The current proposal is aimed at understanding the mode of action of medications that are currently used to treat a variety of depression and anxiety-related disorders. Although selective serotonin reuptake inhibitors (SSRI) are the most commonly prescribed antidepressants and anxiolytics, their mechanisms of action, and particularly the reason for their delayed (4-6 weeks) onset of therapeutic effects, are largely unknown. The general hypothesis that we are proposing to test is that the increased hippocampal neurogenesis elicited by chronic antidepressants contributes to the behavioral effects of these drugs. We, and others, have shown that various chronic antidepressant treatments result in an increase in neurogenesis in the dentate gyrus of the hippocampus. We have also shown that a chronic antidepressant treatment decreases certain anxiety-related behavioral responses. Finally, we have developed two distinct manipulations (a genetic one and radiological one) that disrupt antidepressant-induced hippocampal neurogenesis and also suppress antidepressant-induced behavioral responses. The genetic manipulation is a deletion of the gene encoding the 5-HT1A receptor; the resulting knockout mice are insensitive to the effects of SSRIs such as fluoxetine on both neurogenesis and behavior. The radiological manipulation consists of an X-irradiation of an area of the mouse brain containing the hippocampus; such a treatment prevents the effect of fluoxetine on both neurogenesis and behavior. These two sets of findings strongly suggest that the induction of neurogenesis elicited by fluoxetine in the hippocampus contributes to the behavioral effects of fluoxetine. The following experiments are designed to test this hypothesis and to establish the functional significance of adult hippocampal neurogenesis. 1. We will test the hypothesis that activation of hippocampal 5-HTIA receptors mediates the effects of fiuoxetine on neurogenesis and behavior. To accomplish this goal, we will construct """"""""rescue"""""""" mice that express 5-HT1A receptors only in the hippocampus. 2. We will test the hypothesis that an ablation of neuronal progenitors will suppress the effects of fluoxetine. Such a finding would open new therapeutic avenues based on the stimulation of hippocampal neurogenesis, for the treatment of depression-related disorders.
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