Role of the dorsomedial hypothalamus in glucocorticoid-mediated feedback inhibition of the hypothalamic–pituitary–adrenal axis

Abstract

Previous studies suggest that multiple corticolimbic and hypothalamic structures are involved in glucocorticoid-mediated feedback inhibition of the hypothalamic–pituitary–adrenal (HPA) axis, including the dorsomedial hypothalamus (DMH), but a potential role of the DMH has not been directly tested. To investigate the role of the DMH in glucocorticoid-mediated negative feedback, adult male Sprague Dawley rats were implanted with jugular cannulae and bilateral guide cannulae directed at the DMH, and finally were either adrenalectomized (ADX) or were subjected to sham-ADX. ADX rats received corticosterone (CORT) replacement in the drinking water (25 μg/mL), which, based on initial studies, restored a rhythm of plasma CORT concentrations in ADX rats that was similar in period and amplitude to the diurnal rhythm of plasma CORT concentrations in sham-ADX rats, but with a significant phase delay. Following recovery from surgery, rats received microinjections of either CORT (10 ng, 0.5 μL, 0.25 μL/min, per side) or vehicle (aCSF containing 0.2% EtOH), bilaterally, directly into the DMH, prior to a 40-min period of restraint stress. In sham-ADX rats, bilateral intra-DMH microinjections of CORT, relative to bilateral intra-DMH microinjections of vehicle, decreased restraint stress-induced elevation of endogenous plasma CORT concentrations 60 min after the onset of intra-DMH injections. Intra-DMH CORT decreased the overall area under the curve for plasma CORT concentrations during the intermediate time frame of glucocorticoid negative feedback, from 0.5 to 2 h following injection. These data are consistent with the hypothesis that the DMH is involved in feedback inhibition of HPA axis activity at the intermediate time frame.

• 5-HT_1A
• automated blood sampling
• corticosterone
• dorsomedial hypothalamus
• HPA axis
• negative feedback
• serotonin

Acknowledgements

We are grateful to Peter Hibl, Kathleen Dady, Adam Kapitz, and Laura Shultz for technical support. Finally, we are grateful to Alpha Plastics and Design (Fort Collins, CO) for manufacturing the custom restrainers and providing the 3D rendered image.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

This work was supported by awards from the National Science Foundation to C. A. L. (NSF- IOS 0921969), K. J. R. (NSF-IOS 0921874) and M. O. (NSF-IOS 0922085) and an award from the National Institute of Mental Health to R. L. S. (R01MH075968). C. A. L. also receives grant support from the National Institute of Mental Health (R01MH065702 and R01DA019921), the Depressive and Bipolar Disorder Alternative Treatment Foundation and is the recipient of a NARSAD, Brain & Behavior Research Foundation 2010 Young Investigator Award.

Supplementary material available online

Supplementary Figures 1 and 2.