Glucocorticoids, depression, and mood disorders: structural remodeling in the brain
Introduction
Stressful life events are known to precipitate depressive illness in individuals with certain genetic predispositions [1], [2], and therefore, the study of depression and mood disorders needs to address the question: What do stressors do to the brain? We have known for some time that stress hormones such as cortisol are involved in psychopathology, reflecting emotional arousal and psychic disorganization rather than the specific disorder per se [3]. We now know that adrenocortical hormones enter the brain and produce a wide range of effects upon it (see Refs. [4], [5], [6]).
In Cushing's disease, there are depressive symptoms that can be relieved by surgical correction of the hypercortisolemia [6]. Both major depression and Cushing's disease 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 disease, the duration of the illness and not the age of the subjects predicts a progressive reduction in volume of the hippocampus, determined by structural magnetic resonance imaging [7], [8]. Moreover, there are a variety of other anxiety-related disorders, such as posttraumatic stress disorder, in which atrophy of the hippocampus has been reported, suggesting that this is a common process reflecting chronic imbalance in the activity of adaptive systems, such as the hypothalamus-pituitary-adrenal (HPA) axis, but also including endogenous neurotransmitters, such as glutamate.
Animal models of repeated stress have provided clues as to what may be going on in the human brain in Cushing's disease and major depressive illness, and the hippocampus is the best-studied brain region. The hippocampus contains receptors for adrenal steroids, which regulate excitability and morphological changes [9]. We shall first discuss the hippocampus and then turn to other stress-sensitive brain structures.
Section snippets
Adaptive structural plasticity
One of the ways that stress hormones modulate function within the brain is by changing the structure of neurons. Within the hippocampus, the input from the entorhinal cortex to the dentate gyrus is ramified by the connections between the dentate gyrus and the CA3 pyramidal neurons. One granule neuron innervates, on the average, 12 CA3 neurons, and each CA3 neuron innervates, on the average, 50 other CA3 neurons via axon collaterals, as well as 25 inhibitory cells via other axon collaterals [9].
What about permanent damage as a result of stress?
There is always concern that severe and prolonged stress may damage the brain [22], and in the case of depressive illness, there is a high degree of lifetime recurrence of major depression, which suggests that an underlying pathophysiologic process is involved. What we are learning from animal models of stress and trauma effects in the hippocampus is that the remodeling of the hippocampus in response to stress is largely reversible if CRS is terminated at the end of 3 weeks [5]. Yet, it is well
Stress-induced changes in the prefrontal cortex and amygdala
Repeated stress also causes changes in other brain regions such as the prefrontal cortex and amygdala. Repeated stress causes dendritic shortening in medial prefrontal cortex but produces dendritic growth in neurons in amygdalae [5], [9], [21], [27], [28], [29], [30]. Along with many other brain regions, the amygdala and prefrontal cortex also contain adrenal steroid receptors; however, the role of adrenal steroids, excitatory amino acids, and other mediators has not yet been studied in these
Conclusion
Animal stress models not only tell us how the human brain may change under repeated stress, but they also provide clues about stress-induced behavioral depression, which is relevant to human depressive illness. Psychosocial stress in an animal model of depressive illness, the tree shrew, suppresses neurogenesis and causes dendritic shrinkage in hippocampus [15], [33], [34].
Translational studies of brain changes in major mood and anxiety disorders such as unipolar and bipolar depression and
Acknowledgments
Research support came from the National Institute of Mental Health, Bethesda, Md (grants MH41256 and MH58911).
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