The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building?

Abstract

Hypotheses are scaffoldings erected in front of a building and then dismantled when the building is finished. They are indispensable for the workman; but you mustn't mistake the scaffolding for the building. Johann Wolfgang von Goethe. The neurogenesis hypothesis of affective disorders - in its simplest form - postulates that the generation of neurons in the postnatal hippocampal dentate gyrus is involved in the etiology and treatment efficacy of major depressive disorder (MDD). The hypothesis was established in the 1990s but was built on a broad foundation of earlier research on the hippocampus, serotonin and MDD. It has gone through several growth phases fueled by discoveries both correlative and causative in nature. Recently, the hypothesis has also been broadened to also include potential relevance for anxiety disorders, like post-traumatic stress disorder (PTSD). As any hypothesis should be, it has been tested and challenged, sometimes vigorously. Here we review the current standing of the neurogenesis hypothesis of affective and anxiety disorders, noting in particular how a central postulate - that decreased neurogenesis results in depression or anxiety - has, in general, been rejected. We also review the controversies on whether treatments for these disorders, like antidepressants, rely on intact neurogenesis for their efficacy, and the existence of neurogenesis-dependent and -independent effects of antidepressants. In addition, we review the implications that the hypothesis has for the response to stress, PTSD, and the neurobiology of resilience, and highlight our own work showing that adult-generated neurons are functionally important for the behavioral response to social stress. We conclude by emphasizing how advancements in transgenic mouse technology, rodent behavioral analyses, and our understanding of the neurogenesis process will allow us to refine our conclusions and perform ever more specific experiments. Such scrutiny is critical, since if we "mistake the scaffolding for the building" we could overlook opportunities for translational impact in the clinic. This article is part of a special Issue entitled 'Anxiety and Depression'.

Figure 1. Adult hippocampal neurogenesis and the neurogenesis hypothesis of depression

(A) Dissection of the rodent telecephalon reveals a cross-section through the hippocampus (colored lines) with the dentate gyrus – the site of adult-generated hippocampal neurons – depicted in red. (B) Enlarged schematic of the dentate gyrus shows the superior and inferior blades of the granule cell layer (GCL, brown) and the subgranular zone (SGZ, red) where the hippocampal neurogenesis occurs in the postnatal period through adulthood. (C) Higher magnification of the boxed region from (B) displays the phases of adult hippocampal neurogenesis as a function of time. The neural stem cells (NSCs, green) putatively give rise to the transiently-amplifying progenitors (blue and violet) whose progeny differentiate into immature neurons (dark violet) and finally into fully mature dentate gyrus GC neurons (red). (D) Under normal, physiological conditions, the process from NSCs to mature GC takes approximately 4–6 weeks. (E) The first postulate of the neurogenesis hypothesis of depression states that reduced neurogenesis should result in a depressive phenotype. (F) The second postulate of the neurogenesis hypothesis of depression states that antidepressants require adult neurogenesis for effects in improving mood. As discussed in the text, Figure 2, and Tables 1 and 2, published work supports aspects of the second, but not the first, hypothesis.

Figure 2. Is the efficacy of antidepressants reliant on intact adult hippocampal neurogenesis?

(A) This question is often addressed by depletion adult-generated neurons by cranial irradiation or antimitotic agents (methylazoxymethanol or MAM is shown; see Tables 1, 2 for more approaches) and subsequent administration of antidepressant compounds or environmental manipulations known to have antidepressant efficacy (like running or environmental enrichment). As highlighted in Table 2, the results from these studies are conflicting. Some studies show that after disruption of neurogenesis, antidepressants still produce antidepressant or antianxiety effects in behavioral tests, here summarized as “improved mood”. However, other studies show that after disruption of neurogenesis, antidepressants fail to result in antidepressant or antianxiety effects in behavioral tests, here summarized as “impaired mood”. (B) The conflicting results summarized in (A) may in part be explained by the many factors that influence whether adult-generated neurons are required for antidepressant efficacy or not. Stress or anxiety levels of the experimental animals, difference in animal strain that may influence the basal level of adult neurogenesis, and the type of ablation strategy utilized (such as gancyclovir in tk+ mice) are just some of the factors that appear to influence whether or not antidepressants influence mood regulation via adult-generated neurons.