Hippocampal neurogenesis: regulation by stress and antidepressants

Abstract

Accumulating evidence implicates hippocampal neurogenesis in the pathophysiology of depression. Psychosocial stress reduces neurogenesis in rodents, whereas chronic treatment with antidepressants increases neurogenesis and blocks the effects of stress. The effects of stress and antidepressant treatment on hippocampal neurogenesis parallel behavioral changes in animal models. Moreover, ablating hippocampal neurogenesis renders antidepressants inactive in behavioral paradigms used to model antidepressant response and anxiety-like behavior in mice. In humans, monoamine-modulating antidepressants demonstrate clinical efficacy in treating depression and anxiety, which are often precipitated by psychosocial stress. This review examines the mounting evidence that stress and antidepressant treatment regulate neurogenesis in animals. Special attention is paid to the cellular and molecular mechanisms by which this regulation takes place. An analysis of current animal models used to study response to stress and antidepressants indicates the importance of modeling chronic treatment, which reflects both changes in neurogenesis and clinical response. Exploring responses of hippocampal neurogenesis to experimental challenges in appropriate animal models should delineate the role of adult-born neurons in hippocampal physiology. Focusing on neurogenic response to experimental paradigms of stress and antidepressant treatment is particularly interesting for understanding the pathophysiology of major depressive disorder.

Figure 1.

Hippocampal neurogenesis, stress, and antidepressant treatment: schematic representation of a coronal section through a mouse brain. The expanded views in the panels illustrate the dentate gyrus of the hippocampus with the cell bodies of young neurons (red) in the subgranular layer and dendritic projections traversing the granule cell layer. Baseline neurogenesis is enhanced by antidepressants, reduced by stress and the stress-induced reduction is reversed with antidepressant treatment. The expanded views in the bottom panels show a pyramidal neuron in CA3 with basal and apical (red) dendrites extending outside the pyramidal cell layer (gray). Stress reduces the baseline arborization of apical dendrites. Tianeptine, but not serotonin reuptake inhibitors, reverses the effect of stress on dendritic arborization.

Figure 2.

Acute and chronic responses to antidepressant treatment: treatment with monoamine modulators has acute effects on hippocampal neurochemistry, behavioral responses in animal models, and clinical responses. Chronic treatment results in hippocampal plasticity with increased neurogenesis and separate effects in animal models and clinical use. See text for references.