GLUCOCORTICOID REGULATION OF NEURONS AND APOPTOSIS
Glucocorticoid production is controlled by the hypothalamic-pituitary-adrenal (HPA) axis in which hypothalamic corticotropin releasing hormone (CRH) stimulates cells in the anterior pituitary via the hypophyseal-portal circulation to produce adrenocorticotropic hormone (ACTH). ACTH, in turn, stimulates the adrenal cortices to produce the glucocorticoid hormone cortisol.
Cortisol interacts with glucocorticoid receptors (GR) in the cytoplasm of some neurons to effect dissociation from chaperone proteins such as heat shock protein (hsp) 90 and translocation to the nucleus, where the activated GR interacts with glucocorticoid response elements (GRE) to effect gene transcription. Cortisol acts on many body tissues to promote metabolic and antiinflammatory effects, in the latter case by blocking inflammatory transcription factors such as nuclear factor κB (NF-κB). Under normal conditions, the HPA axis is regulated by feedback at several levels, including regulation of CRH release via the hippocampus, resulting in normal diurnal regulation of systemic cortisol levels. In the hippocampus, low to moderate levels of cortisol provide optimal memory acquisition and consolidation by supporting synaptic plasticity. However, under conditions of chronic stress, sustained high levels of cortisol can negatively affect hippocampal neurons, particularly the granule cells of the dentate gyrus, resulting in decreased neurogenesis, decreased dendritic complexity, and cell death via apoptosis. Hippocampal cell loss and dysfunction can lead to loss of hippocampal control over cortisol release, resulting in loss of normal diurnal release patterns, which is seen in old age and in diseases such as Alzheimer’s. Such changes have also been linked to psychiatric disorders. Loss of diurnal cortisol rhythms also contributes to metabolic dysfunction and truncal obesity in the periphery.