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The Journal of Neuroscience, December 15, 2004, 24(50):11439-11448; doi:10.1523/JNEUROSCI.3459-04.2004

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Behavioral/Systems/Cognitive
Interaction between the Corticotropin-Releasing Factor System and Hypocretins (Orexins): A Novel Circuit Mediating Stress Response

Raphaëlle Winsky-Sommerer,¹ Akihiro Yamanaka,^3,4 Sabrina Diano,⁵ Erzsebet Borok,⁵ Amanda J. Roberts,² Takeshi Sakurai,⁴ Thomas S. Kilduff,³ Tamas L. Horvath,^5,6 and Luis de Lecea^1,2

Departments of ¹Molecular Biology and ²Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, ³Molecular Neurobiology Laboratory, Stanford Research Institute International, Menlo Park, California 94025, ⁴Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan, and Departments of ⁵Obstetrics and Gynecology and ⁶Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520

The hypothalamic neuropeptides hypocretins (orexins) play a crucial role in the stability of arousal and alertness. We tested whether the hypocretinergic system is a critical component of the stress response activated by the corticotropin-releasing factor (CRF). Our results show that CRF-immunoreactive terminals make direct contact with hypocretin-expressing neurons in the lateral hypothalamus and that numerous hypocretinergic neurons express the CRF-R1/2 receptors. We also demonstrate that application of CRF to hypothalamic slices containing identified hypocretin neurons depolarizes membrane potential and increases firing rate in a subpopulation of hypocretinergic cells. CRF-induced depolarization was tetrodotoxin insensitive and was blocked by the peptidergic CRF-R1 antagonist astressin. Moreover, activation of hypocretinergic neurons in response to acute stress was severely impaired in CRF-R1 knock-out mice. Together, our data provide evidence of a direct neuroanatomical and physiological input from CRF peptidergic system onto hypocretin neurons. We propose that, after stressor stimuli, CRF stimulates the release of hypocretins and that this circuit contributes to activation and maintenance of arousal associated with the stress response.

Key words: hypocretin; orexin; corticotropin-releasing factor; hypothalamus; stress; homeostasis

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Received March 2, 2004; revised November 4, 2004; accepted November 10, 2004.

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