Hippocampal Neurogenesis Relieves Depressive Symptoms

By Melissa Lee Phillips
Neuroscience for Kids Consultant
November 21, 2003

In the 1950s, physicians accidentally discovered antidepressant drugs. While administering medications to patients for reasons other than depression, doctors observed unexpected mood changes in some of these people. In studies that followed, many of these drugs systematically relieved the symptoms of major depression, and soon they were prescribed to treat this disorder.

Over the past fifty years, scientists have developed new types of antidepressants, many of them with fewer side effects than the original drugs. Despite decades of study and research, however, a mystery about these drugs has remained: no one really knows why their effects in the brain relieve depression.

Antidepressant drugs were first shown to lessen human depression in the 1950s. Since that time, however, exactly how antidepressants work has remained a mystery. Most antidepressants alter brain levels of neurotransmitters, molecules that carry chemical messages from one neuron to another. Some antidepressants work by preventing reuptake of neurotransmitters from the neuron that released them (reuptake inhibitors). Therefore, reuptake inhibitors allow neurotransmitter molecules to remain in the synaptic cleft between neurons.

It is not known precisely why increased neurotransmitter concentrations in the brain's synapses might relieve symptoms of depression. It is not even known if boosted levels of certain neurotransmitters are, in fact, the direct cause of relief, although many researchers assume this to be the case. A new study, building on the results of many previous studies, provides good evidence that behavioral responses to antidepressant treatment may involve not only short-lived chemical changes, but also substantial, long-lasting structural changes to the brain.

Part of the mystery of antidepressant action is the lag between the time required for chemical response and the time when a person starts to feel better. Generally, neurotransmitter levels are altered in the brain within a few hours. But people who are depressed often do not report feeling better for several weeks after beginning antidepressant treatment (which is one reason that more immediately effective depression treatments, particularly electroconvulsive shock therapy, have stuck around). In the past few years, studies showing anatomical changes in the brains of people who have suffered from depression have led some biologists to speculate that the benefits of antidepressants might be driven by something more enduring than changing chemical levels. The benefits may be the result of the birth of new neurons.

The hippocampus is one of the few places where neurogenesis (the generation of new neurons) occurs in adult mammals. (The olfactory bulb is another, and there is some evidence, although controversial, that neurons may be born in other areas of the adult brain, perhaps even in the neocortex.) Mammals, including humans and other primates, produce a steady stream of new neurons in the hippocampus throughout life. This process appears to be less active in people exposed to high levels of stress -- and a high stress level is a top risk factor for the development of depression.

Imaging and post-mortem ("after death") studies have shown reductions in the volume of the hippocampus in people with depression. The hippocampus of a person who has suffered long-term clinical depression can be as much as 20% smaller than the hippocampus of someone who has never been depressed. Long-term antidepressant treatment (at least a few weeks) can increase hippocampal neurogenesis, and make up for previous volume loss. This effect does not occur if the drug is given for only a few days. The similarity between the timeline of neurogenesis onset and the timeline of mental improvement after antidepressant administration suggests an appealing hypothesis: perhaps an increase in neurogenesis, rather than an increase in neurotransmitter levels, permits a depressed person to feel better. Without evidence for a direct causal link between the birth of new neurons and mental improvement, however, it remained possible that this neurogenesis was simply a correlational side effect of antidepressant action, and was actually unrelated to feeling better.

This sought-after evidence for causation has come in a study by Luca Santarelli and his colleagues at Columbia University, Université François Rabelais, New York University, and Yale University. These scientists studied the effects of a common antidepressant, fluoxetine (brand name Prozac), which raises the levels of the neurotransmitter serotonin in the synaptic space. Two groups of mice were fed the drug. In one of these groups, the researchers simultaneously stopped neurogenesis in the hippocampus, to see if the antidepressants would work anyway.

They employed a standard antidepressant test called the novelty-suppressed feeding test. In this test, the animals are deprived of food for a couple of days, and then placed in a new environment. The stress of being relocated usually causes the mice to refuse to eat for a while, even though they are very hungry. Previous studies have shown that standard antidepressant drug treatment -- for at least three weeks or so -- causes animals to eat sooner. Researchers take this as a sign that they have recovered from their anxiety about their new home.

Santarelli and his colleagues first confirmed this previous work: they observed that mice treated with fluoxetine were quick to begin eating again, unlike the control mice. Also, as expected, the stressed control mice did not show much hippocampal neurogenesis during this period. The fluoxetine mice, however, grew new neurons in their hippocampus.

In the second, crucial part of the study, the researchers delivered low-dose X-rays to the hippocampus of each mouse. These X-rays killed most developing neurons, but left old neurons alone: hippocampal neurogenesis was selectively factored out, while leaving intact any other effects the antidepressant might have. If the relief from depression was due to neurotransmitter concentration changes (serotonin, in this case), then halting neurogenesis should make no difference in the subjective effects of the drug.

What the researchers saw confirmed their hypothesis: mice that were given the antidepressant, but whose neurogenesis was stopped in the hippocampus, showed none of the behavioral effects of the drug. Even though brain levels of serotonin changed, the destruction of new cells in the hippocampus took away the antidepressant's ability to relieve depressive behaviors.

Used with permission of Phat Ha,
University of Waterloo, Ontario.
Importantly, the researchers included several controls, to exclude other possibilities. First, they gave one group of mice X-rays, but not antidepressants. These mice were not at all affected by the X-rays, which indicates that their result was not a general effect of X-rays delivered to the brain. Second, they delivered the X-rays to brain areas right next to the hippocampus, and conducted the same test. There was no effect in the mice that received X-rays, which shows that the outcome the researchers observed was specific to the hippocampus. Third, they measured synaptic transmission and plasticity in the hippocampus, functions that mature hippocampal neurons normally display. The mature neurons behaved normally, which shows that the X-rays were not killing grown neurons, but only the newly developing neurons.

The big question that remains is whether neurogenesis in the hippocampus will turn out to be as important in treating human depression as it appears to be in these stressed-out mice. Some scientists who were not involved in this study have pointed out that it is not really known if this mouse model is a good model for human depression. Although the mice behave in ways that we associate with depression, and although they show decreased neurogenesis that resumes with antidepressant treatment, we cannot be sure that the mouse data will directly relate to human depressive illness. Human depression is a very complex disorder, with many probable underlying causes and triggers, and an as-of-yet undetermined molecular basis.

Also, other physical responses to antidepressants--such as the increase of neurotransmitter molecules floating around the brain--are probably contributing to the relief of depression, as well.

"It is very likely that other factors other than neurogenesis play a role in antidepressant response. Stimulation of neurogenesis seems to be necessary but not sufficient to produce antidepressant response," says Santarelli. Maybe neurogenesis in the hippocampus is responsible for some, but not all, of an antidepressant's behavioral effects.

Many depression researchers hope that this study--and, in the future, others like it--will help to cultivate a new generation of antidepressant medications. Santarelli himself forecasts that future depression treatments may hinge on neurogenesis in the brain. "I believe it may represent the new way to treat depression," he says.

Although many available depression drugs are effective for many people, they do not work for everyone, and they often come with undesired side effects. Until depression has been conquered, brain researchers and healers will be searching for new insights into the disease's mechanism and treatment.

Newly born cells in the mouse dentate gyrus, part of the hippocampus. The red cells are neural precursors. Green lights up in cells that are dividing. The central cell is tagged with both red and green, so it fluoresces yellow around the edges. It is a dividing cell that will one day become a neuron. The blue cells are glia, the support cells of the brain.
In this image, the red cells are mature neurons in the hippocampus, and the green cells are dividing. Its yellow color is a bit difficult to see, but the cell on the right, with the green processes, expresses both markers--it has become a new neuron.
Images courtesy of Dr. Henriette Van Praag.

For references and more information, see:

  1. Changing Dogma: New Tricks for the Old Brain - from Neuroscience for Kids
  2. More Good News for Aging Brains - from Neuroscience for Kids
  3. New Neurons in Neocortex? New Study Says NO! - from Neuroscience for Kids
  4. Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S. Weisstaub, N., Lee, J., Duman, R., Arancio, O., Belzung, C., and Hen, R. "Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants," Science, 8 August 2003: 805-809.
  5. Jacobs, B.L., van Praag, H., and Gage, F.H. "Depression and the Birth and Death of Brain Cells," American Scientist, July-August 2000.
  6. MacQueen, G.M, Campbell, S., McEwen, B.S., Macdonald, K., Amano, S., Joffe, R.T., Nahmiad, C., and Young, L.T. "Course of illness, hippocampal function, and hippocampal volume in major depression," Proceedings of the National Academy of Sciences, 4 February 2003: 1387-1392.
  7. Malberg, J.E., Eisch, A.J., Nestler, E.J., and Duman, R.S. "Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus," Journal of Neuroscience, 15 December 2000: 9104-9110.
  8. Sapolsky, R.M. "Depression, antidepressants, and the shrinking hippocampus," Proceedings of the National Academy of Sciences, 23 October 2001: 12320-12322.
  9. Schatzberg, A.F. "Major Depression: Causes or Effects?" The American Journal of Psychiatry, July 2002: 1077-1079.
  10. Holloway, M. "Young Cells in Old Brains," Scientific American, September 16, 2001.
  11. Wong, M. and Licinio, J. "Research and Treatment Approaches to Depression," Nature Reviews Neuroscience, May 2001: 343-351.
  12. Shelin, Y.I., Sanghavi, M., Mintun, M.A., and Gado, M.H. "Depression Duration But Not Age Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major Depression," Journal of Neuroscience, 15 June 1999: 5034-5043.
  13. Sheline, Y.I., Gado, M.H., and Kraemer, H.C. "Untreated Depression and Hippocampal Volume Loss," The American Journal of Psychiatry, August 2003: 1516-1518.

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