Researchers Try to Explain Link Between Depression, Brain Chemical

Increasing—and intriguing—links are being made between a brain growth factor called brain-derived neurotrophic factor (BDNF) and depression.

For instance, it looks as though abnormally low levels of BDNF may be implicated in depression, since depressed persons have been found to have abnormally low levels of BDNF in their blood, and since depressed persons receiving antidepressants have been found to have higher BDNF levels in their blood.

But how might abnormally low levels of BDNF trigger depression? Perhaps by not being present in large enough quantities in the hippocampus region of the brain, because when rats are given antidepressants, it increases BDNF levels in the hippocampus.

Nonetheless, the answer is probably more complicated, because a new rodent study suggests that when BDNF is injected into some other areas of the brain, it exerts a depression-causing rather than depression-reducing effect.

The study was conducted by Amelia Eisch, Ph.D., an assistant professor of psychiatry at the University of Texas Southwestern Medical Center at Dallas, and coworkers.

Rats, of course, cannot tell anyone when they are depressed, but a number of scientists, including Eisch, believe that a so-called forced-swim test can be used as an indirect gauge of depression-like behaviors in rats. Rats do not like water, so when they are placed in water, they are usually eager to swim and get out of it. If the rats do not swim eagerly to get out, the researchers conclude that they have the equivalent of depression.

Eisch and her group knew that when BDNF is injected into the hippocampus of rats, they do even better on the forced-swim test than control rats do, implying that a surplus of BDNF in the hippocampus can exert an antidepressant effect. So they wondered what effect BDNF would have on several brain areas involved in pleasure.

They injected BDNF into an area of the rats’ brains known to be involved in pleasure—the ventral tegmental area—then had the rats engage in the forced-swim test. The first day afterward, the rats swam just as well as control rats, showing that they had learned the technique with no difficulty. On the second day, however, they did not swim as well as the control rats, suggesting that they were depressed.

Thus, it looks as if BDNF may have exerted a depressive effect in the rats’ ventral tegmental area. Eisch and her colleagues were surprised at this finding. They had expected BDNF to have an antidepressive effect on the ventral tegmental area, just as it has on the hippocampus.

Eisch and her team then decided to see whether the depressive effect that BNDF was exerting on the ventral tegmental area was also being passed on to a neighboring pleasure center, the nucleus accumbens, since the ventral tegmental area was already known to send BDNF to this brain structure.

To test this hypothesis, they injected a protein that blocks BDNF’s action into the nucleus accumbens of rats. The rats were put through the forced-swim test. On the first day, they swam the same as the control rats. On the second day, they swam even better than the control rats. Eisch and coworkers used other tests to find that anxiety and locomotion were not altered in the animals.

This finding thus suggested that, indeed, BDNF made in the ventral tegmental area and then sent to the nucleus accumbens had a depressive effect.

So it looks as though BDNF may exert an antidepressive effect on the hippocampus, but a depressive effect on the ventral tegmental area and nucleus accumbens, Eisch and her team concluded. The results also suggest that while the hippocampus is critical in depression, the pleasure pathways of the brain may play a role as well.

Eisch reported these findings in October at the 15th Annual Scientific Symposium of the National Alliance for Research on Schizophrenia and Depression, which funded the research with a two-year Young Investigator Award. The results are also in press with Biological Psychiatry. ▪