Antidepressant medications are the principal treatment for major depression and chronic anxiety disorders, two syndromes with significant morbidity and mortality. The ultimate neurobiological target of antidepressants is unknown. Although these treatments are highly beneficial in many cases, shortcomings in others include limited efficacy, delayed onset of action, and undesirable side effects. The quest to identify basic mechanisms has yielded the hypothesis that neurogenesis in the adult hippocampus is central to antidepressant efficacy. Tests of this hypothesis, while not definitive, have been supportive. We showed that a non-pharmacological model of antidepressant therapy produces a dramatic increase in hippocampal neurogenesis. We have also obtained preliminary evidence that fluoxetine stimulates hippocampal neurogenesis and prevents depressive behavior and that both effects are abolished by preventing hippocampal neurogenesis. We propose a larger study that will establish the significance of these preliminary findings and will extend them to models that better parallel applications in humans. Three unresolved questions will be addressed: Our pilot data shows that chronic stress induces depression-like behaviors and is accompanied by reduced neurogenesis rates but the relationship between these two processes is unknown.
Aim 1 will determine whether suppression of neurogenesis is sufficient to produce a depressive state under ambient conditions or increases risk of depressive behavior during chronic stress. All studies of antidepressants and depressive behavior in mammals have been modeled on prevention;none have addressed the role of antidepressants in reversing depressive behavior, although this is clearly more relevant to clinical antidepressant therapy.
Aim 2 will determine whether fluoxetine can attenuate or eliminate depressive behavior and whether this is associated with hippocampal neurogenesis. We will then determine whether this improvement with treatment is prevented by blocking hippocampal neurogenesis. We suspect that neurogenesis is necessary for maintaining antidepressant response but not for immediate behavioral effects, because they seem to occur before new neurons can be integrated into neural pathways. Finally, although studies have shown that neurogenesis is necessary for delayed contextual learning, there is inadequate data to suggest any mechanism by which newly generated neurons may reverse depressive behaviors.
Aim 3 seeks to identify the maturational stage and anatomical location where new neurons are preferentially activated with therapeutic response to treatment.
Depression is a devastating and common illness, yet treatments are not universally effective because their mechanisms are only partially understood. Recent evidence from our laboratory and others'suggests that the production of new nerve cells in the brain is critical for antidepressants to treat depression. Since we cannot study new neurons in humans we will conduct a project to test this hypothesis in monkeys because of their similarity to humans.