FEATURE ARTICLE
Depression and the Birth and Death of Brain Cells
The turnover of neurons in the hippocampus might help to explain the onset of and recovery from clinical depression
Henriette van Praag, Barry Jacobs, Fred Gage
Stress and Glucocorticoids
Many scientists believe that stress is the most significant causal agent—with the possible exception of genetic predisposition—in the etiology of depression. In addition, nerve cells in the hippocampal formation are among the most sensitive to the deleterious effects of stress. Consequently, a stress-induced decrease in neurogenesis in the hippocampus might be an important factor in precipitating episodes of depression. On the other hand, increasing serotonergic neurotransmission is the most effective treatment for depression, and it also augments hippocampal neurogenesis. So serotonin-induced increases in neurogenesis might promote recovery from depression. Considering all of this, we suggest that the waning and waxing of neurogenesis in the hippocampal formation might trigger the precipitation of and recovery from episodes of clinical depression.
Gould and her colleagues examined the relation between stress and hippocampal neurogenesis in several species. First, they reported that removing a rat's adrenal glands increased neurogenesis in the adult dentate gyrus. Moreover, they could reverse that effect with the glucocorticoid hormone corticosterone, which normally comes from the adrenals. The circulating level of glucocorticoids apparently suppressed the birth of neurons in the dentate gyrus under normal conditions. In an extension of these results, Gould's group showed that systemic administration of corticosterone to normal animals suppressed dentate gyrus neurogenesis.
This group also examined the effects of naturally stressful situations. For instance, they exposed a rat to the odor of one of its natural predators—a fox—and that suppressed cell proliferation in the rat's dentate gyrus. They also demonstrated reduced dentate-gyrus cell proliferation in adult tree shrews after the psychosocial stress of exposing them to same-sex individuals. Most recently, Gould's group reported suppressed cell division in a marmoset monkey's dentate gyrus after putting it in a cage with another marmoset that had already been living there. In combination, these studies show clearly that stress suppresses the rate of dentate-gyrus cell proliferation in adults of a number of species. Furthermore, it probably does so through increases in brain glucocorticoids.
Additional, but older, literature is also relevant here. Over the past 15 years, work by Robert Sapolsky of Stanford University, Bruce McEwen of Rockefeller University and others has shown, in a number of species, that stress and glucocorticoids cause widespread morphological changes and even cell death in parts of the hippocampus, such as in the CA3 subfields. This region of the hippocampus is the main target of the output of neurons in the dentate gyrus. Whether this hippocampal damage is at least in part dependent on the suppression of neurogenesis in the dentate gyrus is not known.
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