Depression is a chronic psychiatric disorder that affects 25 percent of women and 12 percent of men in the United States, and it cost the U.S. $83 billion in 2000.
It was originally thought that downregulated levels of the neurotransmitter serotonin cause depression. To that end, selective serotonin reuptake inhibitors (SSRIs), the mainstay depression therapy, were developed to restore serotonin levels in individuals. Despite their widespread use, SSRIs leave more than one-third of depressed individuals resistant to drug treatments and exert delayed therapeutic response times of weeks to months. The failure of antidepressant therapies in some people suggests that the neurotransmitter imbalance hypothesis is not sufficient to fully capture the complex cellular and molecular processes that underlie depression. For newer and more efficacious treatments to be developed, a greater understanding of depression pathogenesis must be made to allow for novel identification of therapeutically beneficial drug targets.
One interesting observation from brain imaging studies is that individuals with depression have smaller hippocampi, a brain region known for its role in learning and memory. What could be responsible for this reduction in size? Morphological changes in neurons may contribute to hippocampal atrophy. Some studies suggest that the neurons themselves shrink and display decreased complexity in the wires used for communication known as dendrites. A reduction in the number of neurons could be a contributing factor to reduced hippocampal size as well.
About 20 years ago it was discovered that throughout adult life, the human brain continues to make new neurons in the hippocampus, a process termed adult neurogenesis. That means that as neurons die off every day, adult neurogenesis might be able to provide a reservoir of newborn cells to take over old neurons. If depression affects this “conveyor belt,” then there could be an overall net loss of neuronal cells, which in turn could affect the hippocampal volume.
Animal models of depression have been indispensable to research progress in understanding the disease pathogenesis and the biological targets of antidepressants. The most common model involves chronic stress paradigms, such as physical restraint, that result in depression-like behaviors. Although we can’t really ask whether a mouse is depressed or not, several behavioral tests indicate behaviors that resemble those displayed by humans with depression. For example, a well-known symptom of depression is anhedonia, or loss of pleasure. Individuals with anhedonia typically lose interest in activities that they previously found pleasurable, such as reading or cooking. The mouse equivalent of anhedonia is a loss of interest in sucrose water, which can be measured by the sucrose preference test. Between a bottle of plain water and a bottle of sucrose solution, mice with depression-like behavior will drink more of the plain water than normal mice who would go for the sugar water.
From these models, researchers have been inducing depression in mice by different types of stress to examine how stress-induced depression changes the brain. One striking observation was that stress negatively affects adult neurogenesis, indicated by decreased rates of cellular proliferation and number of newborn cells. The most compelling evidence for a role of neurogenesis in depression shows that antidepressants increase neurogenesis, and blocking neurogenesis no longer makes antidepressant treatment effective in reversing the mood impairments. This data points to neurogenesis as a major player in the pathogenesis of depression and an important therapeutic target for novel antidepressant strategies.
The fact that antidepressants often take weeks to show an effect on behavior correlates with the length of time required for a neural stem cell to become a fully mature neuron, which is several weeks. However, more gain and loss of function studies are needed to further examine the role of adult neurogenesis in depression. For instance, novel advances in genetic methods have allowed scientists to more specifically ablate adult neural stem cells in the hippocampus. Although lack of adult neurogenesis did not by itself result in depression, mice without neurogenesis showed even more depression-like behaviors following stress than normal mice. It may be possible that neurogenesis is required for an endogenous neuronal compensatory response following stressful episodes. As a result, it may also be informative to look at mice in which neurogenesis is increased to see whether upregulated neurogenesis by itself can reduce stress-induced depression.
Although evidence for a role in adult neurogenesis in depression etiology is striking, the neuronal mechanisms that underlie depressive illnesses are likely to involve a multitude of other complex cellular pathways. As a result, decreased rates of neurogenesis could be working with other biological processes to drive the depressive phenotype. A careful examination of neurogenesis in a wide variety of additional depression animal models as well as more neurogenesis experiments could provide clearer answers.
