Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling
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Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited a delayed long-lasting antidepressant-like effect in the forced swim behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on glycogen synthase kinase-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-catenin. Taken together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK-3β/β-catenin signaling pathway.
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The chronic unpredictable stress paradigm models unanticipated stressful experiences that occur in humans and has been widely used as a valid animal model of depression.
“This paradigm models unanticipated stressful experiences that occur in humans, and thus has been widely used as a valid animal model of depression [34, 36, 52].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [52]
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Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases
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- Authors
- Garza, J. C., Guo, M., Zhang, W., & Lu, X.-Y.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Lu, X-Y
- ORCID
- Guo, M
- Venue
- Molecular Psychiatry
- Published
- 2011-12-20
- Volume
- 17
- Issue
- 8
- Pages
- 790-808
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3368076
- OpenAlex
- W2044506930
- Cited by
- 209
- References
- 160
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 4 · 2023: 9 · 2022: 19 · 2021: 15 · 2020: 23 · 2019: 14 · 2018: 13 · 2017: 17 · 2016: 13 · 2015: 23 · 2014: 24 · 2013: 12 · 2012: 10
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH073844, MH076929, R01MH076929, MH083442, R01MH073844, F31MH083442)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- leptin, adult hippocampal neurogenesis, depression, chronic unpredictable mild stress, glucocorticoids, dexamethasone, GSK3β, β-catenin, Wnt signaling, neural stem/progenitor cells, leptin receptor, glucocorticoid receptor, antidepressant-like behavior, forced swim test
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Cells, Cultured, Depression, Dexamethasone, Disease Models, Animal, Hippocampus, Male, Phosphorylation, Recombinant Proteins, Stress, Psychological, Signal Transduction, Cranial Irradiation, Rats, Sprague-Dawley, Leptin, Glycogen Synthase Kinase 3, Cell Proliferation, beta Catenin, Rats, Neurogenesis
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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.
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