Central regulation of stress-evoked peripheral immune responses

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.”

What the sources say

• Disputed

  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.

  cites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [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

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.”

What the sources say

• Disputed

  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.

  cites [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
• Supported

  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)

  cites [85] Monteiro, S. et al. Splenic sympathetic signaling contributes to acute neutrophil infiltration of the injured spinal cord. J. Neuroinflammation 17, 282 (2020). source

In the paper

“It is commonly reported that chronic stress compromises immune function, increasing susceptibility to infection149.”

What the sources say

• Partly supported

  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)

  cites [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

In the paper

“Notably, chronic stress synergizes with high fat feeding in mice to exacerbate insulin insensitivity, as well as adipose tissue inflammation126.”

What the sources say

• Supported

  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)

  cites [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

In the paper

“In turn, somatic states are sensed by the CNS to shape and guide behaviour2.”

What the sources say

• Supported

  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)

  cites [2] Savitz, J. & Harrison, N. A. Interoception and inflammation in psychiatric disorders. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 3, 514–524 (2018). source

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.”

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 supported

  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)

  cites [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

In the paper

“Perpetuating this cycle, there is evidence that depression compromises the immune system and heightens the risk of infection18,19.”

What the sources say

• Partly supported

  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)

  cites [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
• ?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

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”

What the sources say

• Partly supported

  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)

  cites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourceExperimental — accuracy not yet measured
• ?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 supported

  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)

  cites [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
• ?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

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.”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

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.”

What the sources say

• Partly supported

  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)

  cites [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

In the paper

“whereas it activates LC neurons in resilient mice to promote resilience to social avoidance behaviour44–46.”

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
• Supported

  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)

  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). source
• ?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

In the paper

“Moreover, stress activates neurons in the lateral septum to blunt social reward in susceptible mice43”

What the sources say

• Supported

  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)

  cites [43] Li, L. et al. Social trauma engages lateral septum circuitry to occlude social reward. Nature 613, 696–703 (2023). source

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.”

What the sources say

• Partly supported

  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)

  cites [33] Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). sourceExperimental — accuracy not yet measured
• ?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 supported

  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)

  cites [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
• ?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

In the paper

“with the PVH being a key component of the HPA axis that can also coordinate stress responses through neuroendocrine mechanisms52.”

What the sources say

• Supported

  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)

  cites [52] Herman, J. P. et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr. Physiol. 6, 603–621 (2016). source

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.”

What the sources say

• Supported

  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)

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

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.”

What the sources say

• Supported

  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)

  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. source

In the paper

“which normally inhibits haematopoiesis and retains neutrophils and monocytes within the bone marrow62–64.”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

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.”

What the sources say

• Partly supported

  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)

  cites [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

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.”

What the sources say

• Supported

  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)

  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. source

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.”

What the sources say

• Supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

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.”

What the sources say

• Partly supported

  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)

  cites [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
• ?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

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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?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

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”

What the sources say

• Supported

  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)

  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. source

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.”

What the sources say

• Partly supported

  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)

  cites [7] Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [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

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.”

What the sources say

• Supported

  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)

  cites [71] Sawant, K. V. et al. Chemokine CXCL1 mediated neutrophil recruitment: role of glycosaminoglycan interactions. Sci. Rep. 6, 33123 (2016). source
• Supported

  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)

  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. source

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.”

What the sources say

• Supported

  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)

  cites [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 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.”

What the sources say

• Supported

  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)

  cites [102] Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017). source
• Supported

  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)

  cites [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

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.”

What the sources say

• Partly supported

  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)

  cites [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

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.”

What the sources say

• Supported

  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)

  cites [95] Zhu, X. et al. Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Nat. Immunol. 24, 625–636 (2023). source

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.”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [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
• ?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 supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [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

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.”

What the sources say

• Partly supported

  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)

  cites [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
• Supported

  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)

  cites [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

In the paper

“Additionally, it was reported that serotonin exacerbates, while oxytocin inhibits, proinflammatory cytokine expression in a mouse model of necrotizing enterocolitis104.”

What the sources say

• Supported

  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)

  cites [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 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.”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

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.”

What the sources say

• Supported

  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)

  cites [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
• ?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

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).”

What the sources say

• Partly supported

  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)

  cites [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
• ?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

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.”

What the sources say

• Supported

  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)

  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. source

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.”

What the sources say

• Supported

  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)

  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. source

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.”

What the sources say

• Partly supported

  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)

  cites [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

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.”

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

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.”

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

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.”

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.”

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.”

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.”

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

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.”

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

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”

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

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.”

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

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.”

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

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.”

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.”

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

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.”

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

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.”

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

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.”

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

In the paper

“was found to aggravate colitis symptoms triggered by TNB and stress, while the CRH antagonist astressin reduced these symptoms97.”

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

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.”

In the paper

“Moreover, central orexin A infusion inhibits high fat-induced hepatic inflammation and hyperphagia-induced systemic insulin resistance141,142.”

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

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.”

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

In the paper

“Stress has also been shown to exacerbate symptoms of experimental colitis in rodents, with some evidence that this is centrally regulated.”

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.”

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.”

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

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).”

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.”

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

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.”

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).”

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.”

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