title: Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice.
abstract: Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined. The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GRs) is required for appropriate hypothalamic-pituitary-adrenal (HPA) axis regulation. Local PVN GR knockdown (KD) was achieved by breeding homozygous floxed GR mice with Sim1-cre recombinase transgenic mice. This genetic approach created mice with a KD of GR primarily confined to hypothalamic cell groups, including the PVN, sparing GR expression in other HPA axis limbic regulatory regions, and the pituitary. There were no differences in circadian nadir and peak corticosterone concentrations between male PVN GR KD mice and male littermate controls. However, reduction of PVN GR increased ACTH and corticosterone responses to acute, but not chronic stress, indicating that PVN GR is critical for limiting neuroendocrine responses to acute stress in males. Loss of PVN GR induced an opposite neuroendocrine phenotype in females, characterized by increased circadian nadir corticosterone levels and suppressed ACTH responses to acute restraint stress, without a concomitant change in corticosterone responses under acute or chronic stress conditions. PVN GR deletion had no effect on depression-like behavior in either sex in the forced swim test. Overall, these findings reveal pronounced sex differences in the PVN GR dependence of acute stress feedback regulation of HPA axis function. In addition, these data further indicate that glucocorticoid control of HPA axis responses after chronic stress operates via a PVN-independent mechanism.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Matia B
authors.initials: MB
authors.lastname: Solomon
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Matthew
authors.initials: M
authors.lastname: Loftspring
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Annette D
authors.initials: AD
authors.lastname: de Kloet
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Sriparna
authors.initials: S
authors.lastname: Ghosal
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Ryan
authors.initials: R
authors.lastname: Jankord
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Flak
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Aynara C
authors.initials: AC
authors.lastname: Wulsin
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Krause
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Taylor
authors.initials: T
authors.lastname: Rice
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Jessica
authors.initials: J
authors.lastname: McKlveen
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Brent
authors.initials: B
authors.lastname: Myers
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Tasker
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience (M.B.S., M.L., A.D.d.K., S.G., R.J., J.N.F., A.C.W., E.G.K., R.Z., T.R., J.M., B.M., J.P.H.), College of Medicine, University of Cincinnati, Cincinnati, Ohio 45237-1625; Department of Psychology (M.B.S.), University of Cincinnati, Cincinnati, Ohio 45237-1625; and Department of Cell and Molecular Biology (J.G.T.), Tulane University, New Orleans, Louisiana 70118-5698.
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics; D025461:Feedback, Physiological; D005260:Female; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009490:Neurosecretory Systems / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism
chemical_list: D011965:Receptors, Glucocorticoid