The result of the activation of transcription factors and neurotrophins must involve changes in the neuronal network. Two major possibilities have been postulated as the end stage of a final common pathway for depression. One, a decrease in new neurons, i.e., decreased neurogenesis, and second, a decrease in synaptic activity which could result from elimination of synapses or decreased efficacy of synaptic connections.

The first possibility that neurogenesis plays a role in the etiology of depression was put forward by Jacobs and co-workers42 and Duman and co-workers in 200043,44. The primary evidence for this hypothesis is that antidepressants appear to increase neurogenesis and that 5HT appears to play a central role in the control of neurogenesis. However, neurogenesis is known to occur only in two places in the brain, the dentate gyrus of the hippocampus and the subventricular zone, where the cells migrate to the olfactory bulb45. Hippocampal neurogenesis is sensitive to stress, consistent with the role of stress in depression. Clinical studies have suggested that depressed patients have a smaller hippocampus than carefully matched controls, supporting the idea that neurogenesis could be impaired in this condition. This is also consistent with a greater secretion of cortisol in depression, which suppresses neurogenesis. Futhermore, when X-irradiation of a restricted region of mouse brain containing the hippocampus was used to inhibit neurogenesis, it also abrogated the behavioral effects of both 5HT specific and NE specific antidepressants46. The drugs failed to alter the latency to feeding in an open field feeding paradigm in which both antidepressants and antianxiety medications are normally effective in reducing the latency to feeding. These data taken together suggested that altered neurogenesis could be the driving factor in the etiology of depression.

The model of learned helplessness is suitable for separating unspecific stress effects from effects leading to pathologic behavioral and neurobiological changes in analogy to human depression. Using this model, we were able to show that inescapable stress leads to decreased dentate gyrus cell proliferation not only in helpless animals but also in not helpless animals, a finding arguing against a simple causal relation between reduced neurogenesis and depressive behavior47,48. We found that during the training phase of learned helplessness, when the animals are exposed to an unpredictable and uncontrollable stressor, neurogenesis decreased significantly and similarly for all animals exposed to the stressor, however only a small fraction developed helpless behavior. This suggested to us that helpless behavior and by analogy depression in humans may not result from decreases in the rate of neurogenesis, but from other structural changes, such as a decrease in synaptogenesis. Turning the experiment around and decreasing the rate of neurogenesis in naive animals did not result in a greater proportion of animals becoming helpless, regardless if we used stress to decrease neurogenesis or an alkylating agent, "methylazoxymethanol acetate" (MAM ), again suggesting that neurogenesis had little to do with the behavioral changes which result in depression or helplessness. On this basis we have decided to investigate the changes in synaptogenesis in helpless state.

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