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J Chem Neuroanat. 2013 Dec;54:34-41. doi: 10.1016/j.jchemneu.2013.07.004. Epub 2013 Aug 16.

Orexinergic innervation of urocortin1 and cocaine and amphetamine regulated transcript neurons in the midbrain centrally projecting Edinger-Westphal nucleus.

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Department of Anatomy, Donders Institute for Brain Cognition and Behaviour, Radboud University Nijmegen Medical Centre, PO. Box 9100, 6500 HB Nijmegen, The Netherlands.


Orexin is a neuropeptide that has been implicated in several processes, such as induction of appetite, arousal and alertness and sleep/wake regulation. Multiple lines of evidence also suggest that orexin is involved in the stress response. When orexin is administered intracerebroventricular it activates the hypothalamic pituitary adrenal (HPA)-axis, which is the main regulator of the stress response. The HPA-axis is not the only player in the stress response evidence suggests that urocortin 1 (Ucn1), a member of the corticotropin releasing factor (CRF) neuropeptide family, also plays an important role in the stress response adaptation. Ucn1 is primarily synthetized in the centrally projecting Edinger-Westphal nucleus (EWcp), which also receives dense innervation by orexin terminals. In this study we tested the hypothesis that orexin would directly shape the response of EWcp-Ucn1 neurons to acute cold stress. To test this hypothesis, we first assessed whether orexinergic axon terminals would innervate EWcp-Ucn1/CART neurons, and next we exposed orexin deficient (orexin-KO) male mice and their male wild-type (WT) littermates to acute cold stress for 2h. We also assessed stress-associated changes in plasma corticosterone (CORT), as well as the activation of Ucn1/CART neurons in the EWcp nucleus. We found that orexin immunoreactive axon terminals were juxtaposed to EWcp-Ucn1/CART neurons, which also expressed orexin receptor 1 mRNA. Furthermore, acute stress strongly activated the EWcp-Ucn1/CART neurons and increased plasma CORT in both WT littermates and orexin-KO mice, however no genotype effect was found on these indices. Taken together our data show that orexin in general is not involved in the animal's acute stress response (plasma CORT) and it does not play a direct role in shaping the response of EWcp-Ucn1 neurons to acute stress either.


(Acute) stress; ACTH; ANOVA; CART; CORT; CRF; DAB; EWcp; FA; G protein coupled receptors; GPCR; HPA; Hypocretin; KO; LH; NDS; OXR-1; OXR-2; Orexin; Orexin receptor; PBS; PVN; SEM; SSC; SSD; Ucn1; Urocortin 1; WT; aa; adrenocorticotropic hormone; amino acid; analysis of variance; centrally projecting Edinger–Westphal nucleus; cocaine-and amphetamine-regulated transcript; corticosterone; corticotropin releasing factor; diaminobenzidine; formaldehyde; hypothalamic pituitary adrenal; icv; intracerebroventricular; knock-out; lateral hypothalamus; normal donkey serum; orexin receptor-1; orexin receptor-2; paraventricular nucleus of the hypothalamus; phosphate buffered saline; specific signal density; standard error of the mean; standard saline citrate buffer; urocortin 1; wildtype

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