Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response.
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.
Winsky-Sommerer
Raphaëlle
R
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Yamanaka
Akihiro
A
Diano
Sabrina
S
Borok
Erzsebet
E
Roberts
Amanda J
AJ
Sakurai
Takeshi
T
Kilduff
Thomas S
TS
Horvath
Tamas L
TL
de Lecea
Luis
L
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001143:Arousal / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology; D001923:Brain Chemistry / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000032:analysis / Q000502:physiology*; D005260:Female; D007031:Hypothalamus / Q000737:chemistry / Q000502:physiology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000033:anatomy & histology / Q000737:chemistry; D009474:Neurons / Q000737:chemistry / Q000502:physiology; D009479:Neuropeptides / Q000032:analysis / Q000502:physiology*; D064446:Orexin Receptors; D000068797:Orexins; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D011993:Recombinant Fusion Proteins; D013312:Stress, Physiological / Q000503:physiopathology*; D000099052:CRF Receptor, Type 1
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D018019:Receptors, Corticotropin-Releasing Hormone; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D011993:Recombinant Fusion Proteins; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone