Neurogenesis hypothesis of depression

Adult neurogenesis is the process by which functional, mature neurons are produced from neural stem cells (NSCs) in the adult brain. In most mammals, including humans, it only occurs in the subgranular zone of the hippocampus, and in the olfactory bulb. The neurogenesis hypothesis of depression proposes that major depressive disorder is caused, at least partly, by impaired neurogenesis in the subgranular zone of the hippocampus.

Overview
Hippocampal neurogenesis

In the subgranular zone in the dentate gyrus of the hippocampus, NSCs differentiate into granule cells. These new granule cells are implicated in memory formation and learning. The number of granule cells generated in the dentate gyrus each month is approximately 6% of the total population of dentate gyrus neurons. The magnitude of this continuous production of new neurons indicates that they have an important role in hippocampal function.

Inadequacy of the monoamine hypothesis of depression

While depression is a complex condition with many factors involved, it is commonly attributed to an imbalance of several key monoamine neurotransmitters, including serotonin, dopamine and norepinephrine. This monoamine hypothesis of depression is popular because of the simplicity of the explanation. However, the hypothesis is incomplete, as several lines of evidence suggests that depression is more than just a monoamine imbalance. For example, antidepressants usually take several weeks to reduce a patient's depressive symptoms, which is inconsistent with the finding that monoamine levels are affected within hours of using antidepressants. This suggests that antidepressants need to affect other biological systems, apart from monoamines, in order to reduce depressive symptoms.

Relationship between neurogenesis and depression

Stress has been reported to impair many aspects of hippocampal neurogenesis, including:


 * Proliferation rate of neural progenitor cells
 * Survival of neuroblasts and immature neurons
 * Growth and development of new neuron

The neurogenesis hypothesis of depression posits that:


 * Stressful experiences have a negative effect on the process of neurogenesis in the subgranular zone of the dentate gyrus.
 * Alternations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression.

Experimental evidence
The neurogenesis hypothesis of depression gained popularity due to the large number of correlative studies which indicate a relationship between impaired hippocampal neurogenesis and depression. For example, reduced hippocampal volume is associated with depression, which impaired neurogenesis may contribute to.

Conflicting evidence

Studies with rats demonstrated that the administration of antidepressants increases hippocampal neurogenesis. Furthermore, studies with non-human primates found that stress, which is a predisposing factor to depression in humans, impairs hippocampal neurogenesis.

However, other studies have demonstrated that neuronal ablation does not always impair neurogenesis in laboratory animals. Furthermore, it was found that stress does not necessarily impair neurogenesis in laboratory animals. Furthermore, some of the effects of antidepressants are neurogenesis-independent.

Regarding these conflicting findings, Hanson et al., (2011) has suggested that neurogenesis in the adult dentate gyrus “can be regulated by stress and antidepressants under certain as-yet-undefined conditions”.

Lack of human studies

As it is not currently possible to track neurogenesis in humans in real-time, most studies have relied on animal models of depressive behaviours resulting from impaired neurogenesis.