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
Other Possibilities
Despite proposing that alterations in hippocampal neurogenesis play a crucial role in the etiology and recovery from depression, we do not exclude other changes as being important. For example, besides suppressing neurogenesis, increased glucocorticoids might mediate additional direct neuronal effects in the cerebral cortex, hippocampus and other subcortical areas, such as the amygdala. Similarly, changes in serotonin neurotransmission might also exert direct effects in the brain stem, subcortical sites and the cortex. All of these changes, acting in concert, give rise to the complex syndrome of depression.
Although this article focuses on the augmentation of dentate-gyrus neurogenesis by serotonin, other means of increasing neurogenesis might also have clinical relevance. For example, it is well known that exercise, especially running, has an antidepressant action, and we recently found that 4–10 days of running on a wheel induces a significant increase in cell proliferation in a mouse's dentate gyrus. After several weeks of running, neurogenesis increased as well. Also, norepinephrine appears to increase cell division in the dentate gyrus. These factors might also play roles in depression.
There are also several related theories. Pierre Blier and Claude de Montigny of McGill University, for example, suggest that antidepressant therapies act in the hippocampus by increasing neurotransmission at the serotonin 5-HT1A receptor and by decreasing it at the beta-adrenergic receptor, which can be activated by norepinephrine. Watson and his colleagues emphasize the importance of glucocorticoid-induced down regulation of the 5-HT1A receptors in the hippocampus of experimental animals. In examining these and related theories of depression, we find that our theory does not supplant or contradict them. Rather, it complements and extends these previous ideas by pointing to a particular neural event, the rise and fall of dentate-gyrus neurogenesis.
Still, one might wonder how the hippocampus could affect depression. Historically, neurobiologists thought of it as part of the brain's cognitive circuitry and not involved in mediating mood or emotion. Nevertheless, recent evidence indicates that structures considered to be central to the brain's emotional circuitry, such as the amygdala, are strongly interconnected with the hippocampus. This connection would provide the anatomical substrate for linking cognitive and emotional information processing. Consistent with our hypothesis, clinically depressed patients have a variety of memory deficits, which would also point to hippocampal involvement.
In addition to treating clinical depression, advances in controlling neurogenesis might also be used to treat many other diseases where brain cells have died. In this context, two separate strategies are being weighed. Some investigators harvest stem cells from the adult brain, expand them in tissue culture, induce the cells to make specific cell lines, say neurons, and then transplant them to a specific brain region where they could replace or augment endogenous cells. On the other hand, cells already in the brain might be activated by pharmacological or environmental stimulation and induced to proliferate and migrate to a damaged or diseased brain region, where they would take up residence in areas to replace or augment lost function. Although progress is being made on both of these fronts, much additional work remains to make these repair strategies routine. In any case, we now know that structural correlates of neural plasticity extend beyond synaptic reorganization and include the addition of new neurons to important circuits.
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