• Andrey Kostin, Jerome M Siegel, and Md Noor Alam.
• Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA.
• Sleep. 2014 May 1;37(5):1011-20.

Study ObjectivesThe hypocretins (HCRTs) are two hypothalamic peptides predominantly localized to neurons in the perifornical, dorsomedial, and lateral hypothalamic area (PF-LHA). Evidence suggests that HCRT signaling is critical for the promotion and stabilization of active-arousal and its loss or malfunction leads to symptoms of narcolepsy. In the PF-LHA, HCRT neurons are intermingled with glutamate-expressing neurons and also co-express glutamate. Evidence suggests that HCRT-glutamate interactions within the PF-LHA may play a critical role in maintaining behavioral arousal. However, the relative contributions of the glutamate and HCRT in sleep-wake regulation are not known.DesignWe determined whether a lack of HCRT signaling in the prepro-orexin-knockout (HCRT-KO) mouse attenuates/compromises the wake-promoting ability of glutamatergic activation of the PF-LHA region. We used reverse microdialysis to deliver N-methyl-D-aspartate (NMDA) into the HCRT zone of the PF-LHA in HCRT-KO and wild-type (WT) mice to evaluate the contributions of glutamatergic vs. HCRT signaling in sleep-wake regulation.Measurements And ResultsAs compared to respective controls, local perfusion of NMDA into the PF-LHA, dose-dependently increased active-waking with concomitant reductions in nonREM and REM sleep in spontaneously sleeping WT as well as HCRT-KO mice. However, compared to WT, the NMDA-induced behavioral changes in HCRT-KO mice were significantly attenuated, as evidenced by the higher dose of NMDA needed and lower magnitude of changes induced in sleep-wake parameters. Although not observed in WT mice, the number of cataplectic events increased significantly during NMDA-induced behavioral arousal in HCRT-KO mice.ConclusionsThe findings of this study are consistent with a hypothesis that synergistic interactions between hypocretin and glutamatergic mechanisms within the perifornical, dorsomedial, and lateral hypothalamic area are critical for maintaining behavioral arousal, especially arousal involving elevated muscle tone.

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