The DOI matches its Crossref record; 195 of the 195 references it cites were found in a registry or an index.
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'.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Neurogenesis in the adult human hippocampus
Eriksson, P. S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.-M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998) · Nature Medicine · doi:10.1038/3305 · Cited by 6,369
The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions
Gottesman, I. I., & Gould, T. D. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.4.636 · Cited by 5,615
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., et al. (2003) · Science · doi:10.1126/science.1083328 · Cited by 4,321
Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus
van Praag, H., Kempermann, G., & Gage, F. H. (1999) · Nature Neuroscience · doi:10.1038/6368 · Cited by 3,880
More hippocampal neurons in adult mice living in an enriched environment
Kempermann, G., Kuhn, H. G., & Gage, F. H. (1997) · Nature · doi:10.1038/386493a0 · Cited by 3,586
Kuhn, H., Dickinson-Anson, H., & Gage, F. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-06-02027.1996 · Cited by 3,139
Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus
Malberg, J. E., Eisch, A. J., Nestler, E. J., & Duman, R. S. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-24-09104.2000 · Cited by 3,111
Self-citationMechanisms and Functional Implications of Adult Neurogenesis
Zhao, C., Deng, W., & Gage, F. H. (2008) · Cell · doi:10.1016/j.cell.2008.01.033 · Cited by 3,007
Running enhances neurogenesis, learning, and long-term potentiation in mice
van Praag, H., Christie, B. R., Sejnowski, T. J., & Gage, F. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.23.13427 · Cited by 2,904
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889
Flagged first, then by citations
Research works printed but not linked: 7
- Cryan, 2010, GABAB receptors and depression. Current status, Adv. Pharmacol., 58, 427, 10.1016/S1054-3589(10)58016-5 · DOI
- Curtis, 2011, Neurogenesis in humans, Eur. J. Neurosci., 33, 1170, 10.1111/j.1460-9568.2011.07616.x · DOI
- Kempermann, 2011, vol. 2
- McEwen, 2000, The neurobiology of stress: from serendipity to clinical relevance, Brain Res., 886, 172, 10.1016/S0006-8993(00)02950-4 · DOI · Paper page
- Parihar, 2011, Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory, Mol. Psychiatry, 16, 171, 10.1038/mp.2009.130 · DOI
- Perera, 2000, Neurogenesis and depression, J. Psychiatr. Pract., 6, 322, 10.1097/00131746-200011000-00003 · DOI
- Tollefson, 1995, A double-blind, placebo-controlled clinical trial of fluoxetine in geriatric patients with major depression. The Fluoxetine Collaborative Study Group, Int. Psychogeriatr., 7, 89, 10.1017/S1041610295001888 · DOI
Cited by
Sorted by citations
Items 201–220 of 220
NEUROGENESIS: MECHANISMS, REGULATION, AND IMPLICATIONS FOR BRAIN FUNCTION AND DISEASE
Elsharawy, A. F. (2026) · World Journal of Advanced Research and Reviews · doi:10.5281/zenodo.23315877
Simard, S., & Mechawar, N. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03896-7
Okano, M., Yoshino, Y., Verma, A. K., Kumon, H., Mori, H., Hosokawa, M., Iga, J., Dwivedi, Y., Takeuchi, A., & Ueno, S. (2026) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.70111
Chang, M., Li, R., Stephan, M., Schmitt, A., Falkai, P., & Rossner, M. J. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2026.1837159
“Research of cognitive dysfunction and pathological behaviors in psychiatric disorders has been so far dominated by neuron-centric hypotheses, focusing particularly on synaptic plasticity and neurotransmitter imbalance (Petrik et al., 2012; Howes and Onwordi, 2023).”
Yavaş, S. E., & Ersoy, S. (2025) · Pamukkale Medical Journal · doi:10.31362/patd.1657975 · Cited by 1
자발적 운동이 miRNA 조절 항우울 반응에 미치는 효과*
한, 예., 김, 태., & 조, 준. (2024) · 한국체육학회지 · doi:10.23949/kjpe.2024.3.63.2.3
Exercise as part of anxiety coping management in the Covid-19 pandemic era
Agustiningsih, D., & Wibowo, R. A. (2021) · Journal of the Medical Sciences (Berkala Ilmu Kedokteran) · doi:10.19106/jmedsci005303202109
Gao, Y., Zhang, Q., Wu, L., & Dai, J. (2023) · Journal of Biosciences and Medicines · doi:10.4236/jbm.2023.114014
5-HT2B Receptors and Antidepressants
Diaz, S. L. (2021) · The Receptors · doi:10.1007/978-3-030-55920-5_21
Tranquilizer/Anxiolytics: Tandospirone
Li, J. (2021) · Springer eBooks · doi:10.1007/978-3-319-56015-1_167-1
Clarke, M. (2019) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2019-13740
“…stress do not necessarily lead to a depressive-like phenotype; however in the presence of stress, reduced neurogenesis can promote depressive-like symptoms (Egeland et al., 2015), suggesting that reduced neurogenesis can lead to depression through impaired stress modulation (Petrik et al., 2011).”
BackgroundAdult Neurogenesis in Health and Disease
Mobley, A. S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-811014-0.00008-1
Molecular basis of autism-like behavior in SAPAP3-deficient mice
Tesdahl, N. S., Pieper, A. A., Stamnes, M. A., & Weiner, J. A. (2017) · doi:10.17077/etd.jgayg2ix
“Work by our laboratory (91) and others (92-96) has shown that this process”
BackgroundGobinath, A. (2017) · doi:10.14288/1.0357185
“, 1989), and others have indicated an important role of neurogenesis in anxiety (Petrik et al., 2012; Hill et al., 2015).”
BackgroundChapter 2 – Choosing a Research Problem
Smalheiser, N. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-811306-6.00002-6
Novel approaches to the pathophysiology of late-life depression
Eyre, H. (2016) · doi:10.25909/5b3d8feb48000
“Anti-neuroplastic changes which occur in depression include a decrease in proliferation of neural stem cells (NSCs), decreased survival of neuroblasts and immature neurons, impaired neurocircuitry (cortical–striatal–limbic circuits), reduced levels of neurotrophins, reduced spine density and dendritic retraction [52-5…”
BackgroundNeurogenesis and the impact of steroid hormones on behaviour
Rankov-Petrović, B., Rašić-Marković, A., Hrnčić, D., & Stanojlović, O. P. (2016) · Medicinska istrazivanja · doi:10.5937/medist1601023r
“Jasno je definisan model depresije kod životinja izazvan blagim hroničnim stresom, čije se posledice na ćelijskom nivou ogledaju u smanjenoj neurogenezi (90).”
BackgroundIskandarani, E. (2014) · uO Research (University of Ottawa) · doi:10.20381/ruor-3466
Investigating the Regulation of Adult Hippocampal Neurogenesis: Endogenous and Exogenous Cues
Pettit, A. (2012) · doi:10.20381/ruor-6686
“%) support the requirement for neurogenesis in effective 82 therapy (Petrik et al., 2011).”
BackgroundInfluential
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
