The Sleep and Circadian Neurobiology Laboratory  

Basic Research Program

The SCN lab is characterized by a sophisticated in vivo rodent sleep/circadian physiology recording system. Work in the SCN lab focuses on the pharmacological and physiological (and pathophysiological) aspects of sleep/wake regulation and sleep disorders using various animal models, including narcoleptic (knockout and transgenic) mice.

In addition to contributions for a series of discoveries in the pathophysiology of narcolepsy (see publications presented by the Center for Narcolepsy), the SCN lab has:

  1. Identified the major neurotransmitter systems (i.e. adrenergic alpha-1b, alpha-2, dopaminergic D2/3 and cholinergic M2/3 receptor mechanisms) critical for pharmacological control of cataplexy in narcolepsy [1, 2, 3, 4, 5].
  2. Demonstrated preferential involvement of the adrenergic system for mediating anticataplectic effects of tricyclic antidepressants [6].
  3. Identified the presynaptic enhancement of dopaminergic system as the major mode of action of wake-promoting compounds currently available (amphetamine and modafinil) [7, 8, 9].
  4. Found that canine narcolepsy displays periodic leg movements during sleep (PLMS), similar to sleep related involuntary movements seen in human PLMS [10].
  5. Demonstrated that the midbrain (A9 and A10) and diencephalic (A11) dopaminergic nuclei are involved in the regulation of cataplexy in the canine model [11].
  6. Performed detailed analysis of sleep abnormalities in canine narcolepsy and cataplexy [12] and murine models of narcolepsy [13]. These results gave significant insights towards the primary symptoms of narcolepsy.
  7. Characterized the diurnal fluctuation of hypocretin-1 in the CSF and extracellular microdialysis perfusates in freely-moving rats and proposed the model for the regulation of wake and sleep by the hypocretin system [14, 15].
  8. Demonstrated the interaction between the hypocretin and histamine systems and their involvement in sleep regulation [16, 17].
  9. Reported the histamine deficiency in hypocretin receptor 2-mutated narcoleptic Dobermans [18], as well as in human narcolepsy and other hypersomnia of central origins [19, 20].
  10. Conduct studies of hypocretin replacement therapy in hypocretin-receptor-mutated and ligand-deficient narcoleptic dogs [21].
  11. Proposed that narcolepsy may be a unique disease model to study links among fundamental hypothalamic functions in health. and disease [22].
  12. Characterized sleep phenotypes of a murine model human short sleeper (i.e. transgenic mouse of a human mutation in a transcriptional repressor (hDEC2-P385R) [23].
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This project focuses on:

Future projects include looking deeper into sleep and wake controls (especially the interactions between hypocretins and other classical neurotransmitter systems) and exploring the pathophysiology and etiology of sleep and circadian disorders to develop better treatments in human diseases. We use a multidisciplinary approach that involves behavioral, anatomical, genetic and molecular methods using various animal models.

References:

  1. Nishino, S., et al. (1991). Dopamine D2 mechanisms in canine narcolepsy. J Neurosci 11: 2666-2671.
  2. Nishino, S., et al. (1990). Effects of central alpha-2 adrenergic compounds on canine narcolepsy, a disorder of rapid eye movement sleep. J Pharmacol Exp Ther 253: p. 1145-1152.
  3. Nishino, S., et al. (1993). Further characterization of the alpha-1 receptor subtype involved in the control of cataplexy in canine narcolepsy. J Pharmacol Exp Ther 264: p. 1079-1084.
  4. Reid, M.S., et al. (1994). Cholinergic mechanisms in canine narcolepsy: I. Modulation of cataplexy via local drug administration into pontine reticular formation. Neuroscience 59: p. 511-522.
  5. Nishino, S., et al. (1995). Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: implication for the pathophysiology of canine narcolepsy. J Neurosci 15(7 Pt 1): p. 4806-4814.
  6. Nishino, S., et al. (1993). Desmethyl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds. Sleep 16(8): p. 706-12.
  7. Nishino, S., et al. (1998). Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Research Online 1: p. 49-61. http://www.sro.org/1998/Nishino/49/.
  8. Kanbayashi, T., et al. (1997). Differential effects of D-and L-amphetamine isomers on dopaminergic trasmission: Implication for the control of alertness in canine narcolepsy. Sleep Res 26: p. 383.
  9. Wisor, J.P., et al. (2001). Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21(5): p. 1787-94.
  10. Okura, M., et al. (2001). Narcoleptic canines display periodic leg movements during sleep. Psychiatry Clin Neurosci 55(3): p. 243-4.
  11. Okura, M., et al. (2004). The roles of midbrain and diencephalic dopamine cell groups in the regulation of cataplexy in narcoleptic Dobermans. Neurobiol Dis 16(1): p. 274-82.
  12. Nishino, S., et al. (2000). Is narcolepsy REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans. Neuroscience Research 38(4): p. 437-446.
  13. Fujiki, N., et al. (2007). Specificity of direct transition from wake to REM sleep in orexin/ataxin-3 transgenic narcoleptic mice. Exp Neurol 217(1): p. 46-54.
  14. Yoshida, Y., et al. (2001). Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities. Eur J Neurosci 14(7): p. 1075-81.
  15. Fujiki, N., et al. (2001). Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. NeuroReport 12(5): p. 993-7.
  16. Yoshida, Y., et al. (2005). Vigilance Change, Hypocretin And Histamine Release In Rats Before And After A Histamine Synthesis Blocker (Alpha-FMH) Administration. Sleep 28:A18.

  17. Soya, A., et al. (2008). CSF histamine levels in rats reflect the central histamine neurotransmission. Neurosci let 430(3):p. 224-229.
  18. Nishino, S., et al. (2001). Decreased brain histamine contents in hypocretin/orexin receptor-2 mutated narcoleptic dogs. Neurosci Lett 313(3): p. 125-8.
  19. Nishino, S., et al. (2009). I. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep 32(2): p. 181-187.
  20. Kanbayashi, T., et al. (2008). II. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 32(2):p. 175-180.
  21. Fujiki, N., et al. (2003). Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin ligand deficient narcoleptic dog. Sleep 6(8): p. 953-959.
  22. Nishino, S. (2003). The hypocretin/orexin system in health and disease. Biol Psychiatry 54(2): p. 87-95.
  23. He, Y., et al. (2009). The transcriptional repressor DEC2 regulates sleep length in mammals. Science 325(5942):p. 866-870.
  24. Nishino, S., et al. (2004). In Charney DS, Nestler EJ, (eds.) The neurobiology of sleep in relation to mental illness, Neurobiology of Mental Illness, Oxford University Press, New York, 1160-1179.
  25. Fujiki, N., et al. (2005). Attenuated amphetamine induced locomotor sensitization in hypocretin/orexin-deficient narcoleptic mice. Sleep 28(Abstract Supplement ): p. A219.
  26. Fujiki, N., et al. (2006). Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models. Peptides 27(9):2326-2331.
  27. Okuro, M., et al. (2009). A mice model of PTSD: Psychological stress but not physical stress enhances REM sleep. Sleep, Jun; 32, A353-354.
  28. Nishino, S., et al. (2009). Hypocretin neurotransmission differentiates rem sleep changes by physical and psychological stresses. Sleep, 2009, Jun; 32, A354

 

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Seiji Nishino, M.D., Ph.D. and Stanford University, 2011
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