Improvement of anxiety- and depression-related behaviors in mice by treatment with a selective serotonin reuptake inhibitor seems to be dependent on creation of new neurons from stem cells in the hippocampus, according to an article in the August 8th issue of Science. Mice with symptoms such as poor grooming behavior or inability to eat in a novel setting showed a marked increase in neuron creation and improved behaviors when treated with fluoxetine for several weeks. However, treated mice who also received radiation to the hippocampus had reduced neuron formation and did not improve behaviorally. The findings support the hypothesis that neurogenesis is important in improving mood in humans and explains why antidepressants in this class typically take a few weeks to achieve a clinically apparent effect.

Full Text: Inhibition within the hippocampus of neuron formation from stem cells blocks the positive behavioral effects seen in mice treated with antidepressants, according to an article in the August 8th issue of Science. The findings support the hypothesis that neurogenesis is important in improving mood and explain why antidepressants typically take a few weeks to achieve a clinically apparent effect.

"If antidepressants work by stimulating the production of new neurons, there's a built-in delay," explained Rene Hen, PhD, lead investigator in the research. "Stem cells must divide, differentiate, migrate and establish connections with post-synaptic targets -- a process that takes a few weeks."

"This is an important new insight into how antidepressants work," added Thomas Insel, M.D., of the National Institutes of Health. "We have known that antidepressants influence the birth of neurons in the hippocampus. Now it appears that this effect may be
important for the clinical response."

Chronic stress, anxiety, and depression have been linked to atrophy or loss of hippocampal neurons. A few years ago, Hen's colleague and coauthor Ronald Duman, Ph.D., reported that some antidepressants promote hippocampal neurogenesis. For the current work, the researchers chose the mouse model to explore any relationships between generation of new neurons and relief from the symptoms of depression.

The researchers first showed that mice become less anxious -- they begin eating sooner in a novel environment ? after 4 weeks of antidepressant treatment, but not after just
5 days of such treatment. Paralleling the delay in onset of antidepressant efficacy in humans, the mice treated for weeks, but not those treated for only days, showed a 60 percent increases in a telltale marker of neurogenesis in a key area of the hippocampus.

As a next step, the team investigated whether neurogenesis is involved in antidepressants’ mechanism of action by targeting the hippocampus with radiation to kill any proliferating cells. This resulted in a reduction of 85 percent in neurogenesis. Antidepressant treatment had no apparent effect on anxiety and depression-related behaviors in the irradiated mice. For example, fluoxetine normally improves grooming behavior in treated mice, but the effect was not seen in the irradiated mice. Additional evidence suggested that the radiation effect was due to reduction in neurogenesis and not another tissue-level or cellular-level effect.

By knocking out the gene that codes for a key subtype of serotonin receptor (5-HT1A), the researchers created a strain of mice that show anxiety-related traits such as a reluctance to begin eating in a novel environment as adults. Although long-term treatment with fluoxetine did not improve behaviors in these mice, treatment with the tricyclic antidepressant imipramine did have a positive effect, suggesting an independent molecular pathway. Researchers also found that knockout mice treated with fluoxetine did not show any evidence of neurogenesis, whereas normal mice doubled the number of hippocampal neurons after treatment with fluoxetine.

Although the new findings strengthen the case that neurogenesis contributes to the effects of antidepressants, Hen cautioned that ultimate proof may require a "cleaner"
method of suppressing the process of neurogenesis, such as transgenic techniques that will more precisely direct toxins to the appropriate hippocampal circuits.

"Our results suggest that strategies aimed at stimulating hippocampal neurogenesis could provide novel avenues for the treatment of anxiety and depressive disorders," concluded
the authors.