∆FosB: A transcriptional regulator of stress and antidepressant responses
Open accessAbstract
ΔFosB is a member of the Fos family of transcription factors. While other family members are induced rapidly but transiently in response to a host of acute stimuli, ΔFosB is unique in that it accumulates in response to repeated stimulation due to its unusual protein stability. Such prolonged induction of ΔFosB, within nucleus accumbens (NAc), a key brain reward region, has been most studied in animal models of drug addiction, with considerable evidence indicating that ΔFosB promotes reward and motivation and serves as a mechanism of drug sensitization and increased drug self-administration. In more recent years, prolonged induction of ∆FosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ∆FosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ∆FosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ∆FosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.
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FosB is linked to long-term activity levels.
“Since FosB has been linked to long-term activity levels (Nestler, 2015)”
From Perineuronal Nets Regulate the Inhibitory Perisomatic Input onto Parvalbumin Interneurons and γ Activity in the Prefrontal Cortex (2020) · cites this paper as Nestler, 2015
Section 3 (page unavailable) links sustained neural activity to full-length FosB levels, but only as a possibility following repeated fluoxetine treatment in the nucleus accumbens; it says further work is needed to test that explanation. The unqualified claim that FosB is linked to long-term activity levels is broader than this tentative account. (LLM, conf=0.84)
Experimental — accuracy not yet measuredElevated levels of FOSB, PTGS2, IL8, FOS, IL1β, JUNB, and JUN have been associated with senescence and SASP secretion.
“Elevated levels of each of these transcripts have been associated with senescence and SASP secretion [[98], [99], [100], [101], [102], [103], [104]]”
From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [99]
Section 2 associates increased ΔFosB with chronic stress in the nucleus accumbens, not senescence. A search of our copy for senescence, SASP, and inflammatory secretion found no passage linking elevated FOSB to senescence or SASP secretion. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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Self-citationFunctional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse
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- Authors
- Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Nestler, Eric J.
- ORCID
- Nestler, Eric J.
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 753
- Pages
- 66-72
- ISSN
- 0014-2999 (ISSN-L)
- PMC
- PMC4380559
- OpenAlex
- W2049704911
- Cited by
- 220
- References
- 59
- Citations by year
- 2026: 17 · 2025: 32 · 2024: 28 · 2023: 17 · 2022: 16 · 2021: 18 · 2020: 16 · 2019: 22 · 2018: 13 · 2017: 17 · 2016: 14 · 2015: 10
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH51399 and P50MH096890)
- 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, Fos family transcription factors, nucleus accumbens, chronic stress, antidepressant action, depression, drug addiction, drug sensitization, self-administration, stress resilience, protein stability, target gene regulation, reward and motivation
- MeSH terms
- Animals, Antidepressive Agents, Brain, Humans, Nucleus Accumbens, Stress, Psychological, Transcriptional Activation, Proto-Oncogene Proteins c-fos
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