The DOI matches its Crossref record; 214 of the 216 references it cites were found in a registry or an index; 112 of the 187 sources its claims cite were checked for support.
Central regulation of stress-evoked peripheral immune responses
Open accessAbstract
Stress-linked psychiatric disorders, including anxiety and major depressive disorder, are associated with systemic inflammation. Recent studies have reported stress-induced alterations in haematopoiesis that result in monocytosis, neutrophilia, lymphocytopenia and, consequently, in the upregulation of pro-inflammatory processes in immunologically relevant peripheral tissues. There is now evidence that this peripheral inflammation contributes to the development of psychiatric symptoms as well as to common co-morbidities of psychiatric disorders such as metabolic syndrome and immunosuppression. Here, we review the specific brain and spinal regions, and the neuronal populations within them, that respond to stress and transmit signals to peripheral tissues via the autonomic nervous system or neuroendocrine pathways to influence immunological function. We comprehensively summarize studies that have employed retrograde tracing to define neurocircuits linking the brain to the bone marrow, spleen, gut, adipose tissue and liver. Moreover, we highlight studies that have used chemogenetic or optogenetic manipulation or intracerebroventricular administration of peptide hormones to control somatic immune responses. Collectively, this growing body of literature illustrates potential mechanisms through which stress signals are conveyed from the CNS to immune cells to regulate stress-relevant behaviours and comorbid pathophysiology.
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Claims the paper makes
38 Partly supported · 29 Supported · 29 No full text of the sources · 21 Own interpretation · 3 Supported so far · 3 No basis given · 2 Mixed support · 2 Sources not found · 1 Own method · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Circulating pro-inflammatory cytokines, including interleukin-1α (IL1A), IL1B, IL2, IL6, IL8, IL12, IFNγ (also known as IFNG), and tumour necrosis factor α (TNF), as well as chemokines, such as C-C motif chemokine 2 (CCL2), CCL3, CCL11, C-X-C motif chemokine 4 (CXCL4), CXCL7 and CXCL8, are reportedly increased in individuals with MDD compared to control subjects21–25.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not checked — no full text of the sourcecites [21] Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010). source
- Partly supportedcites [22] Leighton, S. P. et al. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis. Mol. Psychiatry 23, 48–58 (2018). sourceExperimental — accuracy not yet measured
The Discussion (page not supplied) reports higher levels of several blood chemokines in depressed versus nondepressed people; CCL3 and CCL11 increases appeared only in the physically healthy subgroup. The paper does not establish the claimed increases across the listed pro-inflammatory cytokines, so it supports the chemokine portion but not the full sentence. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [23] Maes, M. et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9, 853–858 (1997). source
- Not checked — no full text of the sourcecites [24] Simon, N. M. et al. A detailed examination of cytokine abnormalities in major depressive disorder. Eur. Neuropsychopharmacol. 18, 230–233 (2008). source
- Partly supportedcites [25] Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014). sourceExperimental — accuracy not yet measured
The Significance passage and Fig. 1C report higher circulating IL-6 in patients with treatment-resistant MDD than in healthy controls. The paper also refers to multiple inflammatory markers in subsets of patients with MDD, but the passages do not substantiate the citing sentence’s named list of other cytokines and chemokines or extend its own comparison to all individuals with MDD. (LLM, conf=0.88)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Stress-linked psychiatric disorders, including anxiety and major depressive disorder, are associated with systemic inflammation.”
- Also stated in: § Linking chronic stress and inflammation · plain
“individuals with stress-related disorders, such as major depressive disorder (MDD), exhibit signs of chronic low-grade systemic inflammation”
§ Central regulation of stress-evoked peripheral immune responses > Abstract
What the sources say
- Partly supportedcites [4] Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008). sourceExperimental — accuracy not yet measured
The passage beginning “A role for cytokines in depression” (labelled Abstract in our copy; page unavailable) reports increased blood concentrations of inflammatory biomarkers in patients with severe clinical depression, while noting that biomarkers are not always elevated. The paper does not establish the same association for anxiety disorders, so it does not support the full claim about both conditions. (LLM, conf=0.88)
- Partly supportedcites [5] Dantzer, R. Neuroimmune Interactions: from the brain to the immune system and vice versa. Physiol. Rev. 98, 477–504 (2018). sourceExperimental — accuracy not yet measured
In “Activation of the Hypothalamo-Pituitary-Adrenal Axis by Cytokines” (page unavailable), the review reports elevated circulating inflammatory markers in depressed people and says meta-analyses confirm an association between depression and inflammation. It also reports increased circulating IL-6 after stress, but does not establish that people with anxiety disorders have systemic inflammation; its anxiety-like findings concern stressed mice. (LLM, conf=0.87)
- Partly supportedcites [6] Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386–1393 (2015). sourceExperimental — accuracy not yet measured
In “The immune system and major depressive disorder,” the paper reports elevated circulating inflammatory cytokines and leukocytes in patients with depression, supporting the MDD portion of the claim. Its discussion of anxiety concerns anxiety-like behavior in animal stress models, not an association between diagnosed anxiety disorders and systemic inflammation in people. (LLM, conf=0.85)
- Partly supportedcites [7] Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). sourceExperimental — accuracy not yet measured
The Introduction reports higher circulating pro-inflammatory cytokines in patients with major depressive disorder and describes immune activation under chronic stress. It does not establish an association between systemic inflammation and anxiety; the Results discuss anxiety-related behavior, but not that association. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [8] Oines, E., Murison, R., Mrdalj, J., Grønli, J. & Milde, A. M. Neonatal maternal separation in male rats increases intestinal permeability and affects behavior after chronic social stress. Physiol. Behav. 105, 1058–1066 (2012). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Linking chronic stress and inflammation · plain
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These cytokine and chemokine concentrations are often sharply increased at the time that the individual is exposed to a stressor, then diminish with time from the precipitating stressful event(s).”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not checked — no full text of the sourcecites [21] Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010). source
- Could not verifycites [22] Leighton, S. P. et al. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis. Mol. Psychiatry 23, 48–58 (2018). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) compares chemokine levels in depressed and nondepressed groups, rather than levels before and after a stressful event. Searches for acute stress responses and changes over time found no passage in our copy reporting a sharp rise at exposure followed by a decline. (LLM, conf=0.76)
- Not checked — no full text of the sourcecites [23] Maes, M. et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9, 853–858 (1997). source
- Not checked — no full text of the sourcecites [24] Simon, N. M. et al. A detailed examination of cytokine abnormalities in major depressive disorder. Eur. Neuropsychopharmacol. 18, 230–233 (2008). source
- Partly supportedcites [25] Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014). sourceExperimental — accuracy not yet measured
The Results report that several cytokines and chemokines were elevated in mice 20 minutes after social stress. But the paper does not establish that these concentrations generally diminish with time; its opening summary says IL-6 remained elevated for at least one month. The evidence also comes primarily from mice, not people. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Unsurprisingly, people with MDD display high rates of co-morbidity with immune and inflammatory conditions, such as rheumatoid arthritis, cardiovascular disease, metabolic syndrome and inflammatory bowel disease (IBD)9–12.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not checked — no full text of the sourcecites [9] Margaretten, M., Julian, L., Katz, P. & Yelin, E. Depression in patients with rheumatoid arthritis: description, causes and mechanisms. Int. J. Clin. Rheumatol. 6, 617–623 (2011). source
- Not checked — no full text of the sourcecites [10] Halaris, A. Inflammation-associated co-morbidity between depression and cardiovascular disease. Curr. Top. Behav. Neurosci. 31, 45–70 (2017). source
- Partly supportedcites [11] Chan, K. L., Cathomas, F. & Russo, S. J. Central and peripheral inflammation link metabolic syndrome and major depressive disorder. Physiology 34, 123–133 (2019). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) identifies cardiovascular disease as an MDD comorbidity and says comorbidity with metabolic syndrome is well recognized, though it varies across cohorts. The passages retrieved from our copy do not establish high rates of MDD comorbidity with rheumatoid arthritis or inflammatory bowel disease, so the full list is not supported by this source. (LLM, conf=0.88)
- Could not verifycites [12] Barberio, B., Zamani, M., Black, C. J., Savarino, E. V. & Ford, A. C. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 6, 359–370 (2021). sourceExperimental — accuracy not yet measured
The available passages have no section or page information and contain only the paper’s title and repository metadata, not findings. Searches for depression prevalence in IBD and for the other named conditions found no passage addressing the claimed comorbidity; the decisive text appears to be missing from our copy. (LLM, conf=0.70)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It is becoming increasingly recognized that individuals with stress-related disorders, such as major depressive disorder (MDD), exhibit signs of chronic low-grade systemic inflammation.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Partly supportedcites [4] Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008). sourceExperimental — accuracy not yet measured
The paper reports that patients with severe clinical depression have elevated blood concentrations of inflammatory biomarkers, but also cautions that these biomarkers are not always elevated in clinically depressed patients (indexed passage labelled Abstract; page unavailable). It does not establish chronic low-grade systemic inflammation as a general feature of stress-related disorders. (LLM, conf=0.86)
- Supportedcites [5] Dantzer, R. Neuroimmune Interactions: from the brain to the immune system and vice versa. Physiol. Rev. 98, 477–504 (2018). sourceExperimental — accuracy not yet measured
In section C (page not provided), the review reports elevated circulating inflammatory cytokines and acute-phase proteins in depressed people and says meta-analyses confirm the association between depression and inflammation. The same section links chronic stress and related conditions to circulating IL-6 and chronic low-grade inflammation. These passages support the citing sentence as a broad background statement, without implying that every person with MDD has inflammation. (LLM, conf=0.88)
- Partly supportedcites [6] Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386–1393 (2015). sourceExperimental — accuracy not yet measured
The opening discussion and 'The immune system and major depressive disorder' section report elevated circulating inflammatory markers and leukocytes in patients with MDD. The paper specifies subsets of patients and does not establish that people with stress-related disorders generally have chronic, low-grade systemic inflammation. (LLM, conf=0.83)
- Supportedcites [7] Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). sourceExperimental — accuracy not yet measured
The Introduction reports that clinical studies find elevated circulating pro-inflammatory cytokines in people with MDD and describes immune activation under chronic stress. The Discussion also describes elevated serum IL-6 in patients with MDD compared with healthy controls. Together, these passages support the claim's broad characterization of systemic inflammation. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [8] Oines, E., Murison, R., Mrdalj, J., Grønli, J. & Milde, A. M. Neonatal maternal separation in male rats increases intestinal permeability and affects behavior after chronic social stress. Physiol. Behav. 105, 1058–1066 (2012). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Notably, several of these bone marrow-innervating brain regions have been implicated in stress responses, reward processing and the pathogenesis of depression and anxiety disorders.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [39] Zhong, P. et al. HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. eLife 7, e32420 (2018). sourceExperimental — accuracy not yet measured
The Introduction links the ventral tegmental area (VTA) and its projection to the nucleus accumbens with stress responses, reward processing, and depression-like behavior. The Discussion also links this pathway to depressive- and anxiety-like behavior. Neither passage establishes that these regions innervate bone marrow, so the source supports the functional links but not that identifying qualifier (page numbers unavailable in our copy). (LLM, conf=0.86)
- Supportedcites [40] Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013). source
In “The brain’s reward circuitry” (page not provided), the review identifies several brain regions involved in reward processing and discusses their possible contribution to depression. “Effects of stress in rodent models” (page not provided) links reward circuitry to stress and depression- and anxiety-like symptoms. The citation supports those links; the description of the regions as bone marrow-innervating is the citing paper’s framing, not a finding attributed to this review. (LLM, conf=0.89)
- Partly supportedcites [41] Kumar, P. et al. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology 43, 1581–1588 (2018). sourceExperimental — accuracy not yet measured
The Introduction links the striatum, midbrain and habenula to reward or punishment processing and major depressive disorder; the Results report reward-related signals in several brain regions. The paper does not establish that these regions innervate bone marrow or link them to stress responses or anxiety disorders. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [42] Nestler, E. J. & Carlezon, W. A. The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159 (2006). source
- Partly supportedcites [43] Li, L. et al. Social trauma engages lateral septum circuitry to occlude social reward. Nature 613, 696–703 (2023). sourceExperimental — accuracy not yet measured
The Abstract links lateral septum neurons to stress responses and social reward, and the Discussion discusses social stress in relation to depression and anxiety (page numbers unavailable). Our copy does not establish that the regions studied innervate bone marrow or that several such regions are implicated in the pathogenesis of these disorders. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [44] Hahn, M. K. & Bannon, M. J. Stress-induced C-fos expression in the rat locus coeruleus is dependent on neurokinin 1 receptor activation. Neuroscience 94, 1183–1188 (1999). source
- Partly supportedcites [45] Zhang, H. et al. α1- and β3-adrenergic receptor-mediated mesolimbic homeostatic plasticity confers resilience to social stress in susceptible mice. Biol. Psychiatry 85, 226–236 (2019). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) identifies the locus coeruleus–ventral tegmental area–nucleus accumbens circuit as a stress-resilience pathway, and the paper studies it in a model of depression. Our copy does not establish that these regions innervate bone marrow or directly link the circuit to the pathogenesis of anxiety disorders; its reference list alone does not establish those parts of the claim. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [46] Isingrini, E. et al. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat. Neurosci. 19, 560–563 (2016). source
- Not checked — no full text of the sourcecites [47] Senba, E., Matsunaga, K., Tohyama, M. & Noguchi, K. Stress-induced c-fos expression in the rat brain: activation mechanism of sympathetic pathway. Brain Res. Bull. 31, 329–344 (1993). source
- Partly supportedcites [48] de Medeiros, M. A., Carlos Reis, L. & Eugênio Mello, L. Stress-induced c-Fos expression is differentially modulated by dexamethasone, diazepam and imipramine. Neuropsychopharmacology 30, 1246–1256 (2005). sourceExperimental — accuracy not yet measured
The Introduction links several brain regions to stress responses, and “Modulation of inputs to PVH” links stress circuitry to depressive symptoms and identifies the lateral septum as a possible mediator of anxiety states (page numbers unavailable). Our copy does not establish that these regions innervate bone marrow or discuss their role in reward processing. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For example, dopaminergic projections from the VTA to the nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala and hippocampus that regulate responses to rewarding or aversive stimuli are reportedly dysregulated in people with MDD as well as in rodent models of chronic stress39–42.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [39] Zhong, P. et al. HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. eLife 7, e32420 (2018). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) identifies VTA dopamine projections to the NAc, medial PFC and basolateral amygdala, and the Discussion reports altered activity in NAc-projecting neurons after chronic stress in mice. The copy does not establish a hippocampal projection or show that all four pathways are dysregulated in people with MDD and rodent stress models; its reward evidence concerns the NAc pathway, not all four pathways or aversion. (LLM, conf=0.86)
- Partly supportedcites [40] Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013). sourceExperimental — accuracy not yet measured
“The brain’s reward circuitry” describes VTA dopamine projections to the NAc, PFC, amygdala and hippocampus and their roles in reward and aversion. “Functional studies of monosynaptic reward circuits” reports altered VTA–NAc and VTA–PFC activity in chronically stressed mice, but does not establish such changes for the amygdala or hippocampus projections. The human-imaging discussion says the VTA had not yet been characterized functionally or structurally in human depression, so the claim about these dopaminergic projections in people with MDD is not supported. Page numbers were unavailable in our copy. (LLM, conf=0.90)
- Partly supportedcites [41] Kumar, P. et al. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology 43, 1581–1588 (2018). sourceExperimental — accuracy not yet measured
The Results (PPI connectivity; page unavailable) report reduced VTA–right striatum functional connectivity in people with MDD, supporting the reward-related part of the claim. The paper does not establish dysregulation of dopaminergic projections to all four named regions or report that finding in rodent chronic-stress models; it also reports no group difference in the punishment-related connectivity it tested. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [42] Nestler, E. J. & Carlezon, W. A. The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159 (2006). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Of note, similar CNS regions were identified using PRV tracing from bone marrow in mice38, suggesting that these neurocircuits are conserved across species.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [38] Wee, N. K. Y., Lorenz, M. R., Bekirov, Y., Jacquin, M. F. & Scheller, E. L. Shared autonomic pathways connect bone marrow and peripheral adipose tissues across the central neuraxis. Front. Endocrinol. 10, 668 (2019). source
The Medulla, Pons, and Midbrain and Hypothalamus and Forebrain sections report PRV-labeled CNS regions after tracing from mouse bone marrow. The B6 Femur and Tibia section reports similar tracing patterns across two mouse strains and skeletal sites. The provided passages have no page numbers. (LLM, conf=0.92)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Of note, similar CNS regions were identified using PRV tracing from bone marrow in mice38, suggesting that these neurocircuits are conserved across species.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [38] Wee, N. K. Y., Lorenz, M. R., Bekirov, Y., Jacquin, M. F. & Scheller, E. L. Shared autonomic pathways connect bone marrow and peripheral adipose tissues across the central neuraxis. Front. Endocrinol. 10, 668 (2019). source
The citation is attached to the report of PRV tracing from bone marrow in mice. The paper’s section on B6 femur and tibia tracing reports CNS regions similar to those found in C3H mice. Conservation across species is the citing authors’ inference, not a finding attributed directly to this source. (LLM, conf=0.88)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Similarly, regions of the hypothalamus, including the PVH, LH and ARH, are activated by chronic stress in rodents47–51”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [47] Senba, E., Matsunaga, K., Tohyama, M. & Noguchi, K. Stress-induced c-fos expression in the rat brain: activation mechanism of sympathetic pathway. Brain Res. Bull. 31, 329–344 (1993). source
- Partly supportedcites [48] de Medeiros, M. A., Carlos Reis, L. & Eugênio Mello, L. Stress-induced c-Fos expression is differentially modulated by dexamethasone, diazepam and imipramine. Neuropsychopharmacology 30, 1246–1256 (2005). sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports restraint-induced c-Fos expression in the rat hypothalamus, particularly the PVH. The Experimental Design section (page unavailable) shows that the rats underwent one hour of restraint, not chronic stress; the 20-day regimen was drug or saline treatment. The cited passages do not establish stress-induced activation of LH or ARH. (LLM, conf=0.88)
- Partly supportedcites [49] Gomes-de-Souza, L., Costa-Ferreira, W., Mendonça, M. M., Xavier, C. H. & Crestani, C. C. Lateral hypothalamus involvement in control of stress response by bed nucleus of the stria terminalis endocannabinoid neurotransmission in male rats. Sci. Rep. 11, 16133 (2021). sourceExperimental — accuracy not yet measured
The Experimental design and Figure 1 passages describe Fos-positive cells in the lateral hypothalamus of rats after a single 60-minute restraint-stress session, supporting a link between stress and LH activity. They do not establish activation by chronic stress, and the paper does not report stress-induced activation of the PVH or ARH; PVN appears only as an anatomical label in Figure 1. No page numbers are available in our copy. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [50] Yuan, Y. et al. Reward inhibits paraventricular CRH neurons to relieve stress. Curr. Biol. 29, 1243–1251 (2019). source
- Not checked — no full text of the sourcecites [51] Kwon, M.-S. et al. The differential effects of emotional or physical stress on pain behaviors or on c-Fos immunoreactivity in paraventricular nucleus or arcuate nucleus. Brain Res. 1190, 122–131 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Similar to people with MDD, a subset of rodents exposed to CVS or CSDS also have higher levels of pro-inflammatory cytokines and chemokines, such as IL1A, IL1B, IL6, IL12, TNF, CCL2, and CCL5, in the bloodstream compared to unstressed control mice and stress-resilient mice”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Partly supportedcites [25] Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014). sourceExperimental — accuracy not yet measured
The Results (page not provided) report that IL-6 was elevated in mice that later became stress-susceptible compared with both controls and resilient mice. They also state that IL-1β did not differ from controls and that CCL2 rose similarly in susceptible and resilient mice. The CVS passage reports elevated IL-6 versus controls, but not a comparison with resilient mice; the broader claim about cytokines and chemokines across both stress paradigms is therefore not supported. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [27] Brydon, L. et al. Psychological stress activates interleukin-1beta gene expression in human mononuclear cells. Brain Behav. Immun. 19, 540–546 (2005). source
- Not checked — no full text of the sourcecites [28] Stewart, A. M. et al. Cytokine and endocrine parameters in mouse chronic social defeat: implications for translational ‘cross-domain’ modeling of stress-related brain disorders. Behav. Brain Res. 276, 84–91 (2015). source
- Not checked — no full text of the sourcecites [29] Tagliari, B. et al. Chronic variable stress alters inflammatory and cholinergic parameters in hippocampus of rats. Neurochem. Res. 36, 487–493 (2011). source
- Partly supportedcites [30] Deonaraine, K. K. et al. Sex-specific peripheral and central responses to stress-induced depression and treatment in a mouse model. J. Neurosci. Res. 98, 2541–2553 (2020). sourceExperimental — accuracy not yet measured
The Results section (page not supplied) reports higher plasma levels of the listed cytokines and chemokines in female mice exposed to CSDS than in non-CSDS controls. It does not report findings for CVS or a direct comparison of those levels with stress-resilient mice; it reports correlations between some plasma markers and stress-related behavior instead. (LLM, conf=0.89)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Moreover, animals that are exposed to chronic stress are predisposed to the development of inflammatory conditions, such as experimental autoimmune encephalitis, colitis, atherosclerosis and diabetes31–34.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not checked — no full text of the sourcecites [31] Harpaz, I. et al. Chronic exposure to stress predisposes to higher autoimmune susceptibility in C57BL/6 mice: glucocorticoids as a double-edged sword. Eur. J. Immunol. 43, 758–769 (2013). source
- Supportedcites [32] Gao, X. et al. Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response. Proc. Natl Acad. Sci. USA 115, E2960–E2969 (2018). sourceExperimental — accuracy not yet measured
The Results section on colitis development reports that chronic stress increased the severity of DSS-induced colitis in mice; the Discussion likewise describes increased susceptibility. This supports the colitis example attributed to this paper within the grouped citations. (LLM, conf=0.91)
- Partly supportedcites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourceExperimental — accuracy not yet measured
The paper reports that chronic stress increased plaque inflammation in atherosclerosis-prone mice (Abstract; page not provided), supporting the atherosclerosis example. Its discussion of broader implications does not report that stressed animals are more prone to experimental autoimmune encephalitis, colitis, or diabetes. (LLM, conf=0.88)
- Partly supportedcites [34] van der Kooij, M. A. et al. Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory. Proc. Natl Acad. Sci. USA 115, E10187–E10196 (2018). sourceExperimental — accuracy not yet measured
The introduction (p. 1) links chronic stress to metabolic disorders, including diabetes, and the study reports hyperglycemia in a subset of chronically stressed mice. But the Discussion (p. 7) says their glucose levels were not in the diabetic range. The paper does not support the claim about experimental autoimmune encephalitis, colitis, or atherosclerosis, or establish that the mice developed diabetes. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Although the effects of PVH neuron stimulation on monocyte retention by the bone marrow may seem to contradict those expected from studies of chronic stress, it is likely that these differences may arise from differences in monocyte mobilization dynamics during acute stress or HPA axis activation, compared to chronic stress70.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [70] Wohleb, E. S., McKim, D. B., Sheridan, J. F. & Godbout, J. P. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front. Neurosci. 8, 447 (2014). source
The section on neuroendocrine pathways says acute stress produces a transient rise in circulating myeloid cells, whereas chronic stress produces sustained monocyte egress and increased myeloid-cell production. That supports the cited explanation that acute and chronic stress have different mobilization dynamics. The PVH-stimulation result is the citing authors’ finding, not a result attributed to this review. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Further, this effect was found to be HPA axis-dependent, as adrenalectomy prevented these changes69.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [69] Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022). Identifies brain circuits controlling monocyte, neutrophil and lymphocyte retention and mobilization from the bone marrow into circulation during acute stress. source
In “The role of the HPA axis in acute stress” (p. 581), stimulating PVH CRH neurons decreased circulating lymphocytes and monocytes, and the paper says this effect depended on the adrenal glands. The same section links HPA-axis activity to their migration into the bone marrow; Extended Data Fig. 3e describes the before-and-after adrenalectomy experiment. (LLM, conf=0.91)
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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Moreover, as both the PVH and CeA provide inputs to the DMV86,87, it is possible that the DMV integrates signals from stress-responsive brain regions to coordinate peripheral immune responses.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [86] Geerling, J. C., Shin, J.-W., Chimenti, P. C. & Loewy, A. D. Paraventricular hypothalamic nucleus: axonal projections to the brainstem. J. Comp. Neurol. 518, 1460–1499 (2010). source
The Discussion section “Dorsal motor nucleus of the vagus” states that the PVH provides a moderately dense input to the DMX, the paper’s term for the DMV. In the citing sentence, this source supports the PVH-to-DMV input; the proposed role in coordinating immune responses is the citing authors’ own hypothesis. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [87] Gray, T. S. & Magnuson, D. J. Neuropeptide neuronal efferents from the bed nucleus of the stria terminalis and central amygdaloid nucleus to the dorsal vagal complex in the rat. J. Comp. Neurol. 262, 365–374 (1987). source
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In the paper
“Recently, the brain–spleen axis has gained attention for its role as a direct neural pathway through which cognition and emotion can control peripheral immunity during stress79.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Partly supportedcites [79] Wei, Y. et al. Brain-spleen axis in health and diseases: a review and future perspective. Brain Res. Bull. 182, 130–140 (2022). sourceExperimental — accuracy not yet measured
Section 4.1 describes a direct PVN/CeA–splenic nerve pathway that regulated antibody production in mice, including in a mild-stress model. It suggests that psychological conditioning under appropriate stress may affect adaptive immunity, but does not establish the broader claim that cognition and emotion generally control peripheral immunity during stress. The Conclusion also says the axis’s routes remain poorly defined. (LLM, conf=0.86)
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In the paper
“Mechanistically, it has been shown that signaling by noradrenaline released by these sympathetic fibres within the bone marrow niche suppresses expression of CXCL1233”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). source
The Abstract states that sympathetic nerve fibers release noradrenaline, which signals through β3 adrenergic receptors on bone marrow niche cells to decrease CXCL12 levels. This directly supports the attributed mechanism; the supplied copy gives no page number. (LLM, conf=0.95)
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In the paper
“Consequently, these cytokines can directly induce depressive-like behaviours (including social avoidance, reduced sucrose preference and immobility in the forced swim test)25,73.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [25] Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014). sourceExperimental — accuracy not yet measured
The Results (page unavailable) show that blocking or deleting IL-6 prevented stress-induced social avoidance in mice, supporting a role for IL-6 in that behaviour. The cited passages do not show that IL-6 or TNF directly induced behaviour through cytokine administration, or report reduced sucrose preference or forced-swim immobility as outcomes. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [73] Kaster, M. P., Gadotti, V. M., Calixto, J. B., Santos, A. R. S. & Rodrigues, A. L. S. Depressive-like behavior induced by tumor necrosis factor-α in mice. Neuropharmacology 62, 419–426 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“When HSCs from the bone marrow of stress-susceptible mice are transplanted into naïve mice, for example, the recipient mice become socially averse following a subthreshold social defeat that normally does not confer depressive-like behaviour25.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [25] Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014). source
The paper’s “Peripheral Immune System Controls Behavioral Susceptibility” passage describes transplanting bone-marrow hematopoietic progenitor cells from stress-susceptible donors into recipient mice. The Fig. 3D passage reports that the resulting chimeras showed social avoidance after subthreshold defeat, which did not induce social avoidance in controls. The supplied copy does not give page numbers for these passages. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It is well established that bone marrow receives dense sympathetic innervation, which contributes to the mobilization of leukocytes into circulation during stress or under homeostatic conditions60,61.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [60] Hanoun, M., Maryanovich, M., Arnal-Estapé, A. & Frenette, P. S. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86, 360–373 (2015). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says bone marrow is highly innervated by sympathetic nerves and that circadian neural signals influence leukocyte trafficking. The section “Autonomic regulation of hematopoietic homeostasis” (page unavailable) links sympathetic signaling to release of hematopoietic stem and progenitor cells into peripheral blood, both rhythmically and after G-CSF treatment. It does not establish the broader claim that this innervation mobilizes leukocytes into circulation during stress and under homeostatic conditions. (LLM, conf=0.84)
- Partly supportedcites [61] Cosentino, M., Marino, F. & Maestroni, G. J. M. Sympathoadrenergic modulation of hematopoiesis: a review of available evidence and of therapeutic perspectives. Front. Cell. Neurosci. 9, 302 (2015). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says sympathetic fibers innervate bone marrow and that stimulating them releases neutrophils into circulation. “Effect of Stress on the Production of Inflammatory Cells” describes stress-related increases in circulating monocytes and neutrophils, as well as sympathetic regulation of circadian stem-cell trafficking. The copy does not establish that the innervation is dense or specifically show homeostatic mobilization of leukocytes, rather than stem cells. (LLM, conf=0.82)
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This allows pro-inflammatory leukocytes, or their secreted factors (such as IL6 or matrix metalloproteinase-8), to enter the brain parenchyma where they impact neuronal excitability7,75,76 (Fig. 3).”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [7] Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). sourceExperimental — accuracy not yet measured
The Results (page unavailable) show that claudin-5 downregulation permits circulating IL-6 to enter the nucleus accumbens parenchyma, and the Discussion says monocytes at blood vessels can release cytokines that act locally on neurons and glia. But the Results say those monocytes did not enter the parenchyma, and the cited passages do not establish an effect on neuronal excitability or passage of matrix metalloproteinase-8. (LLM, conf=0.90)
- Partly supportedcites [75] Garcia-Oscos, F. et al. Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex. Brain Behav. Immun. 43, 149–158 (2015). sourceExperimental — accuracy not yet measured
The Discussion (section 4; page unavailable) reports that IL-6 decreases GABAergic currents in the rodent prefrontal cortex and that systemic LPS induces central hyperexcitability. It does not establish that reduced claudin-5 permits leukocytes or their secreted factors to enter brain parenchyma, or address matrix metalloproteinase-8. (LLM, conf=0.86)
- Partly supportedcites [76] Russo, S. et al. Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility. Preprint at Res. Sq. https://doi.org/10.21203/rs.3.rs-1647827/v1 (2023). sourceExperimental — accuracy not yet measured
In “Peripheral MMP8 is associated with brain extracellular space abnormalities” (page unavailable), the authors show that injected peripheral MMP8 can access brain parenchyma. “MMP8 depletion regulates brain extracellular space and neurophysiology” (page unavailable) reports that loss of MMP8 attenuated stress-induced neuronal excitability. The paper does not establish reduced claudin-5 as the route of entry; moreover, “Brain-infiltrating monocytes express increased MMP8” says the monocytes remained attached to vasculature rather than entering parenchyma. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, intracisternal injection of orexin (which is largely produced by cells in the LH) can prevent ethanol-induced gastric mucosal damage99.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [99] Yamada, H., Tanno, S., Takakusaki, K. & Okumura, T. Intracisternal injection of orexin-A prevents ethanol-induced gastric mucosal damage in rats. J. Gastroenterol. 42, 336–341 (2007). source
The reported findings state that intracisternal orexin-A suppressed ethanol-induced gastric mucosal lesions in rats. The Introduction also places orexin neurons in the lateral hypothalamus. The effect was specific to orexin-A: intracisternal orexin-B did not suppress the lesions. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The authors then introduced electrolytic lesions bilaterally in the PVH to ablate its function, which caused a significant reduction in adipose tissue ILC2s133.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Partly supportedcites [133] Cardoso, F. et al. Neuro-mesenchymal units control ILC2 and obesity via a brain-adipose circuit. Nature 597, 410–414 (2021). Identifies a role for the PVH in regulating adipose tissue ILC2s and metabolism. sourceExperimental — accuracy not yet measured
The Methods section (page unavailable) describes bilateral electrolytic PVH lesions in mice. The paper reports impaired adipose innate type 2 cytokines after PVH ablation (section labelled Abstract, page unavailable), but does not report a significant reduction in the number of adipose ILC2s. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, a recent study demonstrated a bi-directional gut–brain circuit linking the insular cortex to colon inflammation101.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [101] Koren, T. et al. Insular cortex neurons encode and retrieve specific immune responses. Cell 184, 5902–5915.e17 (2021). Demonstrates that the insular cortex can encode and re-activate immunological memory of peripheral inflammation in the gut. source
The Results report increased insular-cortex activity during DSS-induced colitis and show that reactivating neurons captured during colitis recapitulated colon inflammation. The Results also describe an anatomical path of communication between those neurons and the colon, supporting the claimed bidirectional link in mice. (LLM, conf=0.90)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, broad non-specific chemogenetic inhibition of insular cortex neurons during DSS administration prevents colitis, implying that non-specific inhibition of insular cortex activity can directly alleviate peripheral inflammation in the gut101.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Partly supportedcites [101] Koren, T. et al. Insular cortex neurons encode and retrieve specific immune responses. Cell 184, 5902–5915.e17 (2021). Demonstrates that the insular cortex can encode and re-activate immunological memory of peripheral inflammation in the gut. sourceExperimental — accuracy not yet measured
The Results report that nonspecific chemogenetic inhibition of the insular cortex during DSS treatment reduced several clinical and colonic immune measures in mice. But the paper says not all clinical and histological parameters were affected, so the citing sentence’s claim that inhibition “prevents colitis” overstates the finding. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Since pro-inflammatory polarization of immune cells in the liver directly leads to insulin resistance138, a brain–liver axis may link chronic stress to hyperglycemia via hepatic inflammation.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Supportedcites [138] Morinaga, H. et al. Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice. Diabetes 64, 1120–1130 (2015). source
The citation is attached to the claim that pro-inflammatory liver immune cells contribute to insulin resistance, not to the citing authors’ proposed brain–liver axis. The paper states on p. 2 that recruited hepatic macrophages enhance obesity-induced inflammation and hepatic insulin resistance; the Discussion (p. 8) describes their increased pro-inflammatory activity in high-fat-diet mice. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“This mechanism was re-capitulated by optogenetically activating tyrosine hydroxylase-expressing (TH+) C1 neurons in the medulla88.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [88] Abe, C. et al. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat. Neurosci. 20, 700–707 (2017). source
The Results section reports that ChR2 expression was confined to TH+ neurons in the rostral ventrolateral medulla, most of which were C1 cells. It also reports renal protection elicited by optogenetic C1 stimulation, supporting the claim that activation reproduced the stress-induced protective effect. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These symptoms are common features of IBS, for which stress is a major risk factor96.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Partly supportedcites [96] Fadgyas-Stanculete, M., Buga, A.-M., Popa-Wagner, A. & Dumitrascu, D. L. The relationship between irritable bowel syndrome and psychiatric disorders: from molecular changes to clinical manifestations. J. Mol. Psychiatry 2, 4 (2014). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says stress often worsens IBS symptoms and that psychosocial stressors may contribute to their predisposition, precipitation and maintenance. It does not establish stress as a major risk factor for developing IBS; that stronger characterization is not supported. (LLM, conf=0.84)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Mechanistically, inflammatory intestinal leukocytes, including IL17+ T cells as well as mast cells, may contribute to the breakdown of the intestinal epithelial barrier and the accompanying downregulation of tight junction proteins CLDN5, occludin (OCLN) and tight junction protein 2 (ZO-2)106,107.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Partly supportedcites [106] Santos, J., Yang, P. C., Söderholm, J. D., Benjamin, M. & Perdue, M. H. Role of mast cells in chronic stress induced colonic epithelial barrier dysfunction in the rat. Gut 48, 630–636 (2001). sourceExperimental — accuracy not yet measured
The Abstract (page not specified) reports that chronic stress impaired the colonic barrier in rats with mast cells but not in mast-cell-deficient rats, supporting a possible mast-cell contribution. The Discussion (page not specified) mentions tight-junction proteins only as part of a proposed mechanism for permeability changes in other models. Our copy does not report IL17+ T-cell involvement or downregulation of CLDN5, OCLN, or ZO-2. (LLM, conf=0.90)
- Partly supportedcites [107] Demaude, J., Salvador-Cartier, C., Fioramonti, J., Ferrier, L. & Bueno, L. Phenotypic changes in colonocytes following acute stress or activation of mast cells in mice: implications for delayed epithelial barrier dysfunction. Gut 55, 655–661 (2006). sourceExperimental — accuracy not yet measured
The Results and ‘Role of mast cells and IFN-c’ sections report increased colonic permeability after stress or mast-cell activation in mice, alongside decreased occludin and ZO-2 mRNA. They do not establish downregulation of CLDN5 or implicate IL17+ T cells; the measured decreases are in mRNA, not protein abundance. Page numbers are unavailable in our copy. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“One recent study defined a brain–adipose circuit that controls ILC2 function in adipose tissue133.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Supportedcites [133] Cardoso, F. et al. Neuro-mesenchymal units control ILC2 and obesity via a brain-adipose circuit. Nature 597, 410–414 (2021). Identifies a role for the PVH in regulating adipose tissue ILC2s and metabolism. source
The Abstract reports a brain–adipose circuit that controls ILC2 activity in gonadal fat. The Discussion likewise describes a brain-body axis connected to a sympathetic aorticorenal-adipose interface that regulates ILC2 function. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Importantly, activation of these neurons in the absence of prior DSS challenge did not exert any inflammatory effects in the colon, suggesting that the insular cortex neurons connected to the gut can encode an immunological memory of a peripheral inflammatory state101.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [101] Koren, T. et al. Insular cortex neurons encode and retrieve specific immune responses. Cell 184, 5902–5915.e17 (2021). Demonstrates that the insular cortex can encode and re-activate immunological memory of peripheral inflammation in the gut. source
The Results report that general activation of insular cortex neurons without prior DSS exposure did not induce colon inflammation, whereas reactivation of neurons captured during DSS-induced colitis heightened immune activity in the colon. The Discussion describes this as acquisition and retrieval of specific immune-related information. These passages support the proposed memory of a peripheral inflammatory state; they do not establish a direct anatomical connection from those neurons to the gut. (LLM, conf=0.91)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“This recapitulated aspects of the colonic inflammation, such as increased intraepithelial and lamina propria leukocytes, greater activation of intraepithelial γδT cells, CD4-expressing (CD4+) T cells, and CD8+ T cells, and elevated IL6 and TNF expression by CD4+ T cells and monocytes, respectively101.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [101] Koren, T. et al. Insular cortex neurons encode and retrieve specific immune responses. Cell 184, 5902–5915.e17 (2021). Demonstrates that the insular cortex can encode and re-activate immunological memory of peripheral inflammation in the gut. source
The Results (Figures 2E–2O) report that reactivating insular cortex neurons captured during DSS-induced colitis increased colonic leukocytes, activated intraepithelial γδ T cells, and activated CD4+ and CD8+ T cells. They also report increased IL-6-expressing intraepithelial CD4 T cells and TNF-α-expressing lamina propria monocytes. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similar to humans with MDD, stressed mice are also more susceptible to infections by pathogens such as Escherichia coli, influenza and SARS-CoV-269,150,151.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
What the sources say
- Partly supportedcites [69] Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022). Identifies brain circuits controlling monocyte, neutrophil and lymphocyte retention and mobilization from the bone marrow into circulation during acute stress. sourceExperimental — accuracy not yet measured
The Article section reports that acutely stressed mice had higher SARS-CoV-2 viral titres and mortality, and higher influenza viral loads and more severe pathology. Our copy does not establish increased susceptibility to Escherichia coli or the comparison with humans with MDD. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [150] Kiank, C. et al. Stress susceptibility predicts the severity of immune depression and the failure to combat bacterial infections in chronically stressed mice. Brain. Behav. Immun. 20, 359–368 (2006). source
- Supportedcites [151] Luo, Z. et al. Novel insights into stress-induced susceptibility to influenza: corticosterone impacts interferon-β responses by Mfn2-mediated ubiquitin degradation of MAVS. Signal. Transduct. Target. Ther. 5, 202 (2020). source
The Results section ('Stress increases mortality rate and virus replication in influenza-infected mice') reports higher morbidity and mortality in restraint-stressed mice infected with influenza than in non-stressed infected mice. In the multi-citation sentence, this paper supports the influenza example; the other pathogens and the comparison with humans with MDD are not attributed specifically to it. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In agreement with these findings, a separate study found that optogenetic stimulation of CRH+ neurons in the PVH shifts circulating leukocytes to an ‘immunosuppressed’ profile, characterized by lower frequencies of dendritic cells expressing major histocompatibility complex (MHC) class II molecules, natural killer cells, B cells, and CD4+ T cells155.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
What the sources say
- Supportedcites [155] Li, S.-B. et al. Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression. Sci. Adv. 6, eabc2590 (2020). Profiles circulating leukocyte populations following PVH stimulation and reports an immunosuppressed phenotypic switch. source
The section “Optogenetic activation of CRH PVN neurons causes immunosuppression” (p. 4) reports reduced frequencies of circulating MHCII+ dendritic cells, NK cells, B cells, and CD4+ T cells after optogenetic stimulation. The paper also describes these changes as consistent with immunosuppression (Fig. 6 caption, p. 7). (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
In the paper
“Contemporary neuroscientists now have a growing understanding that psychological states can indeed impact physiological processes in the periphery, such as metabolism, host defense and cardiovascular function1.”
§ Central regulation of stress-evoked peripheral immune responses > Introduction
What the sources say
- Not checked — no full text of the sourcecites [1] O’Connor, D. B., Thayer, J. F. & Vedhara, K. Stress and health: a review of psychobiological processes. Annu. Rev. Psychol. 72, 663–688 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Moreover, we highlight studies that have used chemogenetic or optogenetic manipulation, or intracerebroventricular administration of peptide hormones, to control somatic immune responses.”
§ Central regulation of stress-evoked peripheral immune responses > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Here, we review the specific brain and spinal regions, and the neuronal populations within them, that respond to stress and transmit signals to peripheral tissues via the autonomic nervous system or neuroendocrine pathways to influence immunological function.”
§ Central regulation of stress-evoked peripheral immune responses > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“We comprehensively summarize studies that have employed retrograde tracing to define neurocircuits linking the brain to the bone marrow, spleen, gut, adipose tissue and liver.”
§ Central regulation of stress-evoked peripheral immune responses > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Early work identified autonomic innervation of immune organs, including the bone marrow, which contains haematopoietic stem cells that give rise to all blood cells including monocytes, neutrophils, and lymphocytes, thereby laying the foundation for future investigates of brain-to-body communication35.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [35] Felten, D. L. & Felten, S. Y. Sympathetic noradrenergic innervation of immune organs. Brain Behav. Immun. 2, 293–300 (1988). source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that peripheral inflammation is a direct consequence of psychosocial stress in a subset of vulnerable mice.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, serum cytokine profiles in people with MDD show considerable overlap with those seen in people with common co-morbid inflammatory disorders, including IBD, metabolic syndrome and coronary artery disease, although often the concentrations are lower in magnitude (Table 1).”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not matchedcites Table 1
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
In the paper
“They found GFP in sympathetic chain ganglia at the lumbar level of the spine and in the intermediolateral cell column of the thoracic spinal cord, as well as in the ventrolateral medulla, four days after infection37.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [37] Dénes, A. et al. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience 134, 947–963 (2005). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Therefore, animal models of stress, including chronic variable stress (CVS) and chronic social defeat stress (CSDS), which recapitulate biological and behavioural phenotypes associated with anxiety and depression, are invaluable tools to uncover how the stressed brain communicates with the peripheral immune system (Box 1).”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not matchedcites Box 1
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Not matched
In the paper
“Six days after PRV infection, the virus had spread to regions including the bed nucleus of the stria terminalis (BNST), arcuate nucleus of the hypothalamus (ARH), amygdala, hippocampus, insular cortex, septum and motor cortex37.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [37] Dénes, A. et al. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience 134, 947–963 (2005). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Additionally, chemogenetic activation of dopaminergic neurons in the VTA, which encode reward behaviour, increased circulating B cell numbers72.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [72] Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22, 940–944 (2016). Shows that stimulating VTA neurons enhances peripheral bactericidal function and improves social behaviour. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“By four days post-infection, PRV was found in the CeA, BNST, LC, lateral septum, insular cortex, motor cortex, ARH and the dorsomedial nucleus of the hypothalamus (DMH)80,81.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [80] Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020). Shows that optogenetic stimulation of stress-responsive CNS regions influences splenic plasma cell production. source
- Not checked — no full text of the sourcecites [81] Cano, G., Sved, A. F., Rinaman, L., Rabin, B. S. & Card, J. P. Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing. J. Comp. Neurol. 439, 1–18 (2001). source
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“Of the spleen-innervating brain regions, the PVH and CeA are among those with the most projections to the splenic nerve.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [80] Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020). Shows that optogenetic stimulation of stress-responsive CNS regions influences splenic plasma cell production. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nevertheless, these studies demonstrate the capability of brain activity to regulate leukocyte production, retention and egress from the bone marrow under stressful conditions via the HPA axis, autonomic nervous system and actions of peripheral chemokines (Fig. 2).”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Direct intracerebroventricular injections of AGRP reportedly increases TNF expression in epididymal white adipose tissue by suppressing sympathetic nerve activity131.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Not checked — no full text of the sourcecites [131] Tang, L. et al. Sympathetic nerve activity maintains an anti-inflammatory state in adipose tissue in male mice by inhibiting TNF-α gene expression in macrophages. Endocrinology 156, 3680–3694 (2015). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Mechanistically, a recent study reported that chronic restraint stress aggravates dextran sulfate sodium (DSS)-induced colitis in a pathway that is dependent on the HPA axis.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [100] Schneider, K. M. et al. The enteric nervous system relays psychological stress to intestinal inflammation. Cell 186, 2823–2838.e20 (2023). Characterizes an HPA axis-based pathway in which enteric glia become activated by stress to exacerbate DSS-induced colitis. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, PBMCs isolated from people with MDD exhibit greater TLR4 expression and responses to TLR4 stimulation110,111; thus, stress-induced endotoxemia may contribute to systemic inflammation that impinges on behaviour (Fig. 3).”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these studies illustrate a pathway through which a psychological state such as stress could impact signals from LH orexin neurons to parasympathetic nerves via the DMV to cause hepatic inflammation, which contributes to insulin resistance (Fig. 2).”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This implies that PVH activity may in part normalize systemic glucose homeostasis via a mechanism mediated by adipose tissue ILC2s (Fig. 2).”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Growing data suggest that the enteric nervous system influences intestinal immunity.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Moreover, metabolic inflammation — leukocyte infiltration and pro-inflammatory signaling in insulin-responsive tissues — promotes systemic hyperglycemia113.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Not checked — no full text of the sourcecites [113] Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While these studies demonstrate that gastrointestinal inflammation and homeostasis can be modulated by the CNS, they do not directly demonstrate the specific cells within the brain that regulate these processes.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings highlight specific neuronal populations that may regulate adipose tissue physiology, including inflammation.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Consequently, these T cells produce acetylcholine, which suppresses pro-inflammatory cytokine production by splenic macrophages via the α7”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [89] Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, different segments of the gastrointestinal tract may receive inputs from common CNS regions.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, there are specific neuronal populations in the NTS and hypothalamus that signal to both the adipose tissue and liver, either separately or simultaneously.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There is also evidence indicating that gut inflammation can contribute to stress-relevant behaviours.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Consequently, these T cells produce acetylcholine, which suppresses pro-inflammatory cytokine production by splenic macrophages via the α7 nicotinic acetylcholine receptor89.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [89] Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Under chronic stress, regions such as the hypothalamus, amygdala and insula are pivotal structures that integrate signals in the CNS and then propagate them to the periphery, largely via the autonomic nervous system and HPA axis.”
§ Central regulation of stress-evoked peripheral immune responses > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 60
- Probably not a substantial claim. 8
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Specifically, mice exposed to either CVS or CSDS exhibit an expansion of myeloid progenitor cells, along with a downregulation of lymphoid progenitors33,59.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Disputedcites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourceExperimental — accuracy not yet measured
The passage labeled Abstract (page unavailable) reports higher bone-marrow numbers of both myeloid progenitors and common lymphoid progenitors after chronic variable stress, contrary to the claimed reduction in lymphoid progenitors. This paper’s reported mouse experiment used chronic variable stressors; the cited passages do not establish the CSDS portion of the claim. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Partly supportedcites [59] McKim, D. B. et al. Social stress mobilizes hematopoietic stem cells to establish persistent splenic myelopoiesis. Cell Rep. 25, 2552–2562.e3 (2018). sourceExperimental — accuracy not yet measured
The Results sections report increased myeloid progenitor colony-forming units after repeated social defeat stress, alongside reduced lymphocyte proportions in bone marrow and blood. They do not establish a reduction in lymphoid progenitors. The Introduction mentions increased myeloid cell production under chronic variable stress, but does not report myeloid progenitor expansion or reduced lymphoid progenitors under that condition. Page numbers were not available in our copy. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“As neurons within the DMV drive parasympathetic functions in peripheral tissues84, this suggests that parasympathetic activity has anti-inflammatory roles in the spleen, while sympathetic inputs have known inflammatory functions85.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Disputedcites [84] Breit, S., Kupferberg, A., Rogler, G. & Hasler, G. Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Front. Psychiatry 9, 44 (2018). sourceExperimental — accuracy not yet measured
The citation is attached to the claim that sympathetic inputs have inflammatory functions. In “Vagus Nerve as Modulator of Intestinal Immune Homeostasis” (page unavailable), the paper instead describes a splenic sympathetic anti-inflammatory pathway: stimulation of the splenic sympathetic nerve ultimately inhibits TNF-α release by spleen macrophages. The paper also supports an anti-inflammatory role for vagal activity, but that is not the point to which this citation is attached. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
- Supportedcites [85] Monteiro, S. et al. Splenic sympathetic signaling contributes to acute neutrophil infiltration of the injured spinal cord. J. Neuroinflammation 17, 282 (2020). source
Citation 85 supports the sympathetic-input clause, not the preceding inference about parasympathetic activity. The Background links splenic sympathetic signaling to inflammation and reports that splenic nerve ablation reduced infiltration of inflammatory neutrophils after spinal cord injury. (LLM, conf=0.89)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It is commonly reported that chronic stress compromises immune function, increasing susceptibility to infection149.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
What the sources say
- Partly supportedcites [149] Segerstrom, S. C. & Miller, G. E. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol. Bull. 130, 601–630 (2004). sourceExperimental — accuracy not yet measured
The Results report that chronic stressors negatively affected almost all functional measures of immunity. The Discussion says stressful experiences can confer vulnerability to adverse medical outcomes, but it also says studies had generally not established whether immune changes are the mechanism by which stress increases disease susceptibility. Thus the asserted link from compromised immune function to infection is stronger than this paper establishes. (LLM, conf=0.88)
direct- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Notably, chronic stress synergizes with high fat feeding in mice to exacerbate insulin insensitivity, as well as adipose tissue inflammation126.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Supportedcites [126] Motoyama, S. et al. Social stress increases vulnerability to high-fat diet-induced insulin resistance by enhancing neutrophil elastase activity in adipose tissue. Cells 9, 996 (2020). source
The Discussion describes a synergistic effect of social stress and high-fat feeding on insulin resistance. Results §3.1 reports significantly impaired insulin sensitivity in stressed mice after high-fat feeding, while §3.2 reports more adipose-tissue crown-like structures and neutrophils, consistent with increased local inflammation. The indexed copy provides no page numbers for these sections. (LLM, conf=0.90)
direct- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In turn, somatic states are sensed by the CNS to shape and guide behaviour2.”
§ Central regulation of stress-evoked peripheral immune responses > Introduction
What the sources say
- Supportedcites [2] Savitz, J. & Harrison, N. A. Interoception and inflammation in psychiatric disorders. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 3, 514–524 (2018). source
The Abstract says that bodily physiological state is communicated to the brain through interoceptive signals and that these pathways can lead to changes in behavior. The Introduction likewise describes immune-state signals reaching the brain and altering motivation and other responses. The supplied passages do not give page numbers. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It is important to note, however, that lifestyle factors (such as pain arising from rheumatoid arthritis or social isolation during SARS-CoV-2 infection) can contribute to or exacerbate depressive symptoms16,17.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not checked — no full text of the sourcecites [16] Wolfe, F. & Michaud, K. Predicting depression in rheumatoid arthritis: the signal importance of pain extent and fatigue, and comorbidity. Arthritis Rheum. 61, 667–673 (2009). source
- Partly supportedcites [17] Bzdok, D. & Dunbar, R. I. M. Social isolation and the brain in the pandemic era. Nat. Hum. Behav. 6, 1333–1343 (2022). sourceExperimental — accuracy not yet measured
The section “Consequences of mass social isolation in COVID-19” (pp. 4, 6) links isolation and loneliness during pandemic lockdowns with elevated or worsening depressive symptoms. It does not establish this specifically for people isolated during a SARS-CoV-2 infection. The rheumatoid-arthritis example appears to be covered by the sentence’s other citation and is not assessed here. (LLM, conf=0.84)
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Perpetuating this cycle, there is evidence that depression compromises the immune system and heightens the risk of infection18,19.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Partly supportedcites [18] Blume, J., Douglas, S. D. & Evans, D. L. Immune suppression and immune activation in depression. Brain Behav. Immun. 25, 221–229 (2011). sourceExperimental — accuracy not yet measured
The Abstract and section II associate depression with impaired cellular immunity, supporting the immune-suppression part of the claim. Section II also reports greater ex-vivo HIV infectivity with depressive symptom burden and an association between depressive symptoms and reduced viral clearance in patients receiving hepatitis C treatment. Those findings do not establish that depression generally causes a higher risk of acquiring infections; the paper cautions that relationships between depression and immunity may not always be causal. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [19] Andersson, N. W. et al. Depression and the risk of severe infections: prospective analyses on a nationwide representative sample. Int. J. Epidemiol. 45, 131–139 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent studies have reported stress-induced alterations in hematopoiesis that result in monocytosis, neutrophilia and lymphocytopenia and, consequently, upregulation of pro-inflammatory processes in immunologically-relevant peripheral tissues.”
- Also stated in: § Brain-to-bone marrow neurocircuits · plain
“MDD in humans and chronic stress in rodents are associated with monocytosis, neutrophilia and lymphocytopenia, which can be attributed to altered proliferation of hematopoietic stem cell (HSC) subpopulations or mobilization of leukocytes from the bone marrow”
§ Central regulation of stress-evoked peripheral immune responses > Abstract
What the sources say
- Partly supportedcites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourceExperimental — accuracy not yet measured
The paper reports stress-induced increases in monocytes and neutrophils and, in stressed mice, increased inflammation in atherosclerotic plaques (sections labeled Abstract; page unavailable). It does not support lymphocytopenia: the ICU residents had higher, not lower, blood lymphocyte counts during the stressful rotation. The peripheral-tissue finding is specifically from plaques in atherosclerosis-prone mice, not peripheral immune tissues generally. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [56] Engler, H., Bailey, M. T., Engler, A. & Sheridan, J. F. Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood and spleen. J. Neuroimmunol. 148, 106–115 (2004). source
- Partly supportedcites [57] Pfau, M. L. et al. Role of monocyte-derived microRNA106b∼25 in resilience to social stress. Biol. Psychiatry 86, 474–482 (2019). sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports that repeated social defeat stress increased circulating inflammatory monocytes and neutrophils and decreased B cells in mice; T cells decreased only in susceptible mice. The Introduction (page unavailable) describes stress-induced myelopoiesis and elevated peripheral IL-6, but the paper does not establish that these blood-cell changes consequently upregulate pro-inflammatory processes in peripheral tissues. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [58] Seidel, A. et al. Major depressive disorder is associated with elevated monocyte counts. Acta Psychiatr. Scand. 94, 198–204 (1996). source
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- Also stated in: § Brain-to-bone marrow neurocircuits · plain
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Other stress-sensitive brain regions that project to the bone marrow, such as the BNST and central amygdala (CeA), also integrate emotional signals and activate the HPA axis to promote anxiety or fear responses53–55.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [53] Lebow, M. A. & Chen, A. Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol. Psychiatry 21, 450–463 (2016). sourceExperimental — accuracy not yet measured
The Introduction describes the BNST as integrating threat-related information and distinguishes its role in sustained anxiety from the amygdala’s role in phasic fear. It also describes CeA involvement in the HPA axis; the “BNST: anatomy in humans” section says BNST regions can regulate its activation or attenuation. No passage in our copy supports the claim that the BNST or CeA project to bone marrow (searched: bone marrow, bone marrow projections). Page numbers were unavailable. (LLM, conf=0.88)
- Partly supportedcites [54] Numa, C. et al. Social defeat stress-specific increase in c-Fos expression in the extended amygdala in mice: involvement of dopamine D1 receptor in the medial prefrontal cortex. Sci. Rep. 9, 16670 (2019). sourceExperimental — accuracy not yet measured
The Results (page unavailable) identify the BNST and CeA as parts of the extended amygdala involved in emotional regulation and report their activation by social defeat stress. The Discussion (page unavailable) links the extended amygdala to fear and anxiety. Our copy does not support the additional claims that these regions project to bone marrow or activate the HPA axis to promote those responses. (LLM, conf=0.87)
- Partly supportedcites [55] Keifer, O. P., Hurt, R. C., Ressler, K. J. & Marvar, P. J. The physiology of fear: reconceptualizing the role of the central amygdala in fear learning. Physiology 30, 389–401 (2015). sourceExperimental — accuracy not yet measured
The CeA output-pathways passages (indexed as Abstract; page unavailable) describe CeA projections to the BNST and hypothalamus, a possible CeA–BNST pathway mediating the neuroendocrine stress response, and the hypothalamic PVN’s role in HPA-axis activation. They also link these circuits to fear responses. The paper does not support the claim that the BNST and CeA project to bone marrow, or establish the full asserted sequence from emotional-signal integration through HPA activation to anxiety or fear. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Most commonly, pseudorabies viruses (PRVs) expressing reporter genes have been used for this purpose, as they exhibit rapid trans-synaptic propagation (crossing approximately one synapse every 24 hours after infection)36.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [36] Saleeba, C., Dempsey, B., Le, S., Goodchild, A. & McMullan, S. A student’s guide to neural circuit tracing. Front. Neurosci. 13, 897 (2019). sourceExperimental — accuracy not yet measured
The 'Retrograde Poly-Synaptic Viral Tracers' section (page not specified) describes PRV as a rapid retrograde tracer and the historical tracer of choice, and discusses PRV strains expressing transgenes. It reports trans-synaptic travel within two days in vivo, but does not establish a rate of approximately one synapse every 24 hours after infection. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“whereas it activates LC neurons in resilient mice to promote resilience to social avoidance behaviour44–46.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [44] Hahn, M. K. & Bannon, M. J. Stress-induced C-fos expression in the rat locus coeruleus is dependent on neurokinin 1 receptor activation. Neuroscience 94, 1183–1188 (1999). source
- Supportedcites [45] Zhang, H. et al. α1- and β3-adrenergic receptor-mediated mesolimbic homeostatic plasticity confers resilience to social stress in susceptible mice. Biol. Psychiatry 85, 226–236 (2019). source
The Discussion reports that LC→VTA neurons show increased firing after chronic social defeat stress exclusively in resilient mice. It also reports that activating those neurons in stress-exposed susceptible mice reversed social avoidance and promoted a resilience-like phenotype. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [46] Isingrini, E. et al. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat. Neurosci. 19, 560–563 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, stress activates neurons in the lateral septum to blunt social reward in susceptible mice43”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [43] Li, L. et al. Social trauma engages lateral septum circuitry to occlude social reward. Nature 613, 696–703 (2023). source
The Abstract reports that chronic social defeat stress produces social-reward deficits in susceptible mice and that these mice show heightened activity in lateral septum neurotensin circuitry, which occludes social reward. The ‘NT LS neurons modulate social behaviour’ section further reports that inhibiting those neurons restores social preference in susceptible mice. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“MDD in humans and chronic stress in rodents are associated with monocytosis, neutrophilia and lymphocytopenia, which can be attributed to altered proliferation of hematopoietic stem cell (HSC) subpopulations or mobilization of leukocytes from the bone marrow33,56–58.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourceExperimental — accuracy not yet measured
The paper reports monocytosis and neutrophilia in stressed ICU residents and mice, and increased HSC proliferation in stressed mice (Abstract; page not provided). It does not study humans with MDD or establish HSC activity in humans. The lymphocytopenia claim conflicts with its report of increased lymphocytes in the stressed residents; the authors also favor increased leukocyte production over short-term mobilization as the explanation for their human observations. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [56] Engler, H., Bailey, M. T., Engler, A. & Sheridan, J. F. Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood and spleen. J. Neuroimmunol. 148, 106–115 (2004). source
- Partly supportedcites [57] Pfau, M. L. et al. Role of monocyte-derived microRNA106b∼25 in resilience to social stress. Biol. Psychiatry 86, 474–482 (2019). sourceExperimental — accuracy not yet measured
The Introduction reports increased inflammatory monocytes and neutrophils in subsets of patients with MDD, and the Results report increased monocytes and neutrophils and decreased B cells after chronic social stress in mice; T-cell counts decreased only in susceptible mice. The paper does not establish lymphocytopenia in humans with MDD or attribute these changes to altered HSC-subpopulation proliferation or leukocyte mobilization from bone marrow. Page numbers are unavailable in our copy. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [58] Seidel, A. et al. Major depressive disorder is associated with elevated monocyte counts. Acta Psychiatr. Scand. 94, 198–204 (1996). source
plainconditional- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“with the PVH being a key component of the HPA axis that can also coordinate stress responses through neuroendocrine mechanisms52.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [52] Herman, J. P. et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr. Physiol. 6, 603–621 (2016). source
In the ‘rising’ phase section (page unavailable), the paper describes the PVN’s CRH-producing neurons as important for HPA-axis activation in response to stressors. The stressor-specificity section (page unavailable) likewise describes signals reaching PVN CRH neurons to produce a rapid HPA-axis response. The paper uses ‘PVN’ for the structure the claim calls ‘PVH.’ (LLM, conf=0.90)
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, there are also reported anti-inflammatory effects of stress on the spleen, with restraint stress initiating a cholinergic pathway via the sympathetic nervous system that activates an anti-inflammatory program in splenocytes that protects against ischemia-reperfusion injury in mice88.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [88] Abe, C. et al. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat. Neurosci. 20, 700–707 (2017). source
The Abstract states that restraint stress protected mice from renal ischemia-reperfusion injury through a cholinergic, predominantly sympathetic anti-inflammatory pathway. The Results report that splenocytes from stressed mice transferred protection to unstressed mice, and the Discussion identifies the splenic cholinergic anti-inflammatory pathway as the mechanism. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“conversely ablating CRH expression in the PVH prevented the decrease in T cells, B cells, and monocytes in the blood following acute restraint stress, as did inhibiting CXCR4, the receptor for CXCL1269.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [69] Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022). Identifies brain circuits controlling monocyte, neutrophil and lymphocyte retention and mobilization from the bone marrow into circulation during acute stress. source
The paper reports that deleting Crh from hypothalamic neurons prevented stress-induced reductions in blood B cells, T cells and monocytes (p. 581). In “The role of the HPA axis in acute stress,” it also reports that CXCR4 inhibition blocked these cells’ transit to the bone marrow; Fig. 2g measures blood leukocytes after inhibitor treatment and restraint stress. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“which normally inhibits haematopoiesis and retains neutrophils and monocytes within the bone marrow62–64.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [62] Eash, K. J., Means, J. M., White, D. W. & Link, D. C. CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions. Blood 113, 4711–4719 (2009). sourceExperimental — accuracy not yet measured
The Introduction (page not specified) says CXCL12–CXCR4 signaling retains neutrophils in the bone marrow. It does not establish monocyte retention or say that CXCL12 normally inhibits haematopoiesis; instead, it reports that mice lacking CXCL12 or CXCR4 fail to establish bone marrow myelopoiesis. (LLM, conf=0.88)
- Partly supportedcites [63] Chong, S. Z. et al. CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses. J. Exp. Med. 213, 2293–2314 (2016). sourceExperimental — accuracy not yet measured
The Introduction (page not specified) says CXCR4 signaling retains Ly6Chi monocytes in the bone marrow, and the Discussion describes CXCR4-mediated monocyte homing there. Our copy does not say that CXCL12 inhibits haematopoiesis or establish that it retains neutrophils in the bone marrow. (LLM, conf=0.84)
- Partly supportedcites [64] Jung, H., Mithal, D. S., Park, J. E. & Miller, R. J. Localized CCR2 activation in the bone marrow niche mobilizes monocytes by desensitizing CXCR4. PLoS ONE 10, e0128387 (2015). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says CXCL12–CXCR4 signaling anchors neutrophils in the bone marrow. The Discussion’s Fig. 6 model (page unavailable) says it normally retains monocytes there. Neither passage says CXCL12 inhibits haematopoiesis. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, the spleen is a major site of the germinal centre reaction, in which antigen-specific antibody-producing plasma cells undergo clonal expansion78.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Partly supportedcites [78] De Silva, N. S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Rev. Immunol. 15, 137–148 (2015). sourceExperimental — accuracy not yet measured
The Introduction says GC B cells proliferate and differentiate into antibody-secreting plasma cells; it does not say plasma cells themselves clonally expand in germinal centres. The section on initiation of the GC reaction describes clonal expansion of GC precursor B cells in the spleen, but does not establish that the spleen is a major site of the reaction. Page numbers are not available in our copy. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, acute restraint stress was also shown to induce neutrophilia and this was found to be regulated by different brain regions than those regulating monocyte and lymphocyte mobilization.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [69] Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022). Identifies brain circuits controlling monocyte, neutrophil and lymphocyte retention and mobilization from the bone marrow into circulation during acute stress. source
The Abstract reports that restraint stress increased circulating neutrophils in mice. It also distinguishes motor circuits, which mobilize neutrophils, from the paraventricular hypothalamus, which controls monocyte and lymphocyte movement. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Chronic social stress in mice leads to splenomegaly, attributed to granulocyte accumulation and ectopic (or ‘extramedullary’) myelopoiesis, which consequently elevates circulating monocyte levels59,77.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [59] McKim, D. B. et al. Social stress mobilizes hematopoietic stem cells to establish persistent splenic myelopoiesis. Cell Rep. 25, 2552–2562.e3 (2018). source
The Results section reports an approximately twofold increase in spleen size and mass after social stress, alongside increased splenic granulocytes and monocytes; it also reports increased monocytes in blood. The Abstract and Introduction identify persistent splenic extramedullary myelopoiesis and a pool of releasable splenic monocytes, supporting the paraphrased link. (LLM, conf=0.86)
- Partly supportedcites [77] Zhang, K. et al. Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine. Eur. Arch. Psychiatry Clin. Neurosci. 271, 447–456 (2021). sourceExperimental — accuracy not yet measured
The Results (FACS analysis of spleen samples; page unavailable) report larger spleens and more splenic granulocytes in CSDS-susceptible mice, and suggest that granulocytes might account for the increased weight. The paper does not establish extramedullary myelopoiesis or a consequent rise in circulating monocytes; its Discussion describes monocytes within the spleen, not in circulation. The claim also omits the finding that resilient mice had spleens similar to controls. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“As neurons in the PVH and LC project to sympathetic centres in the brain stem and spinal cord, it is possible that elevated sympathetic tone arising from the activation of these brain regions during chronic stress drives these HSC and leukocyte dynamics in the bone marrow66–68.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [66] Won, E. & Kim, Y.-K. Stress, the autonomic nervous system, and the immune-kynurenine pathway in the etiology of depression. Curr. Neuropharmacol. 14, 665–673 (2016). sourceExperimental — accuracy not yet measured
The section “Stress, the Sympathetic Nervous System and the Parasympathetic Nervous System” (page unavailable) describes PVH and LC projections and continued sympathetic activation during prolonged stress. “The Autonomic Nervous System and the Immune System” links that activation to inflammatory cytokines, but the paper does not address HSC or leukocyte dynamics in bone marrow. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [67] Jones, B. E. & Yang, T. Z. The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J. Comp. Neurol. 242, 56–92 (1985). source
- Not checked — no full text of the sourcecites [68] Kenney, M. J., Weiss, M. L. & Haywood, J. R. The paraventricular nucleus: an important component of the central neurocircuitry regulating sympathetic nerve outflow. Acta Physiol. Scand. 177, 7–15 (2003). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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In the paper
“There is a growing body of literature implicating monocytosis, neutrophilia and dysregulation of hematopoiesis in the manifestation of depression or anxiety-related behaviours following stress in rodents, thus providing a possible link between chronic stress and mood disorders.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [25] Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014). sourceExperimental — accuracy not yet measured
The Discussion reports that mice susceptible to social stress had elevated circulating leukocytes, largely monocytes, and that peripheral immune differences predicted depression-like behavior. The paper also reports behavioral effects of transplanting bone-marrow hematopoietic progenitors. It does not establish neutrophilia or dysregulated hematopoiesis as contributors to stress-related behavior in rodents; neutrophilia appears only in the title of a cited human depression study. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [73] Kaster, M. P., Gadotti, V. M., Calixto, J. B., Santos, A. R. S. & Rodrigues, A. L. S. Depressive-like behavior induced by tumor necrosis factor-α in mice. Neuropharmacology 62, 419–426 (2012). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The authors found that stimulating corticotropin-releasing hormone-expressing (CRH+) neurons in the PVH, which increases plasma corticosterone concentrations, leads to the retention of T cells, B cells and monocytes in the bone marrow, thereby reducing their numbers in circulation”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [69] Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022). Identifies brain circuits controlling monocyte, neutrophil and lymphocyte retention and mobilization from the bone marrow into circulation during acute stress. source
In “The role of the HPA axis in acute stress,” stimulating PVH CRH neurons increased corticosterone and reduced circulating lymphocytes and monocytes in mice. The same section describes B- and T-cell and monocyte migration to bone marrow, and the discussion on p. 581 identifies the PVH–CRH axis as required for their bone marrow homing during acute stress. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“Mechanistically, social defeat stress upregulates inflammatory TNF and/or nuclear factor-κB (NFКB) signaling pathways in endothelial cells and diminishes expression of the tight junction protein claudin-5 (CLDN5)7,74.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Partly supportedcites [7] Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). sourceExperimental — accuracy not yet measured
The Results section on stress vulnerability reports reduced cldn5 mRNA and protein in nucleus accumbens blood vessels of stress-susceptible mice, but not resilient mice. Our copy does not report upregulation of TNF or NF-κB signaling in endothelial cells; searches for those terms did not identify supporting passages. Page numbers are unavailable in the copy. (LLM, conf=0.86)
- Partly supportedcites [74] Dudek, K. A. et al. Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression. Proc. Natl Acad. Sci. USA 117, 3326–3336 (2020). sourceExperimental — accuracy not yet measured
The Discussion reports increased inflammatory mediators involving TNFα/NFκB signaling in nucleus accumbens endothelial cells of stress-susceptible mice, alongside stress-induced cldn5 loss. Figure 6 contrasts this with resilient mice, which maintain cldn5 under chronic stress. The citing sentence omits that susceptibility qualifier and makes the response sound general to social defeat stress. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Stimulation of the motor cortex or medulla using optogenetics led to skeletal muscle expression of CXCL1, a chemokine for neutrophils71, while ablating or inhibiting these regions ameliorated the restraint stress-induced neutrophilia69.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Supportedcites [71] Sawant, K. V. et al. Chemokine CXCL1 mediated neutrophil recruitment: role of glycosaminoglycan interactions. Sci. Rep. 6, 33123 (2016). source
Citation 71 attaches to the description of CXCL1 as a chemokine for neutrophils, not to the optogenetic or restraint-stress findings, which are attributed to citation 69. The Results section (Recruitment profiles of CXCL1 variants; page unavailable) reports CXCL1-mediated neutrophil recruitment. (LLM, conf=0.93)
- Supportedcites [69] Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022). Identifies brain circuits controlling monocyte, neutrophil and lymphocyte retention and mobilization from the bone marrow into circulation during acute stress. source
In “Central motor circuits and neutrophilia,” the paper reports that optogenetic stimulation of motor cortex or medulla increased Cxcl1 expression in skeletal muscle (Fig. 3l,m). It also reports that motor-cortex ablation blunted, and chemogenetic inhibition of rostral medulla neurons prevented, restraint stress-induced neutrophilia (Fig. 3n,o). (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Another recent study explored the link between the DMV and spleen, demonstrating that optogenetic stimulation of neurons in the DMV triggers action potentials in the splenic nerve and inhibits endotoxin-induced production of the pro-inflammatory cytokine TNF83.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [83] Kressel, A. M. et al. Identification of a brainstem locus that inhibits tumor necrosis factor. Proc. Natl Acad. Sci. USA 117, 29803–29810 (2020). Investigates the role of parasympathetic spleen innervation in regulating TNF production to limit inflammation. source
In Results and Discussion, the paper reports that optogenetic stimulation of cholinergic neurons in the dorsal motor nucleus of the vagus (DMN, called DMV in the claim) increased splenic nerve activity. A separate subsection reports that the same targeted photostimulation attenuated serum TNF in endotoxin-challenged mice compared with sham stimulation. The supplied passages do not give page numbers. (LLM, conf=0.94)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“For example, activation of type 2 innate lymphoid cells (ILC2) in the gut mucosa is regulated by neuronally-derived peptides, with neuromedin U initiating102, and α-calcitonin gene-related peptide (αCGRP) antagonizing, type 2 immunity103.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [102] Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017). source
Citation 102 supports the neuromedin U portion of the sentence, not the αCGRP portion, which has a separate citation. The paper’s Abstract reports that mucosal neurons express neuromedin U and that it rapidly activates ILC2s and protective type 2 responses; Extended Data Figure 10 describes this neuron–ILC2 response to worm infection. Page numbers are not provided in our copy. (LLM, conf=0.93)
- Supportedcites [103] Xu, H. et al. Transcriptional atlas of intestinal immune cells reveals that neuropeptide α-CGRP modulates group 2 innate lymphoid cell responses. Immunity 51, 696–708 (2019). source
Citation 103 is attached to the α-CGRP part of the sentence, not the neuromedin U part. The Results report that α-CGRP antagonized intestinal ILC2 expansion and type 2 inflammation in vivo in a mouse model. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Metabolic dysfunction is another common consequence of chronic stress in both humans and animals, with significant co-morbidity existing between MDD and metabolic syndrome112.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Partly supportedcites [112] Dunbar, J. A. et al. Depression: an important comorbidity with metabolic syndrome in a general population. Diabetes Care 31, 2368–2373 (2008). sourceExperimental — accuracy not yet measured
The Conclusions report an association between metabolic syndrome and depression in a general human population, with depression 50% more prevalent among people with metabolic syndrome. They do not establish that metabolic dysfunction is a common consequence of chronic stress, or report findings in animals; the proposed stress-related pathway is presented as a hypothesis. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“One recent study showed that CSDS in mice promotes differentiation of IL17-expressing γδ T cells in the colon, in a process that is dependent on dectin-1 signaling95. When these cells were neutralized or dectin-1 was genetically knocked out, mice were protected against CSDS-induced social avoidance95.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [95] Zhu, X. et al. Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Nat. Immunol. 24, 625–636 (2023). source
The Results section, “Dectin-1 mediates colonic γδ17 T cell differentiation and behavioral deficits” (page unavailable), reports that CSDS increased colonic γδ17 T cells in wild-type mice but not dectin-1-knockout mice, which also did not develop social avoidance. “Inhibition of peripheral γδ T cells blocks social avoidance” (page unavailable) reports that anti-TCR-γδ treatment promoted resilience to CSDS-induced social avoidance. The antibody inhibited γδ T cells broadly rather than selectively targeting the IL-17-expressing subset. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, CSDS in mice reduces orexin expression, the number of orexin-positive neurons and the activation of these neurons in the LH143, while intracerebroventricular orexin infusion or chemogenetic activation of LH orexin+ neurons rescues stress-induced anxiety behaviour in the open field test, immobility in the forced swim test and social avoidance144,145.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Partly supportedcites [143] Lutter, M. et al. Orexin signaling mediates the antidepressant-like effect of calorie restriction. J. Neurosci. 28, 3071–3075 (2008). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [144] Chung, H.-S., Kim, J.-G., Kim, J.-W., Kim, H.-W. & Yoon, B.-J. Orexin administration to mice that underwent chronic stress produces bimodal effects on emotion-related behaviors. Regul. Pept. 194–195, 16–22 (2014). source
- Partly supportedcites [145] Kim, J. G., Ea, J. Y. & Yoon, B.-J. Orexinergic neurons modulate stress coping responses in mice. Front. Mol. Neurosci. 16, 1140672 (2023). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This may contribute to the MDD-associated elevations in circulating bacteria-derived compounds (such as lipopolysaccharide (LPS)108), which is recognized by toll-like receptor 4 (TLR4) on peripheral blood mononuclear cells (PBMCs) that trigger pro-inflammatory cytokine production109.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Partly supportedcites [108] Stevens, B. R. et al. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut 57, 1555–1557 (2017). sourceExperimental — accuracy not yet measured
The paper reports significantly elevated plasma LPS and gut-barrier biomarkers in a combined depressive-disorder/anxiety-disorder group versus controls, and proposes a link between compromised barrier integrity and LPS entering plasma (main text, Figure 2 discussion and study description; page unavailable). It does not establish elevated LPS specifically in MDD. The TLR4/PBMC mechanism is attached to a different citation in the citing sentence, so it is not judged here. (LLM, conf=0.86)
- Supportedcites [109] Vaure, C. & Liu, Y. A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front. Immunol. 5, 316 (2014). source
Citation 109 is attached to the LPS–TLR4–cytokine mechanism, not the preceding MDD-associated elevation claim. The Introduction identifies LPS as a TLR4 ligand; the “Expression pattern and functionality of TLR4 across species” section describes TLR4 in monocytes and LPS-induced cytokine production in blood mononuclear cells. The “TLR4 Signaling” section links TLR4 activation to inflammatory cytokine production. Page numbers are unavailable in our copy. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Additionally, it was reported that serotonin exacerbates, while oxytocin inhibits, proinflammatory cytokine expression in a mouse model of necrotizing enterocolitis104.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Supportedcites [104] Gross Margolis, K. et al. Enteric serotonin and oxytocin: endogenous regulation of severity in a murine model of necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol. 313, G386–G398 (2017). source
In the NEC-model results (Figs. 3 and 5), mice with increased serotonin signaling had higher intestinal proinflammatory cytokine expression, while mice lacking mucosal serotonin synthesis had smaller cytokine increases. The oxytocin results (Fig. 7) report lower intestinal IL-1β, IL-6, and TNF-α transcript levels in oxytocin-treated mice than in vehicle-treated mice. The measurements are of cytokine transcripts, which supports the citing sentence’s description of cytokine expression. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Growing evidence suggests that chronic stress impairs healthy gastrointestinal function, presenting as dysregulated intestinal motility, dysbiosis of the microbiota and initiation of low-grade inflammation94,95.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Partly supportedcites [94] Foster, J. A., Rinaman, L. & Cryan, J. F. Stress & the gut-brain axis: regulation by the microbiome. Neurobiol. Stress 7, 124–136 (2017). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) reports that chronic social-defeat stress shifts gut microbiota composition, and the IBS section (page unavailable) says stress affects colonic motor activity and can alter microbiota profiles. The paper discusses stress-related intestinal permeability and a proposed pathway to inflammatory responses, but its explicit example of low-grade chronic intestinal inflammation concerns a high-fat diet in mice, not chronic stress alone. Thus the claim’s inflammation component is not supported as stated. (LLM, conf=0.85)
- Partly supportedcites [95] Zhu, X. et al. Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Nat. Immunol. 24, 625–636 (2023). sourceExperimental — accuracy not yet measured
The Results sections on altered microbial communities and colonic T cells report gut-microbiota changes and increased colonic γδ17 T cells in stress-susceptible mice. Our copy does not establish dysregulated intestinal motility or the initiation of low-grade gastrointestinal inflammation, so it supports only part of the cited sentence. (LLM, conf=0.87)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“From the LH, these effects may be exerted through parasympathetic neurons in the DMV, as LH orexin neurons project to the DMV146 and parasympathetic input from the vagus nerve dampens hepatic inflammation147.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Supportedcites [146] Dergacheva, O., Yamanaka, A., Schwartz, A. R., Polotsky, V. Y. & Mendelowitz, D. Direct projections from hypothalamic orexin neurons to brainstem cardiac vagal neurons. Neuroscience 339, 47–53 (2016). source
The Discussion reports that stimulation of lateral hypothalamic orexin neurons excites those neurons and that stimulation of their fibers in the DMV evokes responses in cardiac vagal neurons there. This supports the projection attributed to citation 146. The separate claim about vagal input dampening hepatic inflammation is attached to citation 147, not this source. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [147] Nishio, T. et al. Hepatic vagus nerve regulates Kupffer cell activation via α7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis. J. Gastroenterol. 52, 965–976 (2017). Demonstrates that vagal stimulation of the liver decreases hepatic macrophage counts and cytokine expression in a model of non-alcoholic steatohepatitis. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Notably, PBMCs isolated from people with MDD exhibit greater TLR4 expression and responses to TLR4 stimulation110,111; thus, stress-induced endotoxemia may contribute to systemic inflammation that impinges on behaviour (Fig. 3).”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Partly supportedcites [110] Costi, S. et al. Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia. Transl. Psychiatry 11, 565 (2021). sourceExperimental — accuracy not yet measured
The Discussion reports greater release of immune markers from LPS-stimulated PBMCs in depressed subjects than in healthy controls, and the Introduction identifies LPS as a TLR4 agonist. The paper does not report greater TLR4 expression; its Discussion says cellular immune markers were not explored. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [111] Hung, Y.-Y., Kang, H.-Y., Huang, K.-W. & Huang, T.-L. Association between toll-like receptors expression and major depressive disorder. Psychiatry Res 220, 283–286 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Similarly, high pulmonary viral loads were observed in restraint-stressed mice; however, ablating PVH CRH+ neurons ameliorated the immunosuppression brought upon by stress69.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
What the sources say
- Supportedcites [69] Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022). Identifies brain circuits controlling monocyte, neutrophil and lymphocyte retention and mobilization from the bone marrow into circulation during acute stress. source
The Article passage describing Fig. 5 reports higher lung viral loads in restraint-stressed mice after influenza infection. The Article passage describing Fig. 5g–j also states that selective ablation of PVH CRH neurons prevented stress’s detrimental effects on lymphocyte numbers, antiviral antibody titres, and pulmonary viral loads. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“For example, excitation of CRH+ neurons in the PVH prevented pulmonary clearance of influenza A virus, implicating the HPA axis in this response69.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
What the sources say
- Supportedcites [69] Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022). Identifies brain circuits controlling monocyte, neutrophil and lymphocyte retention and mobilization from the bone marrow into circulation during acute stress. source
The Article section reports that selective stimulation of PVH CRH neurons reproduced the stress-associated increase in pulmonary influenza A viral loads in mice (Fig. 5j). The HPA-axis section reports that stimulating these neurons increased corticosterone, supporting the stated link to the HPA axis. The paper measures viral load rather than directly describing clearance. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Interestingly, sepsis results in acute activation of BNST-projecting neurons in the CeA, along with long-term anxiety-like behaviours in the open field test and light-dark box156. When a chemogenetic approach is used to inactivate BNST-projecting CeA neurons, these mice become protected against sepsis-induced sickness behaviours156.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
What the sources say
- Partly supportedcites [156] Bourhy, L. et al. Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours. Brain J. Neurol. 145, 1391–1409 (2022). sourceExperimental — accuracy not yet measured
The Results (Figures 1 and 7; page numbers unavailable) report acute activation of vBNST-projecting CeA neurons, long-term anxiety-like behaviour in the open field and light/dark box, and protection from later anxiety and exaggerated fear after pharmacogenetic silencing. They do not report that silencing protects against sepsis-induced sickness behaviour; Figure 1 says that sickness behaviour was transient and had disappeared by day 15. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
In the paper
“While acute stressors or infections activate the HPA axis, which stimulates the immune system to facilitate clearance of pathogens, chronic stress has immunosuppressive effects152.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
What the sources say
- Not checked — no full text of the sourcecites [152] Dhabhar, F. S. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 16, 300–317 (2009). source
direct- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“A pivotal study in 1987 reported that a subpopulation of people with viral hepatitis treated with interferon (IFN) α — a pro-inflammatory anti-viral cytokine13 — developed depression14, demonstrating that a pro-inflammatory molecule in the periphery could directly influence mood.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not checked — no full text of the sourcecites [14] Renault, P. F. et al. Psychiatric complications of long-term interferon alfa therapy. Arch. Intern. Med. 147, 1577–1580 (1987). source
- Not checked — no full text of the sourcecites [13] Katze, M. G., He, Y. & Gale, M. Viruses and interferon: a fight for supremacy. Nat. Rev. Immunol. 2, 675–687 (2002). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, this growing body of literature illustrates potential mechanisms through which stress signals are conveyed from the CNS to immune cells to regulate stress-relevant behaviours and co-morbid pathophysiology.”
§ Central regulation of stress-evoked peripheral immune responses > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There is now evidence that this peripheral inflammation contributes to the development of psychiatric symptoms, as well as to common co-morbidities of psychiatric disorders, such as metabolic syndrome and immunosuppression.”
§ Central regulation of stress-evoked peripheral immune responses > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies reveal a feedback loop between the nervous and immune systems that becomes hijacked during chronic stress to propagate psychiatric illness and inflammatory co-morbidities.”
§ Central regulation of stress-evoked peripheral immune responses > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“Consistent with this finding, individuals with prior hospitalizations for infections or autoimmune diseases display greater odds of subsequently developing depression, with multiple infections having additive effects15.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not checked — no full text of the sourcecites [15] Benros, M. E. et al. Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry 70, 812–820 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“For example, plasma IL6 levels increase following the Trier social stress test and this increase is greater in subjects with MDD than in healthy control subjects26.”
§ Central regulation of stress-evoked peripheral immune responses > Linking chronic stress and inflammation
What the sources say
- Not checked — no full text of the sourcecites [26] Pace, T. W. W. et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am. J. Psychiatry 163, 1630–1633 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“By five days after infection, PRV was detected in all regions of the spinal cord examined, along with the medulla, including the nucleus of the solitary tract (NTS), gigantocellular reticular nucleus (Gi), lateral paragigantocellular nucleus (LPGi), raphe pallidus nucleus (RPa), as well as in the ventral tegmental area (VTA), periaqueductal grey (PAG), locus coeruleus (LC), paraventricular nucleus”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [37] Dénes, A. et al. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience 134, 947–963 (2005). source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“To illustrate the ethological relevance of this circuit, mice were exposed to mild acrophobic stress, which activated CRH+ neurons in the PVH and CeA and heightened plasma cell production, an effect that was abrogated by splenic denervation80.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [80] Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020). Shows that optogenetic stimulation of stress-responsive CNS regions influences splenic plasma cell production. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In these experiments, PRV was detected in the thoracic spinal nucleus two days after infection and then, after three days, in stress-related brain and brain stem regions — including the PVH, LH, NTS and the dorsal motor nucleus of the vagus (DMV)80,81.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [80] Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020). Shows that optogenetic stimulation of stress-responsive CNS regions influences splenic plasma cell production. source
- Not checked — no full text of the sourcecites [81] Cano, G., Sved, A. F., Rinaman, L., Rabin, B. S. & Card, J. P. Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing. J. Comp. Neurol. 439, 1–18 (2001). source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“It is important to note that while chemogenetic and optogenetic tools have been impactful in uncovering CNS regulation of peripheral immunity, they do not perfectly emulate physiological neuronal activation during stress or the complex signaling that arises from multiple distinct populations of neurons.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“These effects were found to be mediated in part by the sympathetic nervous system, as 6-hydroxydopamine (6-OHDA) treatment to ablate sympathetic neurons in the periphery prevented the peripheral immune responses72.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [72] Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22, 940–944 (2016). Shows that stimulating VTA neurons enhances peripheral bactericidal function and improves social behaviour. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Furthermore, it has been reported that repeated social defeat decreases CXCL12 expression in the bone marrow, thereby increasing monocyte release from the bone marrow, in a mechanism blocked by adrenalectomy or by treatment with metyrapone, a corticosterone synthesis inhibitor65.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-bone marrow neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [65] Niraula, A., Wang, Y., Godbout, J. P. & Sheridan, J. F. Corticosterone production during repeated social defeat causes monocyte mobilization from the bone marrow, glucocorticoid resistance, and neurovascular adhesion molecule expression. J. Neurosci. 38, 2328–2340 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These connections were proven to be immunologically relevant as splenic plasma cell formation was promoted by their chemogenetic activation and diminished by their inhibition or ablation80.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [80] Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020). Shows that optogenetic stimulation of stress-responsive CNS regions influences splenic plasma cell production. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It was shown that optogenetic stimulation of CRH+ neurons in both the PVH and CeA is sufficient to increase the firing rate of the splenic nerve, indicating that CRH+ neurons are functionally connected to the spleen80.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [80] Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020). Shows that optogenetic stimulation of stress-responsive CNS regions influences splenic plasma cell production. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“was found to aggravate colitis symptoms triggered by TNB and stress, while the CRH antagonist astressin reduced these symptoms97.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [97] Million, M., Taché, Y. & Anton, P. Susceptibility of lewis and fischer rats to stress-induced worsening of TNB-colitis: protective role of brain CRF. Am. J. Physiol. 276, G1027–G1036 (1999). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, it is conceivable that central responses to stress contribute to inflammatory processes implicated in glucose metabolism, in addition to behavioural outcomes.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Moreover, central orexin A infusion inhibits high fat-induced hepatic inflammation and hyperphagia-induced systemic insulin resistance141,142.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Not checked — no full text of the sourcecites [141] Tsuneki, H. et al. Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity. Cell Rep. 41, 111497 (2022). Shows that administration of intracerebroventricular orexin or chemogenetic activation of orexin-expressing neurons in the LH dampens hepatic endoplasmic reticulum stress and non-alcoholic steatohepatitis. source
- Not checked — no full text of the sourcecites [142] Tsuneki, H. et al. Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice. Diabetes 64, 459–470 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the spleen, there is evidence that vagus nerve stimulation triggers neurons in the splenic nerve to release noradrenaline, which is detected by the β2-adrenergic receptor on splenic choline acetyltransferase-expressing (ChAT)+ T cells89.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
What the sources say
- Not checked — no full text of the sourcecites [89] Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stress has also been shown to exacerbate symptoms of experimental colitis in rodents, with some evidence that this is centrally regulated.”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This implies that chronic psychosocial stress dampens orexin signaling in the brain, leading to hepatic inflammation, macrophage infiltration, hyperglycemia and depression- and anxiety-like behaviour.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In addition to adipose tissue, the liver plays a critical role in stress-elicited metabolic abnormalities, with chronic foot shock and restraint stress inhibiting glycogenesis and upregulating hepatic gluconeogenesis134.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Not checked — no full text of the sourcecites [134] Marik, P. E. & Bellomo, R. Stress hyperglycemia: an essential survival response! Crit. Care Med. 41, e93–e94 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, it is possible that stress signals in the CNS are transmitted to the gut where they initiate inflammation that consequently influences behaviour (Fig. 2).”
§ Central regulation of stress-evoked peripheral immune responses > Brain-to-spleen and -gut neurocircuits
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“This suggests that brain–liver innervation is dependent on the sympathetic nervous system139; however, the liver also receives parasympathetic innervation via the vagus nerve140.”
§ Central regulation of stress-evoked peripheral immune responses > Brain regulation of immunometabolism
What the sources say
- Not checked — no full text of the sourcecites [139] Kreier, F. et al. Tracing from fat tissue, liver, and pancreas: a neuroanatomical framework for the role of the brain in type 2 diabetes. Endocrinology 147, 1140–1147 (2006). source
- Not checked — no full text of the sourcecites [140] Mizuno, K. & Ueno, Y. Autonomic nervous system and the liver. Hepatol. Res. 47, 160–165 (2017). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This exemplifies how stress is a context-dependent adaptation that is necessary for the body to appropriately respond to threats, but becomes maladaptive and pathological when left unresolved.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies demonstrate bi-directional communication between the brain and body, whereby chronic stress suppresses host defense against pathogens and these infections subsequently activate brain regions that promote anxiety- or depression-like behaviour (Fig. 2).”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In parallel, anther study demonstrated that activating the brain’s reward systems by chemogenetically exciting TH+ VTA neurons enhances peripheral bactericidal action against E. coli, while promoting social interaction72.”
§ Central regulation of stress-evoked peripheral immune responses > Brain signals and immunosuppression
What the sources say
- Not checked — no full text of the sourcecites [72] Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22, 940–944 (2016). Shows that stimulating VTA neurons enhances peripheral bactericidal function and improves social behaviour. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The particular neuronal groups in descending brain-to-body pathways that control systemic immunity are less understood than central control of autonomic functions.
“the specific neuronal populations involved in top-down brain-to-body circuits regulating systemic immune responses are less well understood”
The paper relies on this without support.
The cellular and molecular mechanisms of the bidirectional brain-body relationship that governs psychiatric and inflammatory disease pathogenesis need further investigation.
“the cellular and molecular mechanisms underlying this bi-directional relationship between the brain and body that regulates the pathogenesis of both psychiatric and inflammatory conditions requires further interrogation”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These results suggest that adrenalectomy-model mice fail to exhibit the typical stress-induced immune cell mobilization response, which is characterized by lymphocyte suppression and myeloid cell expansion [3,17,42].”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“RNA-seq analysis revealed increased systemic inflammation, marked by up-regulation of pro-inflammatory cytokines like Cxcl10 and Il-6”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [3]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“While acute stress responses are essential for survival, dysregulation induced by chronic stress is a major risk factor for debilitating psychiatric disorders, including disorder and anxiety [3].”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [3]
Citations
Cites
Diagnostic and Statistical Manual of Mental Disorders
American Psychiatric Association (2013) · doi:10.1176/appi.books.9780890425596 · Cited by 116,369
Obesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,526
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395
Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319451 · Cited by 6,760
A Meta-Analysis of Cytokines in Major Depression
Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E. K., & Lanctôt, K. L. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.09.033 · Cited by 4,729
Cytokine-mediated regulation of CXCR4 expression in human neutrophils
Nagase, H., Miyamasu, M., Yamaguchi, M., Imanishi, M., Tsuno, N. H., Matsushima, K., Yamamoto, K., Morita, Y., & Hirai, K. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.71.4.711 · Cited by 4,713
Type 2 diabetes as an inflammatory disease
Donath, M. Y., & Shoelson, S. E. (2011) · Nature Reviews Immunology · doi:10.1038/nri2925 · Cited by 3,737
Psychological stress and the human immune system: a meta-analytic study of 30 Years of inquiry
Segerstrom, S. C., & Miller, G. E. (2004) · Psychological Bulletin · doi:10.1037/0033-2909.130.4.601 · Cited by 3,334
Cited by
Sorted by citations
Neurobiological basis of stress resilience
Nestler, E. J., & Russo, S. J. (2024) · Neuron · doi:10.1016/j.neuron.2024.05.001 · Cited by 148
Self-citationNeurobiology and systems biology of stress resilience
Kalisch, R., Russo, S. J., & Müller, M. B. (2024) · Physiological Reviews · doi:10.1152/physrev.00042.2023 · Cited by 149
Self-citationJiao, W., Lin, J., Deng, Y., Ji, Y., Liang, C., Wei, S., Xi, J., & Yan, F. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03312-3 · Cited by 132
Organ-specific sympathetic innervation defines visceral functions
Wang, T., Teng, B., Yao, D. R., Gao, W. F., & Oka, Y. (2024) · Nature · doi:10.1038/s41586-024-08269-0 · Cited by 70
Liu, W., Hou, S., Zhang, Q., Yu, S., Zhao, L., Li, H., Wang, Y., & Liu, X. (2025) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2025.105468 · Cited by 56
Metadata
- Authors
- Chan, K. L., Poller, W. C., Swirski, F. K., & Russo, S. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Chan, Kenny L.
- Russo, Scott J.
- Venue
- Nature Reviews Neuroscience
- Published
- 2023-08-25
- Volume
- 24
- Issue
- 10
- Pages
- 591-604
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC10848316
- OpenAlex
- W4386154638
- Cited by
- 207
- References
- 216
- Citations by year
- 2026: 85 · 2025: 74 · 2024: 41 · 2023: 7
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cure Alzheimer's Fund
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- Canadian Institutes of Health Research
- National Heart, Lung, and Blood Institute (R35HL135752, P01HL131478, P01HL142494)
- National Institute of Mental Health (R01MH104559, R01MH127820, R01MH133299)
- National Institute of Diabetes and Digestive and Kidney Diseases (K99DK137037)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Keywords
- stress, systemic inflammation, mental illness, major depressive disorder, anxiety, hematopoiesis, neuroimmune circuits, autonomic nervous system, neuroendocrine pathways, retrograde tracing, chemogenetics, optogenetics, peptide hormones, bone marrow, spleen, intestine, adipose tissue, liver, metabolic syndrome, immunosuppression
- MeSH terms
- Adipose Tissue, Anxiety, Major Depressive Disorder, Humans, Immunity, Inflammation
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.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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.
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