FULL TEXT OF SLIDES, Below
1. This lecture by Bruce McEwen, The Rockefeller University, New York City, discusses how the brain responds to stress hormones and describes when and how these hormones promote adaptative changes in brain structure as well as when and how stress may damage the brain.
2. What do adrenal steroids do to the brain? There is a good side and a bad side to their actions. We have known for some time that they are involved in psychopathology. Their secretion is elevated in depressed patients by their emotional arousal and psychotic disorganization, as is indicated in this quote from the late Edward Sachar at Columbia University in 1970.
Adrenocortical hormones enter the brain and produce effects upon it. These effects include steroid psychosis that can be blocked by glucocorticoid antagonists.
In Cushing's disease, where there is chronically excess cortisol, there are psychotic episodes and depressive symptoms that can be relieved by surgical removal of the pituitary tumor. Both major depression and Cushing's are associated with chronic elevation of cortisol that results in gradual loss of minerals from bone and abdominal obesity.
In major depressive illness as well as in Cushing's, there is a progressive reduction in volume of the hippocampus, determined by structural magnetic resonance imaging. There is also bone mineral loss and abdominal obesity. We shall come back to this at the end of the lecture.
There are many normal and essential actions of adrenocortical hormones on neuronal excitability and memory storing capacity that we will address in a few slides.
3. A major aspect of adrenocortical hormones is their secretion during a stress response. This slide reminds us that the cortisol secretion is regulated by neural inputs to the hypothalamus and mediated by release of corticotrophin releasing hormone (CRH) from the hypothalamus, which releases adrenocorticotrophic hormone (ACTH) from the pituitary. ACTH causes cortisol to be produced by the adrenal cortex.
The slide also tells us that the autonomic nervous system is responding to many stressors and that it does so more rapidly than the rise in cortisol. The sympathetic nervous system responds to stressors with the release of epinephrine from the adrenal medulla and norepinephrine from nerve endings in blood vessels and many internal organs.
4. Stress hormone release occurs during the day-night cycle and has a housekeeping role in relation to metabolism and other physiological functions. During stress, these same hormones promote adaptation and protection in the short run but can cause damage if they are chronically overproduced.
Both cortisol and catecholamines produce their effects on numerous cells and tissues via receptors. Catecholamine receptors are located on the cell surface and regulate signalling pathways involving second messengers such as cyclic AMP. Glucocorticoids bind to receptors that enter the nucleus and bind to DNA sites where they regulate transcription of specific genes. Second messengers like cAMP also activate DNA binding proteins that regulate transcription.
Depending on the intensity and duration of these hormonal signals, the receptors and second messenger systems that are activated promote either adapative or maladaptive responses. In general, turning on these stress-activated hormones when they are needed and turning them off again when they are not needed results in the most efficient and successful adaptation. Overactivity of stress hormones when they are no longer needed is one of the common ways that pathophysiology is accelerated.
5. The hippocampus is a target for adrenal steroids. It contains two types of intracellular receptors that regulate gene expression. The mineralocorticoid receptor (MR) is a high affinity receptor that recognizes levels of glucocorticoids that occur during the diurnal rhythm. The glucocorticoid receptor (GR) has somewhat lower affinity than MR and it responds to stress levels of glucocorticoids.
6. MR is found in high concentrations in neurons in the hippocampus and in small groups of cells in other parts of the brain. There is also a lower level of expression of MR in many other cells throughout the brain. In contrast, GR is found in many cells - both neurons and glia - throughout the nervous system.
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Lecture assembled in August, 2002