ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses
Open accessAbstract
In contrast with the many studies of stress effects on the brain, relatively little is known about the molecular mechanisms of resilience, the ability of some individuals to escape the deleterious effects of stress. We found that the transcription factor DeltaFosB mediates an essential mechanism of resilience in mice. Induction of DeltaFosB in the nucleus accumbens, an important brain reward-associated region, in response to chronic social defeat stress was both necessary and sufficient for resilience. DeltaFosB induction was also required for the standard antidepressant fluoxetine to reverse behavioral pathology induced by social defeat. DeltaFosB produced these effects through induction of the GluR2 AMPA glutamate receptor subunit, which decreased the responsiveness of nucleus accumbens neurons to glutamate, and through other synaptic proteins. Together, these findings establish a previously unknown molecular pathway underlying both resilience and antidepressant action.
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Molecular studies have identified similarities in chromatin remodeling and transcriptional activation between resilient and antidepressant-treated mice, providing new information about therapeutic targets.
“In addition, molecular studies have identified similarities in chromatin remodeling29,30 and transcriptional activation31 between resilient and antidepressant-treated mice, providing new information about therapeutic targets.”
From A standardized protocol for repeated social defeat stress in mice (2011) · cites this paper as [31]
The mGluR5 receptor mediates stress resilience via post-synaptic mGluR5 activation on the nucleus accumbens.
“The mGluR5 receptor also mediates stress resilience via post-synaptic mGluR5 activation on the nucleus accumbens [40,41].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [41]
In mice exposed to chronic social defeat stress, nucleus accumbens ΔFosB is markedly higher in resilient animals than in susceptible ones.
“Additionally, NAc ΔFosB expression is significantly enhanced in mice resilient, but not susceptible to CSDS (82).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [82]
The immediate early gene ΔFosB contributes to stress resilience.
“Significant research on the immediate early gene ΔFosB has demonstrated its role in resilience to stress.”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [82]
In people with depression, nucleus accumbens ΔFosB levels are markedly lower.
“NAc ΔFosB expression is significantly reduced in human depressed patients (82).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [82]
Giving fluoxetine to mice after chronic social defeat stress raises their ΔFosB expression.
“CSDS mice treated with the common SSRI fluoxetine display enhanced ΔFosB expression and enhanced resilience (82).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [82]
Overexpressing ΔFosB in the nucleus accumbens with the 11A bitransgenic mouse line increases resilience to chronic social defeat stress.
“Further, NAc overexpression of ΔFosB using a bitransgenic mouse line 11A, promotes resilience to CSDS, which is thought to be through enhancement of GluR2 expression (82).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [82]
Giving fluoxetine to mice after chronic social defeat stress increases their resilience.
“CSDS mice treated with the common SSRI fluoxetine display enhanced ΔFosB expression and enhanced resilience (82).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [82]
Resilience is mediated in part by an active adaptation that opposes the susceptibility mechanism of increased glutamatergic tone.
“there is recent evidence that resilience is mediated in part via an active adaptation that opposes this susceptibility mechanism52, 71”
From Neurobiology of resilience (2012) · cites this paper as [71]
ΔFosB is induced preferentially in medium spiny neurons of the nucleus accumbens in resilient animals.
“ΔFosB is induced in medium spiny NAc neurons preferentially in resilient animals”
From Neurobiology of resilience (2012) · cites this paper as [71]
GluA2 is an AMPA glutamate receptor subunit that reduces calcium permeability and overall conductance of AMPA channels.
“an AMPA glutamate receptor subunit that reduces the Ca2+ permeability and overall conductance of AMPA channels71”
From Neurobiology of resilience (2012) · cites this paper as [71]
Susceptibility to chronic social defeat stress is associated with increased glutamatergic tone on medium spiny neurons in the nucleus accumbens, including greater frequency of excitatory currents and more glutamatergic synapses.
“While susceptibility to chronic social defeat stress is associated with increased glutamatergic tone, including greater frequency of excitatory currents and number of glutamatergic synapses, on medium spiny neurons in NAc”
From Neurobiology of resilience (2012) · cites this paper as [71]
Reduced levels of ΔFosB and GluA2 have been documented in the nucleus accumbens of depressed humans examined postmortem.
“reduced levels of ΔFosB and GluA2 have been documented in NAc of depressed humans examined postmortem71”
From Neurobiology of resilience (2012) · cites this paper as [71]
ΔFosB promotes resilience partly by inducing expression of GluA2 in the nucleus accumbens.
“where it promotes resilience partly by inducing expression of GluA2 (GluR2)”
From Neurobiology of resilience (2012) · cites this paper as [71]
Prolonged social isolation of adult mice or rats induces depression- and anxiety-like behavioral abnormalities and promotes susceptibility to chronic social defeat stress.
“which induces depression– and anxiety–like behavioral abnormalities49 and promotes susceptibility to chronic social defeat stress71”
From Neurobiology of resilience (2012) · cites this paper as [71]
Examples of resilience-associated molecular changes include ΔFosB, SRF, HDAC2, and the WNT-DVL-GSK3β signaling cascade.
“Examples include ΔFosB and SRF, discussed above, as well as HDAC2 (histone deacetylase–2) and the WNT (wingless)–DVL (disheveled)–GSK3β (glycogen synthase kinase–3β) signaling cascade71, 72, 94”
From Neurobiology of resilience (2012) · cites this paper as [71]
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“As expected on the basis of previous work (54), which demonstrated that mice that overexpress ΔFosB are resilient to”
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Self-citationSerum Response Factor Promotes Resilience to Chronic Social Stress through the Induction of ΔFosB
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- Authors
- Vialou, V., Robison, A. J., LaPlant, Q. C., Covington, H. E., Dietz, D. M., Ohnishi, Y. N., Mouzon, E., Rush, A. J., Watts, E. L., Wallace, D. L., Iñiguez, S. D., Ohnishi, Y. H., Steiner, M. A., Warren, B. L., Krishnan, V., Bolaños, C. A., Neve, R. L., Ghose, S., Berton, O., Tamminga, C. A., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- The University of Texas Southwestern Medical Center (US)
- Florida State University (US)
- Max Planck Institute of Psychiatry (DE)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Nestler, Eric J
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2010-05-16
- Volume
- 13
- Issue
- 6
- Pages
- 745-752
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2895556
- OpenAlex
- W2161234653
- Cited by
- 479
- References
- 50
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 18 · 2023: 23 · 2022: 25 · 2021: 24 · 2020: 32 · 2019: 40 · 2018: 33 · 2017: 36 · 2016: 30 · 2015: 31 · 2014: 40 · 2013: 40 · 2012: 30
- FWCI
- 28.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH051399, P50MH066172)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- ΔFosB, stress resilience, chronic social defeat stress, antidepressant response, fluoxetine, nucleus accumbens, synaptic proteins, brain reward circuits, transcription factors
- MeSH terms
- Animals, Antidepressive Agents, Chronic Disease, Dominance-Subordination, Fluoxetine, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Nucleus Accumbens, Reward, Stress, Psychological, Signal Transduction, Proto-Oncogene Proteins c-fos, Treatment Outcome, Receptors, AMPA, Glutamic Acid, Mice, Resilience, Psychological
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