2017.11.21

Orexin modulates behavioral fear expression through the locus coeruleus

（Nat Commun. 2017 Nov 20;8(1):1606. doi: 10.1038/s41467-017-01782-z.）

Soya S¹, Takahashi TM^1,2, McHugh TJ³, Maejima T², Herlitze S⁴, Abe M⁵, Sakimura K⁵, Sakurai T^1,6,7.

¹International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
²Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University
³Laboratory for Circuit & Behavioral Physiology RIKEN Brain Science Institute
⁴Department of General Zoology and Neurobiology, ND7/31, Ruhr-University Bochum
⁵Department of Cellular Neurobiology, Brain Research Institute, Niigata University
⁶Faculty of Medicine, University of Tsukuba
⁷Life Science Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba

Abstract

Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains unknown. Here we report that noradrenergic neurons in the locus coeruleus (NA^LC neurons) projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons. Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NA^LC and LA neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may cause fear generalization sometimes seen in psychiatric disorders, such as PTSD.

*Reprinted under a CC BY 4.0 license.

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