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Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/Depression
Open accessAbstract
Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.
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In the citing paper
“There is however evidence that not all the antidepressant actions require neurogenesis and that the depletion of neurogenesis in itself is not directly causing anxiety/depression-like behavior (David et al., 2009;Henn and Vollmayr, 2004), a fact that may be partially reconciled by the existence of extra-neurogenic actions of antidepressants exerted on neural plasticity (see below Section 6”
From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as David et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“although the ablation of neurogenesis does not result in anxiety/depression-like symptoms (according to David et al., 2009)”
From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as David et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Adult hippocampal neurogenesis was proposed to be required for the therapeutic action of antidepressants (David et al. 2009; Djavadian 2004; Klempin et al. 2013; Sahay and Hen 2007; Santarelli et al. 2003).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as David et al. 2009
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Negative results of chronic administration were reported (Marlatt et al., 2013) and neurogenesis-independent mechanisms of fluoxetine action were described (David et al., 2009).”
From Serotonin and neuroplasticity – Links between molecular, functional and structural pathophysiology in depression (2017) · cites this paper as David et al., 2009
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 [118]
In the citing paper
“Deficits in AHN may not only explain the learning and memory deficits in MDD, but also play a role in the selective engagement with negative valence memories, mood regulation and antidepressant response118-122.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [118]
In the citing paper
“The novelty-suppressed feeding test (NSF) is a well-validated paradigm for measuring anxiety/depression-like behaviors and estimating antidepressant efficacy in the CORT model.5”
From Synaptic Vesicle 2A (SV2A) Positron Emission Tomography (PET) Imaging as a Marker of Therapeutic Response in a Mouse Model of Depression (2025) · cites this paper as [5]
In the citing paper
“In addition, the NSF has proven to be a robust test to reflect adult hippocampal neurogenesis.5”
From Synaptic Vesicle 2A (SV2A) Positron Emission Tomography (PET) Imaging as a Marker of Therapeutic Response in a Mouse Model of Depression (2025) · cites this paper as [5]
In the citing paper
“In mice, exogenous exposure to corticosterone (the CORT model) is now well related to the emergence of depressive-like endophenotypes, with an impact on anxiety, learning, and memory.5”
From Synaptic Vesicle 2A (SV2A) Positron Emission Tomography (PET) Imaging as a Marker of Therapeutic Response in a Mouse Model of Depression (2025) · cites this paper as [5]
In the citing paper
“one study has observed that antidepressants increase hippocampal neurogenesis only in mice that are co-treated with glucocorticoid hormones, but not in control mice.12”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [12]
In the citing paper
“recent studies have suggested that glucocorticoids are involved in the neurogenic action of antidepressants.12, 17”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [12]
In the citing paper
“These genes were chosen because they have all recently been implicated in antidepressant drug action and neurogenesis.35, 36, 37, 38, 39, 12, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [12]
In the citing paper
“some animal studies have reported that administration of exogenous glucocorticoids, or circadian fluctuations of endogenous glucocorticoids, are required for increased hippocampal cell proliferation upon antidepressant treatment.12, 17”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [12]
In the citing paper
“increased hippocampal cell proliferation by antidepressant treatment in animals occurs always in the context of endogenous glucocorticoid production—which is not present in our in vitro system, unless when cells are co-treated.”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [12]
In the citing paper
“p11 and ß-arrestin-2, which have both recently been implicated in the antidepressant effects on neurogenesis in vivo.12, 40, 42, 43”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [12]
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Metadata
- Authors
- David, D. J., Samuels, B. A., Rainer, Q., Wang, J.-W., Marsteller, D., Mendez, I., Drew, M., Craig, D. A., Guiard, B. P., Guilloux, J.-P., Artymyshyn, R. P., Gardier, A. M., Gerald, C., Antonijevic, I. A., Leonardo, E. D., & Hen, R.
- Affiliations
- Université Paris-Sud (FR)
- Columbia University (US)
- Lundbeck (United States) (US)
- Corresponding author
- David, Denis J.
- Hen, René
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 62
- Issue
- 4
- Pages
- 479-493
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2759281
- OpenAlex
- W2014099101
- Cited by
- 1,267
- References
- 63
- Citations by year
- 2026: 26 · 2025: 51 · 2024: 47 · 2023: 69 · 2022: 63 · 2021: 79 · 2020: 66 · 2019: 91 · 2018: 72 · 2017: 78 · 2016: 87 · 2015: 93 · 2014: 104 · 2013: 99 · 2012: 80
- FWCI
- 24.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1538 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R37MH068542, K08MH076083, K99MH083943, R01MH068542)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD055165, 5-T32HD55165-02)
- 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
- fluoxetine, hippocampal neurogenesis, chronic corticosterone, anxiety, depression, antidepressant mechanism, X-ray irradiation, hypothalamus, β-arrestin2, β-arrestin signaling, candidate genes, mood disorders
- MeSH terms
- beta-Arrestins, beta-Arrestin 2, Doublecortin Domain Proteins, Analysis of Variance, Animals, Anxiety, Bromodeoxyuridine, Cell Survival, Corticosterone, Depression, Disease Models, Animal, Drug Administration Schedule, Exploratory Behavior, Feeding Behavior, Fluoxetine, Gene Expression Regulation, Hippocampus, Hypothalamus, Male, Mice, Inbred C57BL, Microtubule-Associated Proteins, Neuropeptides, Radiation, Reaction Time, RNA, Messenger, Mice, Knockout, Antidepressive Agents, Second-Generation, Arrestins, Cell Proliferation, Mice, GTP-Binding Protein alpha Subunit, Gi2, Neurogenesis
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