@article{ba9a7ee7374949c3bcc365df903bdc0e,
title = "Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes",
abstract = "An increase in corticotropin-releasing factor (CRF) is a putative factor in the pathophysiology of stress-related disorders. As CRF expression in the central nucleus of the amygdala (CeA) is important in adaptation to chronic stress, we hypothesized that unrestrained synthesis of CRF in CeA would mimic the consequences of chronic stress exposure and cause dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increase emotionality and disrupt reproduction. To test this hypothesis, we used a lentiviral vector to increase CRF-expression site specifically in CeA of female rats. Increased synthesis of CRF in CeA amplified CRF and arginine vasopressin peptide concentration in the paraventricular nucleus of the hypothalamus, and decreased glucocorticoid negative feedback, both markers associated with the pathophysiology of depression. In addition, continuous expression of CRF in CeA also increased the acoustic startle response and depressive-like behavior in the forced swim test. Protein levels of gonadotropin-releasing hormone in the medial preoptic area were significantly reduced by continuous expression of CRF in CeA and this was associated with a lengthening of estrous cycles. Finally, sexual motivation but not sexual receptivity was significantly attenuated by continuous CRF synthesis in ovariectomized estradiol-progesterone-primed females. These data indicate that unrestrained CRF synthesis in CeA produces a dysregulation of the HPA axis, as well as many of the behavioral, physiological and reproductive consequences associated with stress-related disorders.",
keywords = "CeA, CRF, Emotionality, Fertility, Sexual motivation, Stress",
author = "E. Keen-Rhinehart and V. Michopoulos and Toufexis, {D. J.} and Martin, {E. I.} and H. Nair and Ressler, {K. J.} and M. Davis and Owens, {M. J.} and Nemeroff, {C. B.} and Wilson, {M. E.}",
note = "Funding Information: We thank Ruth Connelly, Laura Canepa, Valencia Coston and Teal Pelish for their expert technical assistance. We also thank Dr. Gloria Hoffman and Dr Andrea Gore for their immunohistochemistry expertise. This project was supported by a pilot grant from the Center for Behavioral Neuroscience as a part of the STC Program of the National Science Foundation under Agreement No. IBN-9876754 and by NIH grants HD46501, MH-42088, MH-52899, RR00165, and 5K12-GM00680. Author contributions E Keen-Rhinehart oversaw the conduct of the studies, performed the ICC and participated as first author. V Michopoulos assisted Dr Keen-Rhinehart with the conduct of the study and participated as first author. D Toufexis conducted the startle tests and partici- pated as first author. EI Martin worked on the development and characterization of the Lenti-CMV-CRF vector and contributed to the preparation of the article. H Nair contributed to the development of the Lenti-CMV-CRF vector and the preparation of the article. KJ Ressler supervised the development and characterization of the Lenti-CMV-CRF vector and contributed to the preparation of the article. The startle studies were conducted in M Davis{\textquoteright} laboratory and he contributed to the preparation of the article. The Lenti-CMV-CRF vector was developed in MJ Owens{\textquoteright} and CB Nemeroff{\textquoteright}s laboratories and both contributed to the preparation of the article. With the exception of the startle tests, the in vivo studies were conducted in ME Wilson{\textquoteright}s laboratory and he contributed to the analysis of the data and the preparation of the article. Disclosure statement Currently, Dr Nemeroff has served on the Scientific Advisory Board for Astra-Zeneca, Johnson & Johnson, Pharma Neuroboost, Forest laboratories, Quintiles and NARSAD. He is a grant recipient from NIH, NovaDel Pharmaceuticals, Mt. Cook Pharma, Inc. and the George West Mental Health Foundation. He owns equity in CeNeRx and Reevax. He owns stock or stock",
year = "2009",
month = jan,
day = "25",
doi = "10.1038/mp.2008.91",
language = "English (US)",
volume = "14",
pages = "37--50",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "1",
}