title: Pharmacological stimulation of hypoxia inducible factor-1α facilitates the corticosterone response to a mild acute stressor.
abstract: While both glucocorticoids (the principal output of the hypothalamic-pituitary-adrenal axis) and oxidative stress have been implicated in outcomes due to an excessive or prolonged stress response, the precise mechanisms linking these two systems remain poorly elucidated. One potential mediator between the hypothalamic-pituitary-adrenal axis and oxidative stress is the hypoxia inducible factor-1 (HIF-1) pathway. HIF-1 is an oxygen-responsive transcription factor with diverse effects including changes in cellular metabolism. The experiments in this manuscript sought to determine if pharmacological stimulation of HIF-1α via administration of dimethyloxalylglycine (DMOG) would facilitate the corticosterone response to a mild acute stressor. DMOG administration significantly increased plasma corticosterone 5 min after an acute airpuff without changing baseline plasma corticosterone or plasma corticosterone level two hours post-startle. DMOG administration also reduced hippocampal gene expression of the pro-translocation co-chaperone for the glucocorticoid receptor, FKBP4, two hours after airpuff startle. At this same two-hour time point, hippocampal expression of FKBP5, an anti-translocation co-chaperone of the glucocorticoid receptor, in the DMOG-treated group was also positively correlated with plasma corticosterone levels. These data indicate that there is significant crosstalk between the hypothalamic-pituitary-axis and the HIF-1 pathway and extend the current knowledge of glucocorticoid and hypoxia interactions in an ethologically relevant stress model.
authors.affiliation: Department of Physiology, Emory University, Atlanta, GA 30322, United States.
authors.forename: Constance S
authors.initials: CS
authors.lastname: Harrell
authors.affiliation: Department of Physiology, Emory University, Atlanta, GA 30322, United States.
authors.forename: Sydney A
authors.initials: SA
authors.lastname: Rowson
authors.affiliation: Department of Physiology, Emory University, Atlanta, GA 30322, United States; Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, United States. Electronic address: gretchen.neigh@emory.edu.
authors.forename: Gretchen N
authors.initials: GN
authors.lastname: Neigh
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D003345:Corticosterone / Q000097:blood*; D006624:Hippocampus / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000600:Amino Acids, Dicarboxylic; D003345:Corticosterone; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C542344:NR3C1 protein, rat; C403485:tacrolimus binding protein 4; C040947:oxalylglycine
keywords: Airpuff startle; Dimethyloxalylglycine; FKBP4; FKBP5; Hypoxia inducible factor 1α; Stress