Constant Darkness Induces IL-6-Dependent Depression-Like Behavior through the NF- B Signaling Pathway
Open accessAbstract
Substantial experimental evidence indicates a major role for the circadian system in mood disorders. Additionally, proinflammatory cytokines have been proposed to be involved in the pathogenesis of depression. However, the molecular elements determining the functional interplay between these two systems in depression have not been described as yet. Here we investigate whether long-term light deprivation in the constant darkness (DD) paradigm affects depression-like behavior in mice and concomitantly modulates the levels of proinflammatory cytokines. We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-κB pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-κB signaling. Moreover, NF-κB activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF-κB, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression. We here first describe some of the molecular elements bridging chronobiological and inflammatory processes in the constant darkness mouse model of depression.
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Previous studies have identified elevated serum IL-6 and circulating leukocytes in stress disorders, but this generally followed either depression diagnosis in humans or controlled stress exposure in rodents.
“Although previous studies have identified elevated serum IL-6 and circulating leukocytes in stress disorders, this generally followed either depression diagnosis in humans (4, 25) or controlled stress exposure in rodents (26, 27).”
From Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress (2014) · cites this paper as [26]
The experimental methods describe exposing mice to four weeks of constant darkness, and the section on circulating cytokines reports that this raised circulating IL-6. The cited paper does not report elevated circulating leukocytes. The human-diagnosis portion of the sentence has separate citations (4, 25), so it is not attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSocial defeat stress induces downstream inflammatory signaling pathways, such as NFkB, and increases monocyte trafficking throughout a number of CNS structures known to control depression and anxiety behavior.
“Our results are interesting in light of recent studies showing that social defeat stress induces downstream inflammatory signaling pathways, such as NFkB (26, 35 -37), and increases monocyte trafficking (29) throughout a number of CNS structures known to control depression and anxiety behavior.”
From Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress (2014) · cites this paper as [26]
The section 'NF-B activity is increased in hippocampal tissue of mice exposed to constant darkness' reports increased NF-κB activity, supporting the inflammatory-signaling part of the claim. But the stressor studied was constant darkness, not social defeat. The monocyte-trafficking clause has a separate citation and is not attributed to this paper. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIL-6 is elevated in the serum of a subset of depressed patients.
“the inflammatory cytokine interleukin-6 (IL-6) is elevated in the serum of a subset of depressed patients”
From Inflammatory T helper 17 cells promote depression-like behavior in mice (2013) · cites this paper as [8]
The Introduction (page unavailable) says IL-6 is frequently elevated in depressed patients, and the discussion describes it as a peripheral biomarker of depression. Those passages support the general claim, but they do not specify serum; the paper discusses circulating IL-6 and cites a finding about plasma concentrations instead. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIL-6 is activated in conditions associated with depression in humans and in rodent models.
“is activated in conditions associated with depression in humans and in rodent models”
From Inflammatory T helper 17 cells promote depression-like behavior in mice (2013) · cites this paper as [8]
Deletion of the IL-6 gene is protective against depressive-like behavior in rodent models.
“whereas deletion of the IL-6 gene is protective (3–5, 8)”
From Inflammatory T helper 17 cells promote depression-like behavior in mice (2013) · cites this paper as [8]
IL-6 is sufficient to induce depressive-like behavior in rodent models.
“is sufficient to induce depressive-like behavior in rodent models”
From Inflammatory T helper 17 cells promote depression-like behavior in mice (2013) · cites this paper as [8]
Chronically stressed mice upregulate the pro-inflammatory cytokine interleukin 6 (IL-6).
“In the periphery, chronically stressed mice upregulate the pro-inflammatory cytokine interleukin 6 (IL-6) [175–177].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [177]
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- Authors
- Monje, F. J., Cabatic, M., Divisch, I., Kim, E.-J., Herkner, K. R., Binder, B. R., & Pollak, D. D.
- Affiliations
- Medical University of Vienna (AT)
- Corresponding author
- Pollak, D. D.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-06-22
- Volume
- 31
- Issue
- 25
- Pages
- 9075-9083
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6623479
- OpenAlex
- W1971474571
- Cited by
- 178
- References
- 64
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 13 · 2022: 7 · 2021: 11 · 2020: 17 · 2019: 8 · 2018: 16 · 2017: 11 · 2016: 12 · 2015: 13 · 2014: 16 · 2013: 14 · 2012: 14
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- constant darkness, depression-like behavior, interleukin-6, NF-κB signaling, circadian rhythm, light deprivation, inflammatory cytokines, hippocampal cell proliferation, clock genes, Per2, NPAS2, IL1R1, IL-6 knockout mice, mood disorders
- MeSH terms
- Animals, Behavior, Animal, Circadian Rhythm, Darkness, Depression, Humans, Male, Mice, Inbred C57BL, Signal Transduction, Interleukin-6, NF-kappa B, Chronobiology Disorders, Mice
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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