Mineralocorticoid-R Control of HPA Stress Response

DESCRIPTION (provided by applicant): The proposed research will explore the
potential role of the mineralocorticoid receptor (MR) in the regulation of the
hypothalamic-pituitary-adrenal axis (HPA) under conditions of stress. The HPA
secretes increased cortisol or corticosterone (CORT) when an organism is
confronted by stress, while secreting a low level of CORT during non-stress
states. To prevent excessive activity of the axis, CORT negative feedback
limits the operation of this hormone system. Negative feedback is mediated by
two receptors for CORT: the glucocorticoid receptor (GR) and MR. Traditionally,
GR is thought to control the HPA during a stress response and MR thought to
control the HPA in non-stress, basal states. However, the role of MR might also
be to regulate the HPA in stress situations. The role of MR may be especially
important during milder stress. such as the challenges people face every day.
If MR are not functioning properly because of experiential or congenital
effects, an organism may show an increased HPA response to stress. Abnormal HPA
function has been connected with depression, PTSD, and other psychopathologies.
It is therefore relevant to better understand the role of MR in HPA control. To
accomplish this, a range of stressor will be identified in which the HPA
requires MR for normal control of the CORT response. This will be accomplished
via treatment of animals with MR antagonists (e.g., RU28318), and then
observing their CORT, ACTH, and CRH response to stress. Then, the interaction
between MR and GR control of the HPA will be examined in several stressors of
varying intensities. This will be done to better understand the exact nature of
MR contribution to control of the HPA during stress. And finally, the role of
MR in controlling HPA responding will be examined after a stressor has been
experienced repeatedly, a situation previously shown to increase the number of
brain MR.