TY - JOUR
T1 - XModulation of circadian glucocorticoid oscillation via adrenal Opioid-CXCR7 Signaling alters emotional behavior
AU - Ikeda, Yuichi
AU - Kumagai, Hidetoshi
AU - Skach, Amber
AU - Sato, Makito
AU - Yanagisawa, Masashi
N1 - Funding Information:
We thank members of the M.Y. laboratory, Dr. Christopher Sinton, and Dr. James Richardson for technical assistance and scientific discussion. We also thank Tairo Ogura and Tubasa Ibushi (Shimadzu Corporation) for mass spectrometry analyses of adrenal peptides. This research was supported in part by the Perot Family Foundation, the Japan Science and Technology Corporation through Exploratory Research for Advanced Technology (ERATO), and the Japan Society for the Promotion of Science through the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST). M.Y. is an Investigator of the Howard Hughes Medical Institute.
PY - 2013/12/5
Y1 - 2013/12/5
N2 - Circulating glucocorticoid levels oscillate with a robust circadian rhythm, yet the physiological relevance of this rhythmicity remains unclear. Here, we show that modulation of circadian glucocorticoid oscillation by enhancing its amplitude leads to anxiolytic-like behavior. We observed that mice with adrenal subcapsular cell hyperplasia (SCH), a common histological change in the adrenals, are less anxious than mice without SCH. This behavioral change was found to be dependent on the higher amplitude of glucocorticoid oscillation, although the total glucocorticoid secretion is not increased in these mice. Genetic and pharmacologic experiments demonstrated that intermediate opioid peptides secreted from SCH activate CXCR7, a β-arrestin-biased G-protein-coupled receptor (GPCR), to augment circadian oscillation of glucocorticoid levels in a paracrine manner. Furthermore, recapitulating this paracrine axis by subcutaneous administration of a synthetic CXCR7 ligand is sufficient to induce anxiolytic-like behavior. Adrenocortical β-arrestin-biased GPCR signaling is a potential target for modulating circadian glucocorticoid oscillation and emotional behavior.
AB - Circulating glucocorticoid levels oscillate with a robust circadian rhythm, yet the physiological relevance of this rhythmicity remains unclear. Here, we show that modulation of circadian glucocorticoid oscillation by enhancing its amplitude leads to anxiolytic-like behavior. We observed that mice with adrenal subcapsular cell hyperplasia (SCH), a common histological change in the adrenals, are less anxious than mice without SCH. This behavioral change was found to be dependent on the higher amplitude of glucocorticoid oscillation, although the total glucocorticoid secretion is not increased in these mice. Genetic and pharmacologic experiments demonstrated that intermediate opioid peptides secreted from SCH activate CXCR7, a β-arrestin-biased G-protein-coupled receptor (GPCR), to augment circadian oscillation of glucocorticoid levels in a paracrine manner. Furthermore, recapitulating this paracrine axis by subcutaneous administration of a synthetic CXCR7 ligand is sufficient to induce anxiolytic-like behavior. Adrenocortical β-arrestin-biased GPCR signaling is a potential target for modulating circadian glucocorticoid oscillation and emotional behavior.
UR - http://www.scopus.com/inward/record.url?scp=84890019595&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890019595&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.10.052
DO - 10.1016/j.cell.2013.10.052
M3 - Article
C2 - 24315101
AN - SCOPUS:84890019595
SN - 0092-8674
VL - 155
SP - X1323-1336
JO - Cell
JF - Cell
IS - 6
ER -