Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression
Open accessAbstract
Previous studies demonstrated that antidepressant treatment increases the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. The present study was conducted to test the hypothesis that BDNF in the hippocampus produces an antidepressant effect in behavioral models of depression, the learned helplessness (LH) and forced swim test (FST) paradigms. A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor. Infusions of BDNF and NT-3 did not influence locomotor activity or passive avoidance. The results provide further support for the hypothesis that BDNF contributes to the therapeutic action of antidepressant treatment.
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Intrahippocampal infusion of BDNF mitigates stress-induced neurogenic impairments and promotes neurogenesis.
“Interestingly, intrahippocampal infusion of BDNF was shown to mitigate stress-induced neurogenic impairments [115] and promote neurogenesis [116].”
From Chronic Stress-Associated Depressive Disorders: The Impact of HPA Axis Dysregulation and Neuroinflammation on the Hippocampus—A Mini Review (2025) · cites this paper as [115]
The Results section reports that intrahippocampal BDNF infusion improved escape performance after inescapable stress. It does not report a measure of neurogenesis or show that the infusion mitigated stress-induced neurogenic impairments. The separate claim about promoting neurogenesis is attached to [116], not this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect.
“Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect.”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Shirayama et al., 2002
The paper’s opening summary and Results report that a single bilateral BDNF infusion into the hippocampal dentate gyrus produced antidepressant-like effects by 3 days, lasting at least 10 days. Our copy does not report the same effect from infusion into the ventricles; that route is not supported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDirect administration of BDNF into the rodent brain alleviates several depressive phenotypes, curbs addiction, and enhances fear extinction.
“direct administration of BDNF into the rodent brain has been shown to alleviate several depressive phenotypes, curb addiction, and enhance fear extinction (130–133)”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [131]
The paper reports that BDNF infused into the rat hippocampus produced antidepressant-like effects in the learned helplessness and forced swim tests. It does not report that BDNF curbs addiction or enhances fear extinction; the additional behavioral testing described concerns passive avoidance, not fear extinction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAdministering BDNF to the dentate gyrus and CA3 regions of the hippocampus produces antidepressant effects within a few days, primarily through TrkB activation and the MEK-ERK signaling pathway.
“It was also discovered that administering BDNF to the dentate gyrus and CA3 regions of the hippocampus produced antidepressant effects within a few days, primarily through TrkB activation and the MEK-ERK signaling pathway [45].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [45]
The Results (page unavailable) report that BDNF infused into either the dentate gyrus or CA3 improved antidepressant-like behavior when tested three days later. The inhibitor experiments and Discussion (page unavailable) support a role for MEK–ERK signaling in the learned-helplessness response to dentate-gyrus infusion, but the paper does not establish that the effects in both regions occur primarily through TrkB: its Trk inhibitor also acts on other kinases. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn rodents, direct infusion of BDNF in the hippocampus and midbrain shows antidepressant-like effects.
“In rodents, direct infusion of BDNF in the hippocampus (Deltheil et al. 2008, 2009; Shirayama et al. 2002; Sirianni et al. 2010) and midbrain (Siuciak et al. 1997) showed antidepressant-like effects.”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Shirayama et al. 2002
The DG or CA3 regions may be key regions for antidepressant effects acting through BDNF.
“Subsequent work showed that a single bilateral infusion of a low dose of BDNF directly into the DG or CA3, but not CA1, region of the hippocampus was sufficient to induce an antidepressant-like effect within three days (Shirayama et al., 2002), suggesting that these regions may be key regions for antidepressant effects acting through BDNF.”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Shirayama et al., 2002
BDNF produced an antidepressant effect for up to 10 days after the infusion, well past the time frame of the degradation of the protein, suggesting that BDNF may be triggering a sustained plasticity mechanism to mediate the long-term antidepressant effects.
“Rather surprisingly, this study also noted that BDNF produced an antidepressant effect for up to 10 days after the infusion, well past the time frame of the degradation of the protein, suggesting that BDNF may be triggering a sustained plasticity mechanism to mediate the long-term antidepressant effects.”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Shirayama et al., 2002
The antidepressant effects of BDNF were suggested to be mediated by TrkB activation of MEK, acting through the ERK pathway.
“In this latter study, the antidepressant effects of BDNF were suggested to be mediated by TrkB activation of mitogen-activated protein kinase kinase (MEK), acting through the extracellular signal-regulated protein kinase (ERK) pathway.”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Shirayama et al., 2002
Bilateral BDNF infusions into the hippocampus or the ventricles induce antidepressant-like effects in preclinical animal models that can persist for several days.
“As previously discussed, bilateral BDNF-infusions into the hippocampus or the ventricles induces antidepressant-like effects in preclinical animal models that can persist for several days (Shirayama et al., 2002; Siuciak et al., 1997).”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Shirayama et al., 2002
Systemic or intra-hippocampal administration of BDNF exerts antidepressant-like effects.
“With regards to depression, systemic or intra-hippocampal administration of BDNF exerts antidepressant-like effects 153–155, and over-expression of BDNF in the hippocampus leads to resilience to chronic stress 156.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [154]
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“As previously discussed, bilateral BDNF-infusions into the hippocampus or the ventricles induces antidepressant-like effects in preclinical animal models that can persist for several days (Shirayama et al., 2002; Siuciak et al., 1997).”
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- Authors
- Shirayama, Y., Chen, A. C.-H., Nakagawa, S., Russell, D. S., & Duman, R. S.
- Affiliations
- Yale University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-04-15
- Volume
- 22
- Issue
- 8
- Pages
- 3251-3261
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6757539
- OpenAlex
- W2140178312
- Semantic Scholar
- 3a8edbde1ad77b2aedc833527c5cfe4dc8f73a73
- Cited by
- 1,654
- References
- 45
- Citations by year
- 2026: 13 · 2025: 32 · 2024: 36 · 2023: 38 · 2022: 59 · 2021: 78 · 2020: 52 · 2019: 53 · 2018: 62 · 2017: 62 · 2016: 83 · 2015: 99 · 2014: 80 · 2013: 94 · 2012: 109
- FWCI
- 38.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (2 PO1 MH25642, MH45481)
- National Institute of Mental Health (R37MH045481, P01MH025642, R01MH045481)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- brain-derived neurotrophic factor, antidepressant effects, depression, learned helplessness, forced swim test, hippocampus, dentate gyrus, neurotrophin-3, nerve growth factor, intracerebroventricular infusion
- MeSH terms
- Animals, Behavior, Animal, Depression, Disease Models, Animal, Electroshock, Enzyme Inhibitors, Escape Reaction, Helplessness, Learned, Hippocampus, Immunohistochemistry, Male, Microinjections, Motor Activity, Reaction Time, Spatial Behavior, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Dentate Gyrus, Brain-Derived Neurotrophic Factor, Mitogen-Activated Protein Kinases, Nerve Growth Factor, Neurotrophin 3, Rats
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