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The neurogenesis hypothesis of affective and anxiety disorders: Are we mistaking the scaffolding for the building?
Open accessAbstract
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'.
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“A few studies provide evidence that the absence of neurogenesis elicits depressive like symptoms in rodents123, 124, but most studies find that absent neurogenesis is not sufficient to induce a depressive phenotype125 although it is required in mice for the behavioral effects of antidepressants118, 126.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [124]
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Stimulation of entorhinal cortex–dentate gyrus circuitry is antidepressive
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“The hippocampus is involved in learning/memory context-dependent emotional responses (Fanselow, 2000), and mood control (Petrik et al., 2012).”
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“The possibility to activate endogenous NSCs and stimulate the generation of new neurons in the adult brain could have therapeutic potential in pathological conditions in which neurogenesis is altered, such as mood disorders, schizophrenia and neurodegenerative diseases (Kaneko and Sawamoto, 2009; Winner et al., 2011;…”
Wang, H., Wang, L., Zhang, R., Chen, Y.-C., Liu, L., Gao, F., Nie, H., Hou, W., Peng, Z., & Tan, Q. (2014) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.01.004 · Cited by 70
“The hippocampus is one of the several limbic structures that have been extensively studied in individuals with depression (Petrik et al., 2012), it has been shown undergoing morphological changes in response to stress, including atrophy and loss of CA3 pyramidal neurons (Kim et al., 2007; Yang et…”
Felice, D., O’Leary, O. F., Pizzo, R., & Cryan, J. F. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.06.066 · Cited by 70
Additive gene-environment effects on hippocampal structure in healthy humans
Rabl, U., Meyer, B. M., Diers, K., Bartova, L., Berger, A., Mandorfer, D., Popovic, A., Scharinger, C., Huemer, J., Kalcher, K., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3113-13.2014 · Cited by 68
“In line with their effects on the stress system and brain function, these variants have repeatedly been shown to directly affect hippocampal volume (Pezawas et al., 2004; Frodl et al., 2008; Honea et al., 2009), although others failed to show these effects (Dutt et al., 2009; Cole et al., 2011;…”
BackgroundLiang, G., Kow, A. S. F., Yusof, R., Tham, C. L., Ho, Y.-C., & Lee, M. T. (2024) · Biomedicines · doi:10.3390/biomedicines12010184 · Cited by 68
“These results illustrated that neurogenesis plays a vital role in depression and can impact behavioral output and the efficacy of antidepressant therapy, which was also the simplest form of the neurogenesis hypothesis [119].”
BackgroundFunctional and mechanistic exploration of an adult neurogenesis‐promoting small molecule
Petřík, D., Jiang, Y., Birnbaum, S. G., Powell, C. M., Kim, M., Hsieh, J., & Eisch, A. J. (2012) · The FASEB Journal · doi:10.1096/fj.11-201426 · Cited by 70
“Adult-generated hippocampal granule cell (GC) neurons incorporate into hippocampal circuitry (3, 4) and are implicated in many hippocampal functions, including learning and memory (5) and mood control (6).”
BackgroundSelf-citationRief, W., Barsky, A. J., Bingel, U., Doering, B. K., Schwarting, R., Wöhr, M., & Schweiger, U. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.11.008 · Cited by 67
Vulnerability of the Hippocampus to Insults: Links to Blood–Brain Barrier Dysfunction
Davidson, T. L., & Stevenson, R. J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25041991 · Cited by 80
“The second contention is better supported and fits especially neatly with the therapeutic delay observed for anti-depressant medications [307,308], for behavioral interventions [306], and for the beneficial effects of electroconvulsive therapy [309].”
BackgroundSah, A., Schmuckermair, C., Sartori, S. B., Gaburro, S., Kandasamy, M., Irschick, R., Klimaschewski, L. P., Landgraf, R., Aigner, L., & Singewald, N. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.94 · Cited by 67
“increasing or decreasing neurogenesis using knockouts or X-ray or pharmacological treatment is not sufficient to lead to the development of a depression-like phenotype in animals (for review, see Petrik et al.(46) and Sahay”
BackgroundInfluentialLeschik, J., Lutz, B., & Gentile, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147339 · Cited by 77
Opendak, M., Offit, L., Monari, P., Schoenfeld, T. J., Sonti, A. N., Cameron, H. A., & Gould, E. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4435-15.2016 · Cited by 61
“Studies have shown that stress-induced changes in behavior may be adaptive in many circumstances (Lagace et al., 2010; Petrik et al., 2012; Blanchard et al., 2013).”
BackgroundHarris, B. N. (2019) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2019.113355 · Cited by 79
Stress modulation of hippocampal activity – Spotlight on the dentate gyrus
Fa, M., Li, X., Anunu, R., Kehat, O., Kriebel, M., Volkmer, H., & Richter‐Levin, G. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2014.04.008 · Cited by 62
Perceived Stress Is Differentially Related to Hippocampal Subfield Volumes among Older Adults
Zimmerman, M. E., Ezzati, A., Katz, M. J., Lipton, M. L., Brickman, A. M., Sliwinski, M. J., & Lipton, R. B. (2016) · PLoS ONE · doi:10.1371/journal.pone.0154530 · Cited by 61
Yun, S., Donovan, M. H., Ross, M. N., Richardson, D. R., Reister, R., Farnbauch, L. A., Fischer, S. J., Riethmacher, D., Gershenfeld, H. K., Lagace, D. C., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147256 · Cited by 51
Self-citationThe Kynurenine Pathway in Traumatic Brain Injury: Implications for Psychiatric Outcomes
Meier, T. B., & Savitz, J. B. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.05.021 · Cited by 80
Zhao, L., Ren, H.-C., Gu, S.-N., Li, X., Jiang, C., Li, J., Zhang, M.-M., Mu, J.-L., Li, W., Wang, W., et al. (2018) · Psychiatry Research · doi:10.1016/j.psychres.2018.08.017 · Cited by 58
“The hippocampus is one of several limbic structures implicated in depression (Petrik et al., 2012).”
Wu, M. V., Sahay, A., Duman, R. S., & Hen, R. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018978 · Cited by 64
“In contrast, temporal, but not septal, hippocampal lesions result in deficits in predator-induced freezing (Phillips and LeDoux 1992), cued fear conditioning (Maren and Holt 2004), and novelty-induced hyponeophagia (Bannerman et al. 2002).”
BackgroundSex differences in response to chronic mild stress and congenital serotonin deficiency
Sachs, B. D., Ni, J. R., & Caron, M. G. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.11.008 · Cited by 51
“Chronic stress has been reported to inhibit adult hippocampal neurogenesis (Gould et al., 1997, 1998; Malberg and Duman, 2003), but the importance of hippocampal neurogenesis for depression- and anxiety-like behavior remains controversial (Petrik et al., 2012).”
BackgroundDiet-dependent gut microbiota impacts on adult neurogenesis through mitochondrial stress modulation
Ribeiro, M. F., Santos, A. A., Afonso, M. B., Rodrigues, P. M., Santos, S. S., Castro, R. E., Rodrigues, C. M. P., & Solá, S. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa165 · Cited by 56
“, 2006; Hamilton and Holscher, 2012) and psychiatric disorders, particularly depression and anxiety (Petrik et al., 2012; Fang et al., 2018), whereas an increased rate of SGZ neurogenesis induced by treatment with antidepressants improves psychiatric disorders (Perera et al.”
BackgroundHu, P., Wang, Y., Liu, J., Meng, F., Qi, X., Chen, L., van Dam, A., Joëls, M., Lucassen, P. J., & Zhou, J. (2016) · Hippocampus · doi:10.1002/hipo.22574 · Cited by 41
“However, ablation of neurogenesis per se often does not induce a depressive phenotype (Santarelli et al., 2003; Henn and Vollmayr, 2004; Petrik et al., 2012).”
BackgroundSchnell, A., Sandrelli, F., Ranc, V., Ripperger, J. A., Brai, E., Alberi, L. A., Rainer, G., & Albrecht, U. (2015) · Chronobiology International · doi:10.3109/07420528.2015.1062024 · Cited by 55
“A growing body of evidence suggests that mooddisorders are associated with disturbed adult neurogenesis (Benes et al., 1998; Rajkowska, 2000), which appears to be crucial for proper mood control and efficient antidepressant therapy (Petrik et al., 2012; Samuels & Hen, 2011).”
BackgroundInfluentialDiaz, S. L., Narboux‐Nême, N., Boutourlinsky, K., Doly, S., & Maroteaux, L. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2015.12.012 · Cited by 58
“, 2000), it is not clear if defects in neurogenesis play a role in depression (Petrik et al., 2012).”
InfluentialPae, C., Wang, S., Han, C., Lee, S.-J., Patkar, A. A., Masand, P. S., & Serretti, A. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.02.017 · Cited by 61
Dietary Polyphenols and Their Effects on Cell Biochemistry and Pathophysiology
Angeloni, C., Pirola, L., Vauzour, D. D., & Maraldi, T. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/583901 · Cited by 48
“This could be due to their capacities to scavenge NO or to decrease the NO synthase activity [110, 164, 185].”
BackgroundHuntingtin Mediates Anxiety/Depression-Related Behaviors and Hippocampal Neurogenesis
M’Barek, K. B., Pla, P., Orvoën, S., Benstaali, C., Godin, J. D., Gardier, A. M., Saudou, F., David, D. J. P., & Humbert, S. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5110-12.2013 · Cited by 55
Stressing new neurons into depression?
Lucassen, P. J., Fitzsimons, C. P., Kőrösi, A., Joëls, M., Belzung, C., & Abrous, D. N. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.39 · Cited by 29
Modulation of GABAA Receptor Signaling Increases Neurogenesis and Suppresses Anxiety through NFATc4
Quadrato, G., Elnaggar, M. Y., Duman, C., Sabino, A., Forsberg, K., & Giovanni, S. D. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0047-14.2014 · Cited by 43
The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine
Sachs, B. D., Jacobsen, J. P. R., Thomas, T., Siesser, W. B., Roberts, W. L., & Caron, M. G. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.65 · Cited by 48
Marxreiter, F., Ettle, B., May, V. E. L., Esmer, H., Patrick, C., Kragh, C. L., Klucken, J., Winner, B., Rieß, O., Winkler, J., et al. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.07.004 · Cited by 46
“, 2011), whereas other studies did either not observe any change or an decrease in anxiety (recently reviewed by (Petrik et al., 2012).”
Microbiota-Gut-Brain Axis Regulation of Adult Hippocampal Neurogenesis
Guzzetta, K. E., Cryan, J. F., & O’Leary, O. F. (2022) · Brain Plasticity · doi:10.3233/bpl-220141 · Cited by 74
Singh, T., & Goel, R. K. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03274-5 · Cited by 51
Li, G., Yang, J., Wang, X., Zhou, C., Zheng, X., & Lin, W. (2020) · Food & Function · doi:10.1039/d0fo00524j · Cited by 53
Sun, D., Milibari, L., Pan, J., Ren, X., Yao, L.-L., Zhao, Y., Shen, C., Chen, W., Tang, F., Lee, D., et al. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.08.026 · Cited by 50
Dietary Polyphenols and Their Effects on Cell Biochemistry and Pathophysiology 2013
Maraldi, T., Vauzour, D., & Angeloni, C. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/576363 · Cited by 55
“This could be due to their capacities to scavenge NO or to decrease the NO synthase activity [110, 164, 185].”
BackgroundInfluentialPI3K/AKT/GSK3β/CRMP-2-mediated neuroplasticity in depression induced by stress
Wu, Z., Wang, G., Wei, Y., Xiao, L., & Wang, H. (2018) · Neuroreport · doi:10.1097/wnr.0000000000001096 · Cited by 44
Wu, Z., Xiao, L., Wang, H., & Wang, G. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107653 · Cited by 48
Reelin-Related Disturbances in Depression: Implications for Translational Studies
Caruncho, H. J., Brymer, K. J., Romay-Tallón, R., Mitchell, M. A., Baltanás, T. R., Botterill, J. J., Olivares, J. M., & Kalynchuk, L. E. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00048 · Cited by 44
“…from data showing that patients with depression have reduced hippocampal volume (MacQueen et al., 2003; Campbell et al., 2004) and that chronic stress and antidepressant drugs can decrease and increase cell proliferation and survival respectively (Santarelli et al., 2003; Petrik et al., 2012).”
BackgroundSakalem, M. E., Seidenbecher, T., Zhang, M., Saffari, R., Kravchenko, M., Wördemann, S., Diederich, K., Schwamborn, J. C., Zhang, W., & Ambrée, O. (2016) · Hippocampus · doi:10.1002/hipo.22669 · Cited by 44
“Indeed, as recently reviewed, almost every study which could show depressive-like or anxiety-related phenotypes due to neurogenesis impairments used different stressors prior to testing (Petrik et al., 2012).”
Background
Metadata
- Authors
- Petrik, D., Lagace, D. C., & Eisch, A. J.
- Affiliations
- University of Ottawa (CA)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Eisch, Amelia J.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 62
- Issue
- 1
- Pages
- 21-34
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC3698048
- OpenAlex
- W1988200425
- Cited by
- 241
- References
- 204
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 19 · 2020: 11 · 2019: 13 · 2018: 14 · 2017: 12 · 2016: 29 · 2015: 22 · 2014: 35 · 2013: 29 · 2012: 25
- FWCI
- 2.52
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- National Institutes of Health (R01 DA016765, K02 DA023555)
- NASA (NNX07AP84G)
- NSERC (371716)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- adult neurogenesis, dentate gyrus, major depressive disorder, anxiety disorders, post-traumatic stress disorder, antidepressant mechanism, stress response, resilience, social stress, serotonin, transgenic mouse model
- MeSH terms
- Animals, Anxiety, Hippocampus, Humans, Models, Biological, Anti-Anxiety Agents, Mood Disorders, Neurogenesis
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