Lack of hypocretin attenuates behavioral changes produced by glutamatergic activation of the perifornical-lateral hypothalamic area.
OBJECTIVE
The 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.


METHODS
We 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.


RESULTS
As 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.


CONCLUSIONS
The 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.
Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA.
Andrey
A
Kostin
Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA ; Department of Psychiatry and Brain Research Institute, University of California, Los Angeles, CA.
Jerome M
JM
Siegel
Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA ; Department of Medicine, School of Medicine, University of California, Los Angeles, CA.
Md Noor
MN
Alam
D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D009290:Narcolepsy; D009474:Neurons / Q000502:physiology; D009479:Neuropeptides / Q000172:deficiency*; D000068797:Orexins; D012890:Sleep / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D018698:Glutamic Acid; D016202:N-Methylaspartate
N-methyl-D-aspartate; dorsomedial hypothalamus; hypocretin; lateral hypothalamus; orexin; perifornical area; prepro-orexin knockout; sleep