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.
