Central regulation of stress-evoked peripheral immune responses

Circulating pro-inflammatory cytokines and chemokines are higher in people with MDD than in controls.

“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.”

• cites [21] Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010). sourceNot checked — no full text of the source
• cites [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). sourcePartly supported

  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)

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• cites [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). sourceNot checked — no full text of the source
• cites [24] Simon, N. M. et al. A detailed examination of cytokine abnormalities in major depressive disorder. Eur. Neuropsychopharmacol. 18, 230–233 (2008). sourceNot checked — no full text of the source
• cites [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). sourcePartly supported

  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)

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Anxiety and major depressive disorder, as stress-linked psychiatric conditions, are accompanied by systemic inflammation.

“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”

• cites [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). sourcePartly supported

  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)

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• cites [5] Dantzer, R. Neuroimmune Interactions: from the brain to the immune system and vice versa. Physiol. Rev. 98, 477–504 (2018). sourcePartly supported

  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)

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• cites [6] Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386–1393 (2015). sourcePartly supported

  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)

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• cites [7] Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). sourcePartly supported

  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)

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• cites [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). sourceNot checked — no full text of the source

Cytokine and chemokine levels often rise sharply when a person is exposed to a stressor and then fall as time passes from the stressful event.

“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).”

• cites [21] Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010). sourceNot checked — no full text of the source
• cites [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). sourceCould not verify

  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)

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• cites [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). sourceNot checked — no full text of the source
• cites [24] Simon, N. M. et al. A detailed examination of cytokine abnormalities in major depressive disorder. Eur. Neuropsychopharmacol. 18, 230–233 (2008). sourceNot checked — no full text of the source
• cites [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). sourcePartly supported

  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)

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People with MDD frequently also have immune and inflammatory conditions such as rheumatoid arthritis, cardiovascular disease, metabolic syndrome and IBD.

“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.”

• cites [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). sourceNot checked — no full text of the source
• cites [10] Halaris, A. Inflammation-associated co-morbidity between depression and cardiovascular disease. Curr. Top. Behav. Neurosci. 31, 45–70 (2017). sourceNot checked — no full text of the source
• cites [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). sourcePartly supported

  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)

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• cites [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). sourceCould not verify

  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)

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People with stress-related disorders such as MDD show chronic low-grade systemic inflammation.

“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.”

• cites [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). sourcePartly supported

  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)

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• cites [5] Dantzer, R. Neuroimmune Interactions: from the brain to the immune system and vice versa. Physiol. Rev. 98, 477–504 (2018). sourceSupported
  Experimental — accuracy not yet measured
• cites [6] Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386–1393 (2015). sourcePartly supported

  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)

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• cites [7] Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). sourceSupported
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• cites [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). sourceNot checked — no full text of the source

Several brain regions that innervate bone marrow have been linked to stress responses, reward processing and the pathogenesis of depression and anxiety disorders.

“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.”

• cites [39] Zhong, P. et al. HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. eLife 7, e32420 (2018). sourcePartly supported

  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)

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• cites [40] Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013). sourceSupported
• cites [41] Kumar, P. et al. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology 43, 1581–1588 (2018). sourcePartly supported

  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)

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• cites [42] Nestler, E. J. & Carlezon, W. A. The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159 (2006). sourceNot checked — no full text of the source
• cites [43] Li, L. et al. Social trauma engages lateral septum circuitry to occlude social reward. Nature 613, 696–703 (2023). sourcePartly supported

  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)

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• cites [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). sourceNot checked — no full text of the source
• cites [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). sourcePartly supported

  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)

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• cites [46] Isingrini, E. et al. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat. Neurosci. 19, 560–563 (2016). sourceNot checked — no full text of the source
• cites [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). sourceNot checked — no full text of the source
• cites [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). sourcePartly supported

  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)

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Dopaminergic projections from the VTA to NAc, PFC, amygdala and hippocampus that regulate reward and aversion are dysregulated in MDD and in rodent chronic stress models.

“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.”

• cites [39] Zhong, P. et al. HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. eLife 7, e32420 (2018). sourcePartly supported

  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)

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• cites [40] Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013). sourcePartly supported

  “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)

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• cites [41] Kumar, P. et al. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology 43, 1581–1588 (2018). sourcePartly supported

  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)

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• cites [42] Nestler, E. J. & Carlezon, W. A. The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159 (2006). sourceNot checked — no full text of the source

PRV tracing from mouse bone marrow identified similar CNS regions.

“Of note, similar CNS regions were identified using PRV tracing from bone marrow in mice38, suggesting that these neurocircuits are conserved across species.”

• cites [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). sourceSupported

The neurocircuits connecting bone marrow to the CNS are conserved across species.

“Of note, similar CNS regions were identified using PRV tracing from bone marrow in mice38, suggesting that these neurocircuits are conserved across species.”

• cites [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). sourceSupported

Chronic stress activates hypothalamic regions including PVH, LH and ARH in rodents.

“Similarly, regions of the hypothalamus, including the PVH, LH and ARH, are activated by chronic stress in rodents47–51”

• cites [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). sourceNot checked — no full text of the source
• cites [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). sourcePartly supported

  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)

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• cites [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). sourcePartly supported

  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)

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• cites [50] Yuan, Y. et al. Reward inhibits paraventricular CRH neurons to relieve stress. Curr. Biol. 29, 1243–1251 (2019). sourceNot checked — no full text of the source
• cites [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). sourceNot checked — no full text of the source

Some rodents exposed to CVS or CSDS have higher blood levels of pro-inflammatory cytokines and chemokines than unstressed controls and stress-resilient mice.

“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”

• cites [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). sourcePartly supported

  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)

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• cites [27] Brydon, L. et al. Psychological stress activates interleukin-1beta gene expression in human mononuclear cells. Brain Behav. Immun. 19, 540–546 (2005). sourceNot checked — no full text of the source
• cites [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). sourceNot checked — no full text of the source
• cites [29] Tagliari, B. et al. Chronic variable stress alters inflammatory and cholinergic parameters in hippocampus of rats. Neurochem. Res. 36, 487–493 (2011). sourceNot checked — no full text of the source
• cites [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). sourcePartly supported

  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)

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Animals exposed to chronic stress are more prone to develop inflammatory conditions such as experimental autoimmune encephalitis, colitis, atherosclerosis and diabetes.

“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.”

• cites [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). sourceNot checked — no full text of the source
• cites [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). sourceSupported
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• cites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourcePartly supported

  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)

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• cites [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). sourcePartly supported

  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)

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The apparent contradiction between PVH stimulation-induced monocyte retention and chronic stress effects may reflect different monocyte mobilization dynamics in acute stress or HPA activation versus chronic stress.

“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.”

• cites [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). sourceSupported

The effect of PVH CRH+ neuron manipulation on leukocyte retention depends on the HPA axis, since adrenalectomy prevents the changes.

“Further, this effect was found to be HPA axis-dependent, as adrenalectomy prevented these changes69.”

• cites [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. sourceSupported

Because PVH and CeA send inputs to the DMV, the DMV may integrate signals from stress-responsive brain regions to coordinate peripheral immune responses.

“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.”

• cites [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). sourceSupported
• cites [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). sourceNot checked — no full text of the source

The brain-spleen axis is a direct neural pathway through which cognition and emotion can control peripheral immunity during stress.

“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.”

• cites [79] Wei, Y. et al. Brain-spleen axis in health and diseases: a review and future perspective. Brain Res. Bull. 182, 130–140 (2022). sourcePartly supported

  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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Noradrenaline released by sympathetic fibres in the bone marrow niche suppresses CXCL12 expression.

“Mechanistically, it has been shown that signaling by noradrenaline released by these sympathetic fibres within the bone marrow niche suppresses expression of CXCL1233”

• cites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourceSupported

Cytokines such as IL6 and TNF can directly induce depressive-like behaviours including social avoidance, reduced sucrose preference and forced swim immobility.

“Consequently, these cytokines can directly induce depressive-like behaviours (including social avoidance, reduced sucrose preference and immobility in the forced swim test)25,73.”

• cites [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). sourcePartly supported

  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)

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• cites [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). sourceNot checked — no full text of the source

Transplanting HSCs from stress-susceptible mice into naïve mice causes the recipients to become socially averse after a subthreshold social defeat that normally does not produce depressive-like behaviour.

“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.”

• cites [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). sourceSupported

Bone marrow has dense sympathetic innervation that helps mobilize leukocytes into circulation during stress and under homeostatic conditions.

“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.”

• cites [60] Hanoun, M., Maryanovich, M., Arnal-Estapé, A. & Frenette, P. S. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86, 360–373 (2015). sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites [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). sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Reduced claudin-5 permits pro-inflammatory leukocytes or their secreted factors to enter brain parenchyma and affect neuronal excitability.

“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).”

• cites [7] Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites [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). sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites [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). sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Intracisternal orexin can prevent ethanol-induced gastric mucosal damage.

“Similarly, intracisternal injection of orexin (which is largely produced by cells in the LH) can prevent ethanol-induced gastric mucosal damage99.”

• cites [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). sourceSupported

Bilateral electrolytic lesions of the PVH cause a significant reduction in adipose tissue ILC2s.

“The authors then introduced electrolytic lesions bilaterally in the PVH to ablate its function, which caused a significant reduction in adipose tissue ILC2s133.”

• cites [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. sourcePartly supported

  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)

  Experimental — accuracy not yet measured

A bi-directional gut-brain circuit links the insular cortex to colon inflammation.

“Interestingly, a recent study demonstrated a bi-directional gut–brain circuit linking the insular cortex to colon inflammation101.”

• cites [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. sourceSupported

Non-specific inhibition of insular cortex activity can directly alleviate peripheral inflammation in the gut.

“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.”

• cites [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. sourcePartly supported

  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)

  Experimental — accuracy not yet measured

A brain-liver axis may link chronic stress to hyperglycemia via hepatic inflammation.

“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.”

• cites [138] Morinaga, H. et al. Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice. Diabetes 64, 1120–1130 (2015). sourceSupported

Optogenetic activation of TH+ C1 neurons in the medulla reproduces this protective mechanism.

“This mechanism was re-capitulated by optogenetically activating tyrosine hydroxylase-expressing (TH+) C1 neurons in the medulla88.”

• cites [88] Abe, C. et al. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat. Neurosci. 20, 700–707 (2017). sourceSupported

Stress is a major risk factor for irritable bowel syndrome.

“These symptoms are common features of IBS, for which stress is a major risk factor96.”

• cites [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). sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Inflammatory intestinal leukocytes, including IL17+ T cells and mast cells, may contribute to breakdown of the intestinal epithelial barrier and downregulation of CLDN5, OCLN, and ZO-2.

“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.”

• cites [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). sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites [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). sourcePartly supported

  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)

  Experimental — accuracy not yet measured

A brain-adipose circuit controls ILC2 function in adipose tissue.

“One recent study defined a brain–adipose circuit that controls ILC2 function in adipose tissue133.”

• cites [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. sourceSupported

Insular cortex neurons connected to the gut can encode an immunological memory of a peripheral inflammatory state.

“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.”

• cites [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. sourceSupported

Reactivation of insular cortex neurons activated by DSS-induced colitis recapitulates aspects of colonic inflammation, including increased leukocytes, T cell activation, and elevated IL6 and TNF.

“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.”

• cites [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. sourceSupported

Stressed mice are more susceptible to infections by pathogens such as Escherichia coli, influenza, and SARS-CoV-2, similar to humans with MDD.

“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.”

• cites [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. sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites [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). sourceNot checked — no full text of the source
• cites [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). sourceSupported

Optogenetic stimulation of PVH CRH+ neurons shifts circulating leukocytes to an immunosuppressed profile with lower dendritic cells expressing MHC class II, natural killer cells, B cells, and CD4+ T cells.

“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.”

• cites [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. sourceSupported

Psychological states can affect peripheral physiological processes such as metabolism, host defense and cardiovascular function.

“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.”

• cites [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). sourceNot checked — no full text of the source

Chemogenetic or optogenetic manipulation, and intracerebroventricular peptide hormone administration, have been used to control somatic immune responses.

“Moreover, we highlight studies that have used chemogenetic or optogenetic manipulation, or intracerebroventricular administration of peptide hormones, to control somatic immune responses.”

Specific brain and spinal regions and their neuronal populations react to stress and send signals to peripheral tissues through autonomic or neuroendocrine routes to affect immune function.

“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.”

Retrograde tracing studies have mapped neural circuits connecting the brain to the bone marrow, spleen, gut, adipose tissue and liver.

“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.”

Early research identified autonomic innervation of immune organs, including the bone marrow.

“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.”

• cites [35] Felten, D. L. & Felten, S. Y. Sympathetic noradrenergic innervation of immune organs. Brain Behav. Immun. 2, 293–300 (1988). sourceNot checked — no full text of the source

In a subset of vulnerable mice, peripheral inflammation follows directly from psychosocial stress.

“This suggests that peripheral inflammation is a direct consequence of psychosocial stress in a subset of vulnerable mice.”

Serum cytokine profiles in MDD overlap substantially with those in IBD, metabolic syndrome and coronary artery disease, though the concentrations are often lower.

“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).”

• cites Table 1Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Four days after PRV Bartha injection into the femoral bone marrow of male Wistar rats, GFP was found in lumbar sympathetic chain ganglia, the thoracic spinal cord intermediolateral cell column and the ventrolateral medulla.

“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.”

• cites [37] Dénes, A. et al. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience 134, 947–963 (2005). sourceNot checked — no full text of the source

Animal stress models such as CVS and CSDS reproduce biological and behavioural features linked to anxiety and depression.

“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).”

• cites Box 1Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Six days after PRV infection, the virus had reached BNST, ARH, amygdala, hippocampus, insular cortex, septum and motor cortex.

“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.”

• cites [37] Dénes, A. et al. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience 134, 947–963 (2005). sourceNot checked — no full text of the source

Chemogenetic activation of dopaminergic VTA neurons increases circulating B cell numbers.

“Additionally, chemogenetic activation of dopaminergic neurons in the VTA, which encode reward behaviour, increased circulating B cell numbers72.”

• cites [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. sourceNot checked — no full text of the source

Four days after spleen PRV infection, virus was found in CeA, BNST, LC, lateral septum, insular cortex, motor cortex, ARH and DMH.

“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.”

• cites [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. sourceNot checked — no full text of the source
• cites [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). sourceNot checked — no full text of the source

Among spleen-innervating brain regions, PVH and CeA have some of the most projections to the splenic nerve.

“Of the spleen-innervating brain regions, the PVH and CeA are among those with the most projections to the splenic nerve.”

• cites [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. sourceNot checked — no full text of the source

Brain activity can regulate leukocyte production, retention and exit from bone marrow under stress through the HPA axis, autonomic nervous system and peripheral chemokines.

“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).”

Intracerebroventricular AGRP increases TNF expression in epididymal white adipose tissue by suppressing sympathetic nerve activity.

“Direct intracerebroventricular injections of AGRP reportedly increases TNF expression in epididymal white adipose tissue by suppressing sympathetic nerve activity131.”

• cites [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). sourceNot checked — no full text of the source

Chronic restraint stress aggravates DSS-induced colitis through an HPA-axis-dependent pathway.

“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.”

• cites [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. sourceNot checked — no full text of the source

Stress-induced endotoxemia may contribute to systemic inflammation that impinges on behaviour.

“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).”

A pathway exists through which stress impacts signals from LH orexin neurons to parasympathetic nerves via the DMV to cause hepatic inflammation, which contributes to insulin resistance.

“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).”

PVH activity may in part normalize systemic glucose homeostasis via a mechanism mediated by adipose tissue ILC2s.

“This implies that PVH activity may in part normalize systemic glucose homeostasis via a mechanism mediated by adipose tissue ILC2s (Fig. 2).”

The enteric nervous system influences intestinal immunity.

“Growing data suggest that the enteric nervous system influences intestinal immunity.”

Metabolic inflammation, defined as leukocyte infiltration and pro-inflammatory signaling in insulin-responsive tissues, promotes systemic hyperglycemia.

“Moreover, metabolic inflammation — leukocyte infiltration and pro-inflammatory signaling in insulin-responsive tissues — promotes systemic hyperglycemia113.”

• cites [113] Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011). sourceNot checked — no full text of the source

Gastrointestinal inflammation and homeostasis can be modulated by the central nervous system.

“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.”

Specific neuronal populations may regulate adipose tissue physiology, including inflammation.

“These findings highlight specific neuronal populations that may regulate adipose tissue physiology, including inflammation.”

These ChAT+ T cells produce acetylcholine, which suppresses pro-inflammatory cytokine production by splenic macrophages through the α7 receptor.

“Consequently, these T cells produce acetylcholine, which suppresses pro-inflammatory cytokine production by splenic macrophages via the α7”

• cites [89] Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011). sourceNot checked — no full text of the source

Different segments of the gastrointestinal tract may receive inputs from common central nervous system regions.

“Thus, different segments of the gastrointestinal tract may receive inputs from common CNS regions.”

Specific neuronal populations in the NTS and hypothalamus signal to both adipose tissue and liver, either separately or simultaneously.

“Thus, there are specific neuronal populations in the NTS and hypothalamus that signal to both the adipose tissue and liver, either separately or simultaneously.”

Gut inflammation can contribute to stress-relevant behaviours.

“There is also evidence indicating that gut inflammation can contribute to stress-relevant behaviours.”

T cells produce acetylcholine, which suppresses pro-inflammatory cytokine production by splenic macrophages through the α7 nicotinic acetylcholine receptor.

“Consequently, these T cells produce acetylcholine, which suppresses pro-inflammatory cytokine production by splenic macrophages via the α7 nicotinic acetylcholine receptor89.”

• cites [89] Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011). sourceNot checked — no full text of the source

Under chronic stress, the hypothalamus, amygdala, and insula are pivotal structures that integrate central nervous system signals and propagate them to the periphery largely via the autonomic nervous system and HPA axis.

“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.”