Elsevier

Biological Psychiatry

Volume 56, Issue 3, 1 August 2004, Pages 140-145
Biological Psychiatry

Debates in neuroscience
Depression: a case of neuronal life and death?

https://doi.org/10.1016/j.biopsych.2004.02.033Get rights and content

Abstract

Preclinical and clinical studies have demonstrated that stress or depression can lead to atrophy and cell loss in limbic brain structures that are critically involved in depression, including the hippocampus. Studies in experimental animals demonstrate that decreased birth of new neurons in adult hippocampus could contribute to this atrophy. In contrast, antidepressant treatment increases neurogenesis in the hippocampus of adult animals and blocks the effects of stress. Moreover, blockade of hippocampal neurogenesis blocks the actions of antidepressants in behavioral models of depression, demonstrating a direct link between behavior and new cell birth. This perspective reviews the literature in support of the hypothesis that altered birth of new neurons in the adult brain contributes to the etiology and treatment of depression and considers research strategies to test this hypothesis.

Section snippets

Neurogenesis in adult brain

The presence of neural progenitor cells that give rise to new neurons in the adult brains of a variety of species, including humans, has been firmly established (Figure 1; Duman et al., 2001, Gage, 2000, Gould et al., 1999). Adult neurogenesis is restricted to the subventricular zone, which gives rise to granule cells in the olfactory bulb and in the subgranular zone, which generates new granule cells in the adult hippocampus. Immature neurons in subgranular zone of the hippocampus migrate into

Clinical evidence for atrophy of hippocampus in mood disorders

Indirect evidence suggesting that altered neurogenesis could occur in mood disorders is provided by brain imaging studies of hippocampus. These studies report that hippocampus volume is decreased in patients with depression (Bremner et al., 2000, Frodl et al., 2002, MacQueen et al., 2003, Mervaala et al., 2000, Saarelainen et al., 2003, Shah et al., 1998, Sheline et al., 1996, Sheline et al., 1999, Sheline et al., 2003, Steffens et al., 2000, Vermetten et al., 2003). Other studies have reported

Hippocampus and depression

The hippocampus is a brain region most often associated with control of learning and memory; however, reduced volume of this brain region in depressed patients suggests that the hippocampus could also contribute to certain symptoms of depression. Cognitive dysfunction and altered control of the hypothalmic-pituitary-adrenal (HPA) axis could be explained in part by decreased function of the hippocampus. The hippocampus has also been implicated in anxiety as local infusions of anxiolytics or

Antidepressant treatment increases adult neurogenesis

Another important link between neurogenesis and mood disorders comes from studies of antidepressant drugs. In contrast to the effects of stress, antidepressant treatment increases neurogenesis in adult hippocampus (Table 1) (Czeh et al., 2001, Madsen et al., 2000, Malberg et al., 2000, Manev et al., 2001, Santarelli et al., 2003). The induction of neurogenesis by antidepressants is dependent on chronic treatment, consistent with the time course for the therapeutic action of these medications.

Antidepressant treatment blocks the effects of stress on adult neurogenesis

Antidepressant treatment also blocks the effects of stress, or normalizes levels of neurogenesis, in adult hippocampus. This interaction has been observed with several types of stress models and antidepressant treatments (Table 1). Chronic administration of an atypical antidepressant, tianeptine, blocks the effects of subordination stress on neurogenesis in the hippocampus of adult tree shrews (Czeh et al 2001). A similar effect has been observed after chronic administration of a neurokinin-1

Conclusions

The studies cited and discussed in this review provide support for the hypothesis that regulation of neurogenesis in the adult hippocampus contributes to the treatment, and possibly the pathophysiology, of depression. Additional studies, in both experimental animals and in humans, are required to test this hypothesis. It is possible that neurogenesis in hippocampus underlies specific symptoms of depression but that alternate adaptive mechanisms in hippocampus as well as other limbic structures

Acknowledgements

This work is supported by U.S. Public Health Service Grant Nos. MH45481 and 2 PO1 MH25642, a Veterans Administration National Center Grant for Posttraumatic Stress Disorder, and by the Connecticut Mental Health Center.

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