Antidepressive and BDNF effects of enriched environment treatment across ages in mice lacking BDNF expression through promoter IV
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Reduced promoter IV-driven expression of brain-derived neurotrophic factor (BDNF) is implicated in stress and major depression. We previously reported that defective promoter IV (KIV) caused depression-like behavior in young adult mice, which was reversed more effectively by enriched environment treatment (EET) than antidepressants. The effects of promoter IV-BDNF deficiency and EET over the life stages remain unknown. Since early-life development (ED) involves dynamic epigenetic processes, we hypothesized that EET during ED would provide maximum antidepressive effects that would persist later in life due to enhanced, long-lasting BDNF induction. We tested this hypothesis by determining EET effects across three life stages: ED (0–2 months), young adult (2–4 months), and old adult (12–14 months). KIV mice at all life stages showed depression-like behavior in the open-field and tail-suspension tests compared with wild-type mice. Two months of EET reduced depression-like behavior in ED and young adult, but not old adult mice, with the largest effect in ED KIV mice. This effect lasted for 1 month after discontinuance of EET only in ED mice. BDNF protein induction by EET in the hippocampus and frontal cortex was also the largest in ED mice and persisted only in the hippocampus of ED KIV mice after discontinuance of EET. No gender-specific effects were observed. The results suggest that defective promoter IV causes depression-like behavior, regardless of age and gender, and that EET during ED is particularly beneficial to individuals with promoter IV-BDNF deficiency, while additional treatment may be needed for older adults.
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Studies in animal models report an increase in brain BDNF levels when aged animals are submitted to protocols such as long-term environmental enrichment or physical activity.
“Studies in animal models report an increase in brain BDNF levels when aged animals are submitted to protocols such as long-term environmental enrichment [47–49] or physical activity [50, 51].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [49]
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Griñán-Ferré, C., Izquierdo, V., Otero, E., Puigoriol-Illamola, D., Corpas, R., Sanfeliu, C., Ortuño-Sahagún, D., & Pallàs, M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00224 · Cited by 94 · see citing works
- Authors
- Jha, S., Dong, B. E., Xue, Y., Delotterie, D. F., Vail, M. G., & Sakata, K.
- Affiliations
- University of Tennessee Health Science Center (US)
- Corresponding author
- Sakata, K
- Venue
- Translational Psychiatry
- Published
- 2016-09-20
- Volume
- 6
- Issue
- 9
- Pages
- e896-e896
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC5048201
- OpenAlex
- W2521848146
- Cited by
- 33
- References
- 92
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 7 · 2017: 2
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R21MH105567, R03MH102445)
- 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, depression-like behavior, antidepressant effects, early life development, life stage effects, hippocampus, frontal cortex, major depressive disorder, epigenetic mechanisms
- MeSH terms
- Animals, Behavior, Animal, Depression, Female, Frontal Lobe, Hippocampus, Male, Promoter Regions, Genetic, Social Environment, Brain-Derived Neurotrophic Factor, Mice, Gene Knock-In Techniques
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