title: Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus.
abstract: Survival in a dangerous environment requires learning about stimuli that predict harm. Although recent work has focused on the amygdala as the locus of aversive memory formation, the hypothalamus has long been implicated in emotional regulation, and the hypothalamic neuropeptide orexin (hypocretin) is involved in anxiety states and arousal. Nevertheless, little is known about the role of orexin in aversive memory formation. Using a combination of behavioral pharmacology, slice physiology, and optogenetic techniques, we show that orexin acts upstream of the amygdala via the noradrenergic locus coeruleus to enable threat (fear) learning, specifically during the aversive event. Our results are consistent with clinical studies linking orexin levels to aversive learning and anxiety in humans and dysregulation of the orexin system may contribute to the etiology of fear and anxiety disorders.
authors.affiliation: Center for Neuroscience, New York University, New York, NY 10003.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sears
authors.forename: Ann E
authors.initials: AE
authors.lastname: Fink
authors.forename: Mattis B
authors.initials: MB
authors.lastname: Wigestrand
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Farb
authors.forename: Luis
authors.initials: L
authors.lastname: de Lecea
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Ledoux
mesh_terms: D000161:Acoustic Stimulation; D000679:Amygdala / Q000502:physiology*; D000818:Animals; D001583:Benzoxazoles / Q000008:administration & dosage / Q000494:pharmacology; D000075402:Channelrhodopsins; D003214:Conditioning, Classical; D005239:Fear; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007858:Learning / Q000502:physiology*; D008125:Locus Coeruleus / Q000502:physiology*; D008297:Male; D009287:Naphthyridines; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D062308:Optogenetics; D000068797:Orexins; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D000075402:Channelrhodopsins; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D014508:Urea
keywords: channelrhodopsin-2; fear conditioning; norepinephrine