studies to date have used c-Fos to identify the neuronal mechanisms generating sleep. To the best of our knowledge no current program is examining transcription factors as playing a role in the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS030140-09S1
Application #
6325269
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Kitt, Cheryl A
Project Start
1991-09-30
Project End
2002-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
9
Fiscal Year
2000
Total Cost
$25,000
Indirect Cost
Name
Harvard University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
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Liu, Meng; Blanco-Centurion, Carlos; Konadhode, RodaRani et al. (2011) Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. J Neurosci 31:6028-40
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Kaur, Satvinder; Thankachan, Stephen; Begum, Suraiya et al. (2009) Hypocretin-2 saporin lesions of the ventrolateral periaquaductal gray (vlPAG) increase REM sleep in hypocretin knockout mice. PLoS One 4:e6346
Liu, Meng; Thankachan, Stephen; Kaur, Satvinder et al. (2008) Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice. Eur J Neurosci 28:1382-93
Murillo-Rodriguez, Eric; Liu, Meng; Blanco-Centurion, Carlos et al. (2008) Effects of hypocretin (orexin) neuronal loss on sleep and extracellular adenosine levels in the rat basal forebrain. Eur J Neurosci 28:1191-8
Kaur, Satvinder; Thankachan, Stephen; Begum, Suraiya et al. (2008) Entrainment of temperature and activity rhythms to restricted feeding in orexin knock out mice. Brain Res 1205:47-54
Blanco-Centurion, Carlos; Gerashchenko, Dmitry; Shiromani, Priyattam J (2007) Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake. J Neurosci 27:14041-8
Zhang, S; Lin, L; Kaur, S et al. (2007) The development of hypocretin (orexin) deficiency in hypocretin/ataxin-3 transgenic rats. Neuroscience 148:34-43
Blanco-Centurion, Carlos; Xu, Man; Murillo-Rodriguez, Eric et al. (2006) Adenosine and sleep homeostasis in the Basal forebrain. J Neurosci 26:8092-100

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