Exploring the Effects of Corticosteroids on the Human Hippocampus
Status:
Recruiting
Trial end date:
2024-03-31
Target enrollment:
Participant gender:
Summary
Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus
in both humans and in animal models. The hippocampus has a high concentration of
glucocorticoid receptors (GCRs), and the pre-clinical literature demonstrates shortening of
apical dendrites in the CA3 region of the hippocampus and decreased neurogenesis in the
dentate gyrus (DG) following CS administration. In humans, both stress and CS exposure are
associated with a decline in declarative memory performance (a process mediated by the
hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in
patients with excessive CS release due to Cushing's disease, and, by our group, in patients
receiving prescription CS therapy. These findings have important implications for patients
with mood disorders, as a large subset of people with major depressive disorder (MDD) show
evidence of HPA axis activation, elevated cortisol and, importantly, resistance to the
effects of CSs on both the HPA axis and on declarative memory. Thus, resistance to
corticosteroids appears to be a consequence of MDD.
this study will examine changes in declarative memory, as well as use state-of-the-art
high-resolution multimodal neuroimaging, including structural and functional (i.e.,
task-based and resting state) MRI, in both men and women healthy controls, and, as an
exploratory aim, a depressed group, given 3-day exposures to hydrocortisone (160 mg/day) or
placebo. The study will translate preclinical findings to humans, provide valuable data on
possible sex differences in the response to cortisol and, for the first time, identify
specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS
effects. Using resting state fMRI data and whole brain connectomics using graph theoretical
approaches, we will determine the effects of cortisol exposure on functional brain networks.
Furthermore, this will be the first study to use neuroimaging to compare the brain's response
to CSs in people with depression vs. controls, and determine whether depressed people
demonstrate glucocorticoid resistance within the hippocampus. We hypothesize that hippocampal
response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in men,
and that depressed people will show a blunted hippocampal response to CSs compared to
controls. A multidisciplinary research team with extensive experience in CS effects on the
brain and hippocampal subfield neuroimaging, and a prior history of research collaboration,
will conduct the project.