Role of Mesolimbic Brain-Derived Neurotrophic Factor in Depression
Open accessAbstract
Brain-derived neurotrophic factor (BDNF) is widely accepted as being critical for neural and synaptic plasticity throughout the nervous system. Recent work has shown that BDNF in the mesolimbic dopamine (DA) circuit, originating in ventral tegmental area DA neurons that project to the nucleus accumbens, is crucial in the development of depressive-like behaviors following exposure to chronic social defeat stress in mice. Whereas BDNF modulates DA signaling in encoding responses to acute defeat stress, BDNF signaling alone appears to be responsible for the behavioral effects after chronic social defeat stress. Very different patterns are seen with another widely used chronic stress paradigm in mice, chronic mild stress (also known as chronic variable or unpredictable stress), where DA signaling, but not BDNF signaling, is primarily responsible for the behavioral effects observed. This review discusses the molecular, cellular, and circuit basis of this dramatic discrepancy, which appears to involve the nature of the stress, its severity and duration, and its effects on distinct cell types within the ventral tegmental area-to-nucleus accumbens mesolimbic circuit.
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Findings in mood disorders reveal alterations at the levels of intracellular signaling, gene expression, neurotrophic factors, neurogenesis, neuroinflammation, excitatory and inhibitory neurotransmission, and synaptic number and function in several brain regions implicated in depression.
“These findings reveal alterations at the levels of intracellular signaling, gene expression, neurotrophic factors, neurogenesis, neuroinflammation, excitatory and inhibitory neurotransmission, and synaptic number and function, and have been described in several brain regions implicated in depression 13-22 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [20]
The Brief Introduction to Mesolimbic BDNF Signaling discusses altered BDNF signaling in depression across several brain regions. The Downstream Targets of BDNF Activation section also reports changes in intracellular signaling, gene regulation, excitatory input, and dendritic structure in stress-susceptible mice. The paper does not establish the full attributed list: in particular, it does not substantiate neurogenesis, neuroinflammation, inhibitory neurotransmission, or changes in synaptic number as depression-related findings. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSocial defeat stress increases BDNF in the VTA-NAc pathway, leading to enhanced function that is thought to contribute to disruption of reward and motivation behaviors in depression.
“For example, studies demonstrate that social defeat stress increases BDNF in the VTA-NAc pathway, leading to enhanced function that is thought to contribute to disruption of reward and motivation behaviors in depression 20,21 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [20]
Elevated BDNF-trkB signaling may be crucial within mesolimbic circuits.
“As elsewhere in the brain, elevated BDNF -trkB signaling may be crucial within these mesolimbic circuits [243].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [243]
Alterations in VTA DA activity affect activity in multiple downstream targets, including the NAc and mPFC, which appear to be particularly important for mediating social avoidance.
“Alterations in VTA DA activity will affect activity in multiple downstream targets, including the NAc and mPFC, which appear to be particularly important for mediating social avoidance [149, 150, 156-159].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [158]
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References 150 · Cited by 112
Research works printed but not linked: 1
- [100]Han MH, Nestler EJ (2017): Neural Substrates of Depression and Resilience. Neurotherapeutics. 14: 677– 686. 28397115 PMC5509625
- Authors
- Koo, J. W., Chaudhury, D., Han, M.-H., & Nestler, E. J.
- Affiliations
- Korea Brain Research Institute (KR)
- New York University Abu Dhabi (AE)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Han, Ming-Hu
- Nestler, Eric J.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 86
- Issue
- 10
- Pages
- 738-748
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC6814503
- OpenAlex
- W2948900932
- Cited by
- 112
- References
- 150
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 25 · 2023: 18 · 2022: 24 · 2021: 19 · 2020: 13 · 2019: 2
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- New York University Abu Dhabi
- National Institute of Mental Health (P50MH096890, R01MH051399, R21MH112081, R56MH115409)
- National Research Foundation of Korea
- National Institute on Alcohol Abuse and Alcoholism
- Hope for Depression Research Foundation
- National Alliance for Research on Schizophrenia and Depression
- Al Jalila Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- brain-derived neurotrophic factor, depression, ventral tegmental area, nucleus accumbens, chronic social defeat stress, chronic mild stress, unpredictable stress, dopamine signaling, synaptic plasticity
- MeSH terms
- Animals, Behavior, Animal, Depression, Neural Pathways, Neuronal Plasticity, Nucleus Accumbens, Social Behavior, Stress, Psychological, Ventral Tegmental Area, Brain-Derived Neurotrophic Factor, Mice, Dopaminergic Neurons
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