Elsevier

Current Opinion in Neurobiology

Volume 30, February 2015, Pages 51-58
Current Opinion in Neurobiology

The current state of the neurogenic theory of depression and anxiety

https://doi.org/10.1016/j.conb.2014.08.012Get rights and content

Highlights

  • Diverse animal models of depression and anxiety have impaired neurogenesis.

  • Neurogenesis is consistently boosted by antidepressants in animal models when animals are stressed.

  • Ablation of neurogenesis in animal models impairs cognitive functions relevant to depression, but only a minority of studies find that ablation causes depression or anxiety.

  • Recent human neuroimaging and postmortem studies are consistent with the neurogenic theory, but they are indirect.

  • A novel drug developed based on the neurogenic theory is promising in animal models.

Newborn neurons are continuously added to the adult hippocampus. Early studies found that adult neurogenesis is impaired in models of depression and anxiety and accelerated by antidepressant treatment. This led to the theory that depression results from impaired adult neurogenesis and restoration of adult neurogenesis leads to recovery. Follow up studies yielded a complex body of often inconsistent results, and the veracity of this theory is uncertain. We propose five criteria for acceptance of this theory, we review the recent evidence for each criterion, and we draw the following conclusions: Diverse animal models of depression and anxiety have impaired neurogenesis. Neurogenesis is consistently boosted by antidepressants in animal models only when animals are stressed. Ablation of neurogenesis in animal models impairs cognitive functions relevant to depression, but only a minority of studies find that ablation causes depression or anxiety. Recent human neuroimaging and postmortem studies are consistent with the neurogenic theory, but they are indirect. Finally, a novel drug developed based on the neurogenic theory is promising in animal models.

Introduction

Within each adult human hippocampal dentate gyrus, approximately 700 newborn granule cells are added daily [1••]. First formally proposed in 2000, the neurogenic theory of depression posits that impaired adult hippocampal neurogenesis (AHN) triggers depression and restoration of AHN leads to recovery [2]. This speculative theory initially rested several correlations between depression and AHN: depressed patients on average have smaller hippocampi (reviewed in [3]), elevation of glucocorticoids can trigger depression and impair AHN [4], and serotonergic agents used to treat depression can boost AHN [5]. Major depression is more often than not accompanied by an anxiety disorder [6], and the neurogenic theory has been extended to anxiety disorders because stress and glucocorticoid dysregulation also induce anxiety, and serotonergic agents are also effective for anxiety disorders [7].

The neurogenic theory is mechanistically plausible, as adult born neurons are added to the ventral dentate gyrus, a key regulator of mood and anxiety [8]. Furthermore, adult born hippocampal neurons are required for efficient pattern separation and cognitive flexibility in rodents–cognitive functions that can be impaired in patients with depression and anxiety disorders [7, 9•]. Finally, as detailed throughout this review, AHN is required for some effects of antidepressants in animal models [10].

While speculative, this theory is exciting because the pathophysiology of depression and anxiety is poorly understood and the theory may lead to neurogenesis targeted treatments. New treatments are sorely needed as depression is the second leading cause of disability worldwide by some measures [11], depression persists in approximately 70% of patients after first-line treatment, and at least 30% of patients remain depressed even after exhaustively proceeding through four rounds of distinct treatments [12].

Mood and anxiety disorders are highly heterogeneous and any one theory of their pathophysiology or treatment will not capture their complexity. However, the neurogenic theory may help to subcategorize these disorders and guide treatment.

In this review, we propose five criteria for the acceptance of the neurogenic theory of depression and anxiety (Table 1). We organize evidence for each criterion by species. Each of these criteria should be met in human studies before fully accepting the theory. We take stock of the current evidence for each criterion, with a focus on recent studies, and we propose future studies. We contend that addressing the fifth criterion–namely, that boosting neurogenesis is sufficient to alleviate depression or anxiety–is essential as the viability of neurogenesis based treatments rests on this.

Section snippets

Evidence that AHN is altered in depression and anxiety

If impaired AHN triggers depression or anxiety, then AHN should be impaired in animal models and depressed and anxious patients.

Evidence that impaired AHN is sufficient to induce depression or anxiety

Impaired AHN is just one of many structural hippocampal changes that correlate with depression and anxiety. It is unclear if impaired AHN can cause depression and anxiety, or if it is a barometer of general dentate gyrus dysfunction.

Evidence that treatments of depression and anxiety alter AHN

If AHN is important for the effects of antidepressants, then antidepressant treatment should alter AHN.

Evidence that AHN is required for antidepressant efficacy

If AHN is essential for antidepressant efficacy, then antidepressants should lose their effects after AHN ablation.

Evidence that increased AHN is sufficient to treat depression or anxiety

There are no published studies showing that selectively boosting AHN is sufficient to treat depression or anxiety. This is an essential gap in the field and it is unclear if developing AHN directed therapies will be effective. Genetic tools are now available in rodents to test if selectively boosting AHN can reverse stress induced depression and anxiety-like behaviors. Studies addressing this are underway in our laboratory, and we have preliminary evidence that boosting AHN in chronically

Conflict of interest statement

R.H. is a consultant for Roche and Lundbeck.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are grateful to Christoph Anacker, Alexis Hill, and Jae-eun Kang Miller for helpful comments on this manuscript. B.R.M. is supported by the Leon Levy Foundation and the National Institute for Mental Health (R25: MH086466-03). R.H. is supported by the National Institute for Mental Health (R37 MH068542 (MERIT)), the National Institute on Aging (R01 AG043688), the National Institute of Neurological Disorders and Stroke (R01NS081203-01A1), NYSTEM (C029157), and the Hope for Depression Research

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