The glucocorticoid receptor in the limbic system of the human brain

Glucocorticoid hormones (GCs) are important mediators of the stress response in mammals including humans. GCs are released from the adrenal in response to stress and affect numerous processes in the body and brain. Their levels are controlled via negative feedback exerted by GC binding to brain glucocorticoid receptors (GR). In particular the hypothalamus, hippocampus and amygdala are important brain regions involved in this feedback regulation of the stress response. Whereas the anatomical distribution of brain GR was well known for various animal species, very little was known about GR presence and (subregional) distribution in human brain, nor about possible alterations in stress-related brain disorders.
We here describe the first anatomical distribution of GR protein in key areas of the human brain involved in stress regulation. We next studied changes in GR protein in relation to aging and disorders like major/bipolar depression and Alzheimer’s disease (AD).
We found abundant GR-immunoreactivity (GR-ir) to be present in almost all neuronal nuclei of the human hypothalamus, hippocampus and amygdala and in +/-50% of the astrocytes. In major depression, hippocampal GR-ir correlated positively with age, and increased GR-ir was found in depressed women relative to depressed men. In the human amygdala, GR-ir was significantly increased in major, but not bipolar, depression. In AD, higher GR levels were found in female relative to male AD patients, a difference absent in age-matched controls.
These first studies on the human GR may help better understand the molecular mechanisms underlying stress-related disorders and can possibly improve future therapeutic development.