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  • Depressive-like phenotype evoked by lifelong nutritional omega-3 deficiency in female rats: crosstalk among kynurenine, Toll-like receptors and amyloid beta oligomers
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-24
    Maria Grazia Morgese; Stefania Schiavone; Angela Bruna Maffione; Paolo Tucci; Luigia Trabace

    Depression is one of the most common psychiatric diseases and the prevalence of depressive symptoms in women is almost twice compared to men, although the reasons of this gender difference are not fully understood yet. Recently, soluble amyloid beta (Aβ)1-42 peptide has been receiving great importance in the development of depression, also considering that depression is highly comorbid with Alzheimer’s disease and other neurodegenerative illnesses. The central role played by Aβ in the development of depressive-like symptoms in rodents has been evidenced in environmental rodent model of depression. Indeed, we have previously found that lifelong exposure to n-3 polyunsaturated fatty acids (PUFA) deficient diet in female rats at 8 weeks of life leads to depressive like- symptoms and higher susceptibility to stress associated with increased Aβ levels. In order to understand if such effects were maintained over time, rats were exposed to the same diet regimen until 6 or 21 weeks of life. We found that both timepoints of exposure to n-3 PUFA deficient diet lead to depressive-like phenotype. Furthermore, a significant alteration in brain neurochemistry was retrieved. In particular, in hippocampal area a significant reduction in serotonin (5-HT) and noradrenaline (NA) content was evidenced. Considering the prominent role of NA in counterbalancing neuroinflammatory state, we quantified in the same brain area kynurenine levels, a metabolite of tryptophan implicated in inflammatory state and brought to the fore for its implication in depression. Interestingly, kynurenine levels were significantly increased in hippocampus (HIPP) of female rats exposed to such diet. In addition, lifelong deficiency in n-3 PUFA dietary intake led to systemic increase of corticosterone, hence hypothalamic pituitary adrenal (HPA) axis hyperactivation, and higher proinflammatory cytokine production. Increased production of kynurenine, along with HPA axis hyperactivation, have been associated with immune system modulation, particularly through Toll-like receptor type 2 (TLR2) and Toll-like receptor type 4 (TLR4) involvement. In addition, it has been shown that soluble forms of Aβ1-42 can induced depressive like-phenotype in consequence to a crosstalk between TLR4 and 5-HTergic system. Thus, considering that in this model we have previously reported increased plasma Aβ1-42 level, we quantified TRL2 and 4 expression in HIPP of treated rats. We found that chronic exposure to a diet characterized by very low n-3 PUFA content led to higher expression of TLR2 and TLR4 in HIPP of female treated rats, indicating an activation of the immune system and was accompanied by increased expression of oligomeric Aβ. Taken together, our data indicate that the pro-depressive effects induced by a diet poor in n-3 PUFA can be attributable to a shift of hippocampal tryptophan metabolism toward inflammatory metabolite ultimately corresponding to altered immune response and increased Aβ oligomerization.

    更新日期:2020-01-24
  • A role for glia maturation factor dependent activation of mast cells and microglia in MPTP induced dopamine loss and behavioural deficits in mice
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-23
    Govindhasamy Pushpavathi Selvakumar; Mohammad Ejaz Ahmed; Ramasamy Thangavel; Duraisamy Kempuraj; Iuliia Dubova; Sudhanshu P. Raikwar; Smita Zaheer; Shankar S. Iyer; Asgar Zaheer

    The molecular mechanism mediating degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease (PD) is not yet fully understood. Previously, we have shown the contribution of glia maturation factor (GMF), a proinflammatory protein in dopaminergic neurodegeneration mediated by activation of mast cells (MCs). In this study, methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal neurodegeneration and astro-glial activations were determined by western blot and immunofluorescence techniques in wild type (WT) mice, MC-deficient (MC-KO) mice and GMF-deficient (GMF-KO) mice, with or without MC reconstitution before MPTP administration. We show that GMF-KO in the MCs reduces the synergistic effects of MC and Calpain1 (calcium-activated cysteine protease enzyme)-dependent dopaminergic neuronal loss that reduces motor behavioral impairments in MPTP-treated mouse. Administration of MPTP increase in calpain-mediated proteolysis in nigral dopaminergic neurons further resulting in motor decline in mice. We found that MPTP administered WT mice exhibits oxidative stress due to significant increases in the levels of malondialdehyde, superoxide dismutase and reduction in the levels of reduced glutathione and glutathione peroxidase activity as compared with both MC-KO and GMF-KO mice. The number of TH-positive neurons in the ventral tegmental area, substantia nigra and the fibers in the striatum were significantly reduced while granulocyte macrophage colony-stimulating factor (GM-CSF), MC-Tryptase, GFAP, IBA1, Calpain1 and intracellular adhesion molecule 1 expression were significantly increased in WT mice. Similarly, tyrosine hydroxylase, dopamine transporters and vesicular monoamine transporters 2 proteins expression were significantly reduced in the SN of MPTP treated WT mice. The motor behavior as analyzed by rotarod and hang test was significantly reduced in WT mice as compared with both the MC-KO and GMF-KO mice. We conclude that GMF-dependent MC activation enhances the detrimental effect of astro-glial activation-mediated oxidative stress and neuroinflammation in the midbrain, and its inhibition may slowdown the progression of PD.

    更新日期:2020-01-23
  • Baseline high levels of complement component 4 predict worse clinical outcome at 1-year follow-up in first-episode psychosis
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-22
    Valeria Mondelli; Marta Di Forti; B. Paul Morgan; Robin M. Murray; Carmine M. Pariante; Paola Dazzan

    Background Recent evidence has highlighted the potential role of complement component 4 (C4) in the development of schizophrenia. However, it remains unclear whether C4 is also relevant for clinical outcome and if it could be considered a possible therapeutic target. The aim of this naturalistic longitudinal study was to investigate whether baseline levels of C4 predict worse clinical outcome at 1-year follow-up in patients with first episode psychosis. Methods Twenty-five patients with first episode psychosis were assessed at baseline and followed-up prospectively for their clinical outcome at 1 year from baseline assessment. Concentrations of complement component 4 (C4) were measured using ELISA methods from baseline serum samples. Twelve patients were classified as non-responders and 13 as responders. ANCOVA analyses were conducted to investigate differences in baseline C4 levels between responders and non-responders at 1-year covarying for baseline severity of symptoms and for levels of C reactive protein. Results Non-responders show significantly higher baseline C4 levels compared with responders when controlling for baseline psychopathology and baseline levels of C reactive protein (552.5±31.3 vs 437.6±25.5 mcg/ml; p=0.008). When investigating the ability of C4 levels to distinguish responders from non-responders, we found that the area under the ROC curve was 0.795 and the threshold point for C4 to distinguish between responders and non-responders appear to be around 490 mcg/ml. Conclusions Our preliminary findings show that baseline C4 levels predict clinical outcome at 1-year follow-up in patients with first episode psychosis.

    更新日期:2020-01-22
  • Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-21
    Virginia Mela; Bibiana C. Mota; Mark Milner; Aoife McGinley; Kingston H.G. Mills; Áine M Kelly; Marina A. Lynch

    Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial activation. Recent evidence indicates that inflammatory microglia are glycolytic, driven by an increase in 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that is described as the master regulator of glycolysis. Here we investigated whether microglia from aged animals exhibited a glycolytic signature and whether exercise exerted a modulatory effect on this metabolic profile. Young (4 month-old) and aged (18 month-old) mice were trained for 10 days on a treadmill. One day before sacrifice, animals were assessed in the novel object recognition and the object displacement tests. Animals were sacrificed after the last bout of exercise, microglial cells were isolated, cultured for 5 days and assessed for metabolic profile. Performance in both behavioural tests was impaired in sedentary aged animals and exercise attenuated this age-related effect. A significant increase in glycolysis, glycolytic capacity and PFKFB3 was observed in microglia from aged animals and exercise ameliorated these effects, while it also increased the phagocytic capacity of cells. The senescent markers, β-galactosidase and p16INK4A, were increased in microglia from sedentary aged mice, and expression of these markers was significantly decreased by exercise. The data demonstrate that the exercise-related improved cognition is orchestrated by a normalization of the metabolic profile and functionality of microglia.

    更新日期:2020-01-22
  • The Relationship between Plasma Serotonin and Kynurenine Pathway Metabolite Levels and the Treatment Response to Escitalopram and Desvenlafaxine
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-21
    Yu Sun; Wayne Drevets; Gustavo Turecki; Qingqin S. Li

    Introduction The response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels. Methods The levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤ 7. Results Response to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p = 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047). Conclusions In MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.

    更新日期:2020-01-22
  • The combined association of depressive symptoms and C-reactive protein for incident disease risk up to 12 years later. Findings from the English Longitudinal of Ageing (ELSA)
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-20
    Lydia Poole; Andrew Steptoe

    Background Depression and inflammation are interrelated, and both are associated with the development of long-term conditions (LTCs). We investigated whether the combination of elevated depressive symptoms and elevated C-reactive protein (CRP) was associated with the rate of onset of a range of LTCs. Methods We analysed data from 5360 participants (65.77±9.46 years; 54.1% female) from the English Longitudinal Study of Ageing (ELSA). Depressive symptoms were indicated using the Centre for Epidemiological Studies Depression (CES-D) scale and scores were combined with high sensitivity (hs)-CRP values to reflect the additive interaction between low/high depressive symptoms (CES-D ≥4) and low/high CRP (>3mg/L). Participants were followed-up for up to 12 years to predict incident illness. Cox proportional hazard regression was used controlling for covariates. Results In fully adjusted models, the combination of elevated depressive symptoms and elevated CRP was an independent predictor of CHD (HR = 1.68, 95% C.I. = 1.01-2.78), stroke (HR = 2.02; 95% C.I. = 1.48-2.76), diabetes/high blood glucose (HR = 1.69; 95% C.I. = 1.11-2.57), and pulmonary disease (HR = 1.79; 95% C.I. = 1.02-3.15) relative to low depressive symptoms/low CRP, independently of age, sex, wealth, cohabitation, smoking status, body mass index and hypertension. Elevated depressive symptoms and low CRP was associated with arthritis incidence (HR = 1.49; 95% C.I. = 1.15-1.92). No association was found for cancer incidence. Conclusion A combination of depressive symptoms and CRP was implicated in the onset of CHD, stroke, diabetes/high blood glucose, and pulmonary disease up to 12 years later, reflecting the role of psychobiological processes across multiple disease states.

    更新日期:2020-01-21
  • Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-11
    Keenan A. Walker; Alden L. Gross; Abhay R. Moghekar; Anja Soldan; Corinne Pettigrew; Xirui Hou; Hanzhang Lu; Alfonso J. Alfini; Murat Bilgel; Michael I. Miller; Marilyn S. Albert; Jeremy Walston

    Background Systemic inflammation has emerged as a risk factor for cognitive decline and Alzheimer’s disease, but inflammation’s effect on distributed brain networks is unclear. We examined the relationship between peripheral inflammatory markers and subsequent functional connectivity within five large-scale cognitive networks and evaluated the modifying role of cortical amyloid and APOE ε4 status. Methods Blood levels of soluble tumor necrosis factor-alpha receptor-1 and interleukin 6 were assessed in 176 participants (at baseline mean age: 65 (SD 9) years; 63% women; 85% cognitively normal, 15% mild cognitive impairment (MCI)) and were combined to derive an Inflammatory Index. Approximately six years later, participants underwent resting-state functional magnetic resonance imaging to quantify functional connectivity; a subset of 137 participants also underwent 11C Pittsburgh compound-B (PiB) PET imaging to assess cortical amyloid burden. Results Using linear regression models adjusted for demographic characteristics and cardiovascular risk factors, a higher Inflammatory Index was associated with lower connectivity within the Default Mode (β=-0.013; 95% CI: -0.023, -0.003) and the Dorsal Attention Networks (β=-0.017; 95% CI: -0.028, -0.006). The strength of these associations did not vary by amyloid status (positive/negative). However, there was a significant interaction between Inflammatory Index and APOE ε4 status, whereby ε4-positive participants with a higher Inflammatory Index demonstrated lower connectivity. Inflammatory Index was unrelated to connectivity within other large-scale cognitive networks (Control, Limbic, and Salience/Ventral Attention networks). Conclusion Peripheral pro-inflammatory signaling in older adults without dementia, especially among APOE ε4-positive individuals, is associated with altered connectivity within two large-scale cognitive networks.

    更新日期:2020-01-13
  • Regulation of Immune-Driven Pathogenesis in Parkinson’s Disease by Gut Microbiota
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-10
    Wenxia Zheng; Rongni He; Zhenxing Yan; Yaowei Huang; Wei Huang; Zhuoyi Cai; Yuying Su; Siqin Liu; Yiting Deng; Qing Wang; Huifang Xie

    Parkinson’s disease (PD) is one of the most significant medical and social burdens of our time. The prevalence of PD increases with age and the number of individuals diagnosed with PD is expected to double from 6.9 million in 2015 to 14.2 million in 2040. To date, no drugs can stop the ongoing neurodegeneration caused by PD due to its unclear and complex pathogenic mechanisms. It has been wildly recognized that both gut microbiota and neuro-immunity are involved in the pathology of PD. In this review, we intend to provide a comprehensive overview of current knowledge on how gut microbiota involved in immune-driven pathogenesis of PD, and its potential as a new target of dietary and/or therapeutic interventions for PD.

    更新日期:2020-01-11
  • T-cell Defects and Postpartum Depression
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-08
    Lauren M. Osborne; Janneke Gilden; Astrid M. Kamperman; Witte.J.G. Hoogendijk; Julie Spicer; Hemmo A. Drexhage; Veerle Bergink

    Background Most studies of immune dysregulation in perinatal mood and anxiety disorders have focused on peripheral cytokines, but literature from non-perinatal mood disorders also implicates T-cell defects. We sought to characterize proportions of T-cell subtypes in women with postpartum depression. Materials and Methods We enrolled 21 women with postpartum depression (PPD), 39 healthy postpartum controls, and 114 healthy non-postpartum women. Blood was collected in sodium-heparin EDTA tubes and was analyzed using flow cytometry. We conducted statistical tests including linear regression analysis that were aimed at determining differences in proportions of T cell populations among groups. Results Mean counts of T-cells (all CD3+ T cells), T-helper cells, (CD3+CD4+ T cells), and T-cytotoxic cells (CD3+CD8+ T cells) were significantly increased in healthy postpartum women compared to healthy non-postpartum controls (p < 0.001, p = 0.007, and p = 0.002, respectively), but not in women with PPD. The increases in healthy postpartum women were driven by increases in TH1 cells and T regulatory cells, increases that were nonexistent or attenuated in women with postpartum depression. Mean counts of CD4+ T-helper memory cells were also increased in healthy postpartum women (p = 0.009), but slightly decreased in women with PPD (p = 0.066), when compared to healthy non-postpartum controls. Conclusions Our study confirms that the postpartum period in healthy women is a time of enhanced T cell activity. Women with postpartum depression failed to show physiological enhanced T-cell activity postpartum, and future research is needed to elucidate etiological mechanisms and consequences.

    更新日期:2020-01-09
  • Effects of Adjunctive Inflammatory Modulation on IL-1β in Treatment Resistant Bipolar Depression
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-07
    Stephen Murata; Michael Murphy; Debra Hoppensteadt; Jawed Fareed; Amanda Welborn; Angelos Halaris

    Background Adjunctive inflammatory modulation improved remission rates in treatment-resistant bipolar depression (TRBDD), but reliable biomarkers must be established to characterize the biosignature of TRBDD and the mechanisms underlying treatment response. In this molecular profiling study, we describe TRBDD and treatment response from the standpoint of interleukin-1 Beta (IL-1β) and KYN/TRP. Methods 47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10mg – 40mg daily dose range) + celecoxib (CBX) (200mg twice daily), or ESC (10mg – 40mg daily dose range) + placebo (PBO) (twice daily). Plasma cytokine levels were measured in both treatment arms at baseline and week 8, and in a healthy control (HC) group of subjects (N=43) once. A linear mixed model (LMM) was applied to evaluate whether clinical outcome is related to CBX and changes to biomarkers throughout treatment. A binary logistic regression model was formulated from this series to predict both the primary outcome of treatment response to CBX, and the secondary outcome of diagnosis of TRBDD using age, BMI, gender, and IL-1β at baseline. Results Patients receiving ESC + CBX had 4.278 greater odds of responding (p=0.021) with NNT=3, and 15.300 times more likely to remit (p<0.001) with NNT=2, compared with ESC + PBO patients. Patient BMI (p=0.003), baseline IL-1β (p=0.004), and baseline KYN/TRP (p=0.001) were most predictive of TRBDD diagnosis. By Week 8, responders showed a downtrend in IL-1β compared to non-responders in the ESC+CBX treatment arm. However, there was no statistical difference in the IL-1β or KYN/TRP change after treatment between placebo and ESC+CBX group responders/non-responders (p=0.239, and p=0.146, respectively). While baseline IL-1β was elevated in TRBDD compared to HC (p<0.001), there was no difference in IL-1β between treatment responders at Week 8 compared to HC (p=0.067). Conclusions Elevated IL-1β and low KYN/TRP at baseline are components of the TRBDD molecular signature. CBX but not baseline IL-1β or KYN/TRP predict treatment response. Change in IL-1β and KYN/TRP did not predict treatment response.

    更新日期:2020-01-07
  • The LFA-1 antagonist BIRT377 reverses neuropathic pain in prenatal alcohol-exposed female rats via actions on peripheral and central neuroimmune function in discrete pain-relevant tissue regions
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-07
    Shahani Noor; Joshua J. Sanchez; Melody S. Sun; Zinia Pervin; Jacob E. Sanchez; Mara A. Havard; Lauren T. Epler; Monique V. Nysus; Jeffrey P. Norenberg; Carston R. Wagner; Suzy Davies; Wagner Jennifer L; Daniel D. Savage; Lauren L. Jantzie; Nikolaos Mellios; Erin.D. Milligan

    Previous reports show that moderate prenatal alcohol exposure (PAE) poses a risk factor for developing neuropathic pain following adult-onset peripheral nerve injury in male rats. Recently, evidence suggests that immune-related mechanisms underlying neuropathic pain in females are different compared to males despite that both sexes develop neuropathy of similar magnitude and duration following chronic constriction injury (CCI) of the sciatic nerve. Data suggest that the actions of peripheral T cells play a greater role in mediating neuropathy in females. The goal of the current study is to identify specificity of immune cell and cytokine changes between PAE and non-PAE neuropathic females by utilizing a well-characterized rodent model of sciatic nerve damage, in an effort to unmask unique signatures of immune-related factors underlying the risk of neuropathy from PAE. Cytokines typically associated with myeloid cell actions such as interleukin (IL)-1β, tumor necrosis factor (TNF), IL-6, IL-4 and IL-10 as well as the neutrophil chemoattractant CXCL1, are examined. In addition, transcription factors and cytokines associated with various differentiated T cell subtypes are examined (anti-inflammatory FOXP3, proinflammatory IL-17A, IL-21, ROR-γt, interferon (IFN)-γ and T-bet). Lymphocyte function associated antigen 1 (LFA-1) is an adhesion molecule expressed on peripheral immune cells including T cells and regulates T cell activation and extravasation into inflamed tissue regions. A potential therapeutic approach was explored with the goal of controlling proinflammatory responses in neuroanatomical regions critical for CCI-induced allodynia by blocking LFA-1 actions using BIRT377. The data show profound development of hindpaw allodynia in adult non-PAE control females following standard CCI, but not following minor CCI, while minor CCI generated allodynia in PAE females. The data also show substantial increases in T cell-associated proinflammatory cytokine mRNA and proteins, along with evidence of augmented myeloid/glial activation (mRNA) and induction of myeloid/glial-related proinflammatory cytokines, CCL2, IL-1β and TNF in discrete regions along the pain pathway (damaged sciatic nerve, dorsal root ganglia; DRG, and spinal cord). Interestingly, the characteristic anti-inflammatory IL-10 protein response to nerve damage is blunted in neuropathic PAE females. Moreover, T cell profiles are predominantly proinflammatory in neuropathic Sac and PAE females, augmented levels of Th17-specific proinflammatory cytokines IL-17A and IL-21, as well as the Th1-specific factor, T-bet, are observed. Similarly, the expression of RORγt, a critical transcription factor for Th17 cells, is detected in the spinal cord of neuropathic females. Blocking peripheral LFA-1 actions with intravenous (i.v.) BIRT377 reverses allodynia in Sac and PAE rats, dampens myeloid (IL-1β, TNF, CXCL1)- and T cell-associated proinflammatory factors (IL-17A and RORγt) and spinal glial activation. Moreover, i.v. BIRT377 treatment reverses the blunted IL-10 response to CCI observed only in neuropathic PAE rats and elevates FOXP3 in pain-reversed Sac rats. Unexpectedly, intrathecal BIRT377 treatment is unable to alter allodynia in either Sac or PAE neuropathic females. Together, these data provide evidence that: 1) fully differentiated proinflammatory Th17 cells recruited at the sciatic nerve, DRGs and lumbar spinal cord may interact with the local environment to shape the immune responses underlying neuropathy in female rats, and, 2) PAE primes peripheral and spinal immune responses in adult females. PAE is a risk factor in females for developing peripheral neuropathy after minor nerve injury.

    更新日期:2020-01-07
  • Serum cytokines associated with behavior: a cross-sectional study in 5-year-old children
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-07
    Susana Barbosa; Olfa Khalfallah; Anne Forhan; Cédric Galera; Barbara Heude; Nicolas Glaichenhaus; Laetitia Davidovic

    Nearly 10% of 5-year-old children experience social, emotional or behavioral problems and are at increased risk of developing mental disorders later in life. While animal and human studies have demonstrated that cytokines can regulate brain functions, it is unclear whether individual cytokines are associated with specific behavioral dimensions in population-based pediatric samples. Here, we used data and biological samples from 786 mother-child pairs participating to the French national mother-child cohort EDEN. At the age of 5, children were assessed for behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) and had their serum collected. Serum samples were analyzed for levels of well-characterized effector or regulatory cytokines. We then used the Elastic net model, a penalized logistic regression method, to investigate associations between serum levels of cytokines and each of the five SDQ-assessed behavioral dimensions after adjustment for relevant covariates and confounders, including psychosocial variables. We found that interleukin (IL)-6, IL-7, and IL-15 were associated with increased odds of problems in prosocial behavior, emotions, and peer relationships, respectively. In contrast, eight cytokines were associated with decreased odds of problems in one dimension: IL-8, IL-10, and IL-17A with emotional problems, Tumor Necrosis Factor (TNF)-α with conduct problems, C-C motif chemokine Ligand (CCL)2 with hyperactivity/inattention, C-X-C motif chemokine Ligand (CXCL)10 with peer problems, and CCL3 and IL-16 with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines regulate brain functions and behavior and provide a rationale for launching longitudinal studies.

    更新日期:2020-01-07
  • Locus coeruleus neurons are most sensitive to chronic neuroinflammation-induced neurodegeneration
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-07
    Qingshan Wang; Esteban A. Oyarzabal; Sheng Song; Belinda Wilson; Janine H. Santos; Jau-Shyong Hong

    Parkinson’s disease (PD) develops over decades through spatiotemporal stages that ascend from the brainstem to the forebrain. The mechanism behind this caudo-rostral neurodegeneration remains largely undefined. In unraveling this phenomenon, we recently developed a lipopolysaccharide (LPS)-elicited chronic neuroinflammatory mouse model that displays sequential losses of neurons in brainstem, substantia nigra, hippocampus and cortex. In this study, we aimed to investigate the mechanisms of caudo-rostral neurodegeneration and focused our efforts on the earliest neurodegeneration of vulnerable noradrenergic locus coeruleus (NE-LC) neurons in the brainstem. We found that compared with neurons in other brain regions, NE-LC neurons in untreated mice displayed high levels of mitochondrial oxidative stress that was severely exacerbated in the presence of LPS-elicited chronic neuroinflammation. In agreement, NE-LC neurons in LPS-treated mice displayed early reduction of complex IV expression and mitochondrial swelling and loss of cristae. Mechanistically, the activation of the superoxide-generating enzyme NADPH oxidase (NOX2) on NE-LC neurons was essential for their heightened vulnerability during chronic neuroinflammation. LPS induced early and high expressions of NOX2 in NE-LC neurons. Genetic or pharmacological inactivation of NOX2 markedly reduced mitochondrial oxidative stress and dysfunction in LPS-treated mice. Furthermore, inhibition of NOX2 significantly ameliorated LPS-induced NE-LC neurodegeneration. More importantly, post-treatment with NOX2 inhibitor diphenyleneiodonium when NE-LC neurodegeneration had already begun, still showed high efficacy in protecting NE-LC neurons from degeneration in LPS-treated mice. This study strongly supports that chronic neuroinflammation and NOX2 expression among vulnerable neuronal populations contribute to caudo-rostral degeneration in PD.

    更新日期:2020-01-07
  • Sleep enhances numbers and function of monocytes and improves bacterial infection outcome in mice
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-03
    Julia Hahn; Manina Günter; Juliane Schuhmacher; Kristin Bieber; Simone Pöschel; Monika Schütz; Britta Engelhardt; Henrik Oster; Christian Sina; Tanja Lange; Stella E. Autenrieth

    Sleep strongly impacts both humoral and cellular immunity; however, its acute effects on the innate immune defense against pathogens are unclear. Here, we elucidated in mice whether sleep affects the numbers and functions of innate immune cells and their defense against systemic bacterial infection. Sleep significantly increased numbers of classical monocytes in blood and spleen of mice that were allowed to sleep for six hours at the beginning of the normal resting phase compared to mice kept awake for the same time. The sleep-induced effect on classical monocytes was neither caused by alterations in corticosterone nor myelopoiesis, bone marrow egress or death of monocytes and did only partially involve Gαi-protein coupled receptors like chemokine receptor 2 (CCR2), but not the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) or lymphocyte function-associated antigen 1 (LFA-1). Notably, sleep suppressed the expression of the clock gene Arntl in splenic monocytes and the sleep-induced increase in circulating classical monocytes was abrogated in Arntl-deficient animals, indicating that sleep is a prerequisite for clock-gene driven rhythmic trafficking of classical monocytes. Sleep also enhanced the production of reactive oxygen species by monocytes and neutrophils. Moreover, sleep profoundly reduced bacterial load in blood and spleen of mice that were allowed to sleep before systemic bacterial infection and consequently increased survival upon infection. These data provide the first evidence that sleep enhances numbers and function of innate immune cells and therewith strengthens early defense against bacterial pathogens.

    更新日期:2020-01-04
  • Increased circulatory IL-6 during 8-week fluoxetine treatment is a risk factor for suicidal behaviors in youth
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-27
    Maya Amitai; Michal Taler; Reut Ben-Baruch; Maya Lebow; Ron Rotkopf; Alan Apter; Silvana Fennig; Abraham Weizman; Alon Chen

    Objective Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat anxiety and/or depression in pediatric populations. However, the response rates are low (approximately 50%). Moreover, SSRI use is frequently associated with adverse events (AE). Currently there are no available biomarkers for treatment response/AE. Identification of biomarkers predicting early response and/or AE could help maximize the benefit-risk ratio for the use of SSRIs, and accelerate matching of treatments to patients. Pro-inflammatory cytokines were proposed as potential biomarkers. Method Ninety-two patients (35 boys and 57 girls) with major depressive disorder or anxiety disorders, aged 13.90 ± 2.41 years, were treated with fluoxetine (FLX) for 8 weeks. Plasma concentrations of TNFα, IL-6, and IL-1β were measured by enzyme linked immunosorbent assays before and after FLX treatment. Clinical response and AE were measured using several clinical scales, including the Clinical Global Impression – improvement, Children's Depression Rating Scale–Revised, the Beck Depression Inventory, the Screen for Child Anxiety Related Emotional Disorders, the Columbia suicide severity rating scale, and the Suicide Ideation Questionnaire. Results IL-6 levels increased after treatment only in the group of children who developed FLX-associated suicidality. Conclusion An increase in IL-6 levels during treatment may be a risk factor for the emergence of FLX-associated suicidality (OR=1.70). Further studies are necessary to clarify the role and mechanism(s) of this cytokine in the pathogenesis of this life-threatening AE.

    更新日期:2019-12-27
  • Peripheral immune aberrations in fibromyalgia: A systematic review, meta-analysis and meta-regression
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-27
    Laura Andrés-Rodríguez; Xavier Borràs; Albert Feliu-Soler; Adrián Pérez-Aranda; Natalia Angarita-Osorio; Patrícia Moreno-Peral; Jesús Montero-Marin; Javier García-Campayo; Andre F. Carvalho; Michael Maes; Juan V. Luciano

    The objective was to identify immune alterations in patients with fibromyalgia syndrome (FMS) compared to healthy controls (HC) using meta-analysis and meta-regression. Six electronic databases were searched for suitable original articles investigating immune biomarkers in FMS in comparison to HC. We extracted outcomes and variables of interest, such as mean and SD of peripheral blood immune biomarkers, age or sex. A random-effects model with restricted maximum-likelihood estimator was used to compute effect sizes (standardized mean difference and 95% CI, Hedges’ g) and meta-analysis, group meta-analysis and meta-regressions were conducted. Forty-three papers were included in this systematic review, of which 29 were suitable for meta-analysis. Interleukin (IL)-6 (g=0.36 (0.09-0.63); I2=85.94; p=0.01), IL-4 (g=0.50 (0.03-0.98); I2=81.87; p=0.04), and IL-17A (g=0.53 (0.00-1.06); I2=87.15; p=0.05), were significantly higher in FMS compared to HC while also combinations of cytokines into relevant phenotypes were significantly upregulated including M1 macrophage (g=0.23 (0.03-0.43); I2=77.62; p=0.02), and immune-regulatory (g=0.40 (0.09-0.72); I2=84.81; p=0.01) phenotypes. Heterogeneity levels were very high and subgroup and meta-regression analyses showed that many covariates explained part of the heterogeneity including medication washout, sex, time of blood sampling and exclusion of patients with major depressive disorder. In conclusion, FMS is accompanied by a disbalance between upregulated pro-inflammatory (M1 and Th-17) and immune-regulatory cytokines although effect sizes are small-to-moderate. Based on our results we provide specific methodological suggestions for future research, which should assess Th-1, Th-17, chemokines, and Th-2 phenotypes while controlling for possible confounding variables specified in this study.

    更新日期:2019-12-27
  • Subcutaneous Mycobacterium vaccae promotes resilience in a mouse model of chronic psychosocial stress when administered prior to or during psychosocial stress
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-27
    Mattia Amoroso; Alexandra Böttcher; Christopher A. Lowry; Dominik Langgartner; Stefan O. Reber

    Chronic psychosocial stress is a risk factor for many mental disorders, including affective disorders, anxiety disorders, and trauma- and stressor-related disorders (i.e. posttraumatic stress disorder, PTSD). As these disorders are associated with an overreactive immune system and chronic low-grade inflammation, immunoregulatory approaches counterbalancing basal and/or stress-induced immune activation should be protective in this context. In support of this hypothesis, we recently demonstrated that repeated subcutaneous (s.c) preimmunization with a heat-killed preparation of the immunoregulatory bacterium Mycobacterium vaccae (M. vaccae; National Collection of Type Culture (NCTC) 11659) promoted proactive stress coping and protected against stress-induced anxiety and intestinal pathology in a mouse model of chronic psychosocial stress. To induce development of a chronic anxiety-like state, the chronic subordinate colony housing (CSC) paradigm was used. Here we employed the CSC paradigm (start day 1) to confirm the stress-protective effects of repeated s.c. M. vaccae administrations prior to CSC exposure (days -21, -14, and -7) and to extend these findings to the stress-protective role of M. vaccae when administered repeatedly during CSC exposure (days 2, 8 and 15). As readouts we assessed the stress coping behavior on days 1, 8, and 15 and general and/or social anxiety-related behavior on days 19 (elevated plus-maze), 20 (open-field/novel object test) and day 21 (social preference/avoidance test) of CSC exposure. In line with our previous study, M. vaccae administered prior to CSC strongly promoted active stress coping and moderately reduced CSC-induced general and social anxiety. Although M. vaccae administered during CSC did not affect stress coping, this treatment protocol profoundly protected against CSC-induced general, and to a lesser extent social, anxiety. Taken together, these data broaden the framework for developing bioimmunoregulatory approaches, based on the administration of immunoregulatory microorganisms, for the prevention and/or treatment of affective disorders, anxiety disorders, and trauma- and stressor-related psychiatric disorders like PTSD.

    更新日期:2019-12-27
  • The Long-term Association of Adverse Childhood Experiences with C-reactive Protein and Hair Cortisol: Cumulative Risk versus Dimensions of Adversity
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-27
    Eleonora Iob; Rebecca Lacey; Andrew Steptoe

    Background Exposure to adverse childhood experiences (ACEs) may lead to stress-induced upregulation of inflammatory and neuroendocrine processes. However, it remains unclear whether such effects persist into later life, and which dimensions of ACEs might have the strongest impact on these biological mechanisms. Therefore, this study investigated the effects of ACEs on C-reactive protein (CRP) and hair cortisol in a large sample of older adults, distinguishing between cumulative exposure and dimensions of ACEs. Methods We utilised data from the English Longitudinal Study of Ageing. ACEs were assessed through retrospective reports at wave 3(2006/07). CRP (N=4,198) was measured at waves 4(2008/09) and 6(2012/13), and hair cortisol (N=3,357) at wave 6. The effects of ACEs cumulative exposure were examined using linear and ordinal logistic regression analysis. ACEs dimensions (i.e. threat, household dysfunction, low parental bonding, and loss of an attachment figure) were identified using explorative and confirmatory factor analysis with cross-validation. All analyses were adjusted for relevant confounders. Results Participants with three or more ACEs had higher CRP levels at wave 4 and an elevated risk of high CRP concentrations across waves 4 and 6 compared with those who did not experience any ACEs. The four ACEs dimensions were all positively associated with both CRP outcomes and had similar effect sizes. In contrast, neither the cumulative score nor the dimensions of ACEs were significantly related to hair cortisol. However, there was a positive, yet small, interaction effect between ACEs and age on hair cortisol. Conclusion Older adults who retrospectively reported three or more ACEs had chronically elevated CRP levels and exhibited a slightly steeper increase in hair cortisol with age. Different dimensions of ACEs had similar associations with the biomarkers.

    更新日期:2019-12-27
  • Can stress promote the pathophysiology of brain metastases? A critical review of biobehavioral mechanisms
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-24
    Annina Seiler; Anil K. Sood; Josef Jenewein; Christopher P. Fagundes

    Chronic stress can promote tumor growth and progression through immunosuppressive effects and bi-directional interactions between tumor cells and their microenvironment. β-adrenergic receptor signaling plays a critical role in mediating stress-related effects on tumor progression. Stress-related mechanisms that modulate the dissemination of tumor cells to the brain have received scant attention. Brain metastases are highly resistant to chemotherapy and contribute considerably to morbidity and mortality in various cancers, occurring in up to 20% of patients in some cancer types. Understanding the mechanisms promoting brain metastasis could help to identify interventions that improve disease outcomes. In this review, we discuss biobehavioral, sympathetic, neuroendocrine, and immunological mechanisms by which chronic stress can impact tumor progression and metastatic dissemination to the brain. The critical role of the inflammatory tumor microenvironment in tumor progression and metastatic dissemination to the brain, and its association with stress pathways are delineated. We also discuss translational implications for biobehavioral and pharmacological interventions.

    更新日期:2019-12-25
  • A silent agonist of α7 nicotinic acetylcholine receptors modulates inflammation ex vivo and attenuates EAE
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-23
    Jean-Rémi Godin; Patrick Roy; Marta Quadri; Deniz Bagdas; Wisam Toma; Ramya Narendrula-Kotha; Osama A. Kishta; M. Imad Damaj; Nicole A. Horenstein; Roger L. Papke; Alain R. Simard

    Nicotinic acetylcholine receptors (nAChRs) are best known to function as ligand-gated ion channels in the nervous system. However, recent evidence suggests that nicotine modulates inflammation by desensitizing non-neuronal nAChRs, rather than by inducing channel opening. Silent agonists are molecules that selectively induce the desensitized state of nAChRs while producing little or no channel opening. A silent agonist of α7 nAChRs has recently been shown to reduce inflammation in an animal model of inflammatory pain. The objective of this study was to determine whether a silent agonist of α7 nAChRs can also effectively modulate inflammation and disease manifestation in an animal model of multiple sclerosis. We first evaluated the effects of various nAChR ligands and of an α7 nAChR-selective silent agonist, 1-ethyl-4-(3-(bromo)phenyl)piperazine (m-bromo PEP), on the modulation of mouse bone marrow-derived monocyte/macrophage (BMDM) numbers, phenotype and cytokine production. The non-competitive antagonist mecamylamine and the silent agonist m-bromo PEP reduced pro-inflammatory BMDM numbers by affecting their viability and proliferation. Both molecules also significantly reduced cytokine production by mouse BMDMs and significantly ameliorated disease in experimental autoimmune encephalomyelitis. Finally, m-bromo PEP also reduced chronic inflammatory pain in mice. Taken together, our results further support the hypothesis that nAChRs may modulate inflammation via receptor desensitization rather than channel opening. α7 nAChR-selective silent agonists may thus be a novel source of anti-inflammatory compounds that could be used for the treatment of inflammatory disorders.

    更新日期:2019-12-23
  • Angiotensin type 2 receptors: role in aging and neuroinflammation in the substantia nigra
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-19
    Ana I. Rodriguez-Perez; Pablo Garrido-Gil; Maria A. Pedrosa; Maria Garcia-Garrote; Rita Valenzuela; Gemma Navarro; Rafael Franco; Jose L. Labandeira-Garcia
    更新日期:2019-12-19
  • Interleukin-17 acts in the hypothalamus reducing food intake
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-18
    Guilherme Nogueira; Carina Solon; Rodrigo S. Carraro; Daiane F. Engel; Albina F. Ramalho; Davi Sidarta-Oliveira; Rodrigo S. Gaspar; Bruna Bombassaro; Ana C. Vasques; Bruno Geloneze; Marco A. Vinolo; Jose Donato Junior; Licio A. Velloso

    Interleukin-17 (IL-17) is expressed in the intestine in response to changes in the gut microbiome landscape and plays an important role in intestinal and systemic inflammatory diseases. There is evidence that dietary factors can also modify the expression of intestinal IL-17. Here, we hypothesized that, similar to several other gut-produced factors, IL-17 may act in the hypothalamus to modulate food intake. We confirm that food intake increases IL-17 expression in the mouse ileum and human blood. There is no expression of IL-17 in the hypothalamus; however, IL-17 receptor A is expressed in both pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. Upon systemic injection, IL-17 promoted a rapid increase in hypothalamic POMC expression, which was followed by a late increase in the expression of AgRP. Both systemic and intracerebroventricular injections of IL-17 reduced calorie intake without affecting whole-body energy expenditure. Systemic but not intracerebroventricular injection of IL-17 increase brown adipose tissue temperature. Thus, IL-17 is a gut-produced factor that is controlled by diet and modulates food intake by acting in the hypothalamus. Our findings provide the first evidence of a cytokine that is acutely regulated by food intake and plays a role in the regulation of eating.

    更新日期:2019-12-19
  • The antioxidant and immunomodulatory compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole attenuates depression-like behavior and cognitive impairment developed in a mouse model of breast tumor
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-16
    Angela Maria Casaril; Micaela Domingues; Suely Ribeiro Bampi; Darling de Andrade Lourenço; Thiago Smaniotto; Natália Segatto; Beatriz Vieira; Fabiana K. Seixas; Tiago Collares; Eder João Lenardão; Lucielli Savegnago
    更新日期:2019-12-17
  • C-reactive protein and response to lurasidone treatment in children and adolescents with bipolar I depression: Results from a placebo-controlled trial
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-16
    Charles L. Raison; Cynthia Siu; Andrei Pikalov; Michael Tocco; Antony Loebel

    This study sought to investigate associations between levels of high-sensitivity c-reactive protein (hsCRP) prior to treatment and change in depressive symptoms and cognition in a short-term, double-blind, placebo-controlled study of lurasidone in children and adolescents with bipolar I depression. Patients 10-17 years of age with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexibly dosed lurasidone (20-80 mg/day) (n=173) or placebo (n=170). The primary efficacy measure was change from baseline to week 6 in the Children’s Depression Rating Scale, Revised (CDRS-R). Treatment response was defined as 50% or greater improvement on the CDRS-R from baseline to week 6. Cognitive function was evaluated with the computerized Brief Cogstate Battery at baseline and week 6. Analyses were adjusted for baseline BMI, as well as age. HsCRP was evaluated as a logarithmically transformed continuous variable and as a categorical variable dichotomized into lower (< 1 mg/L) and higher (≥ 1 mg/L) subgroups. A significant interaction was found between baseline hsCRP and treatment group for change in CDRS-R score at study endpoint, with larger placebo-corrected effect sizes for lurasidone in the higher baseline hsCRP group (≥ 1 mg/L). A significant BMI-by-hsCRP-by-treatment interaction was found for response rate with higher baseline hsCRP levels associated with greater antidepressant response to lurasidone (vs. placebo) in the normal BMI range subgroup (NNT=2 in higher hsCRP vs. NNT=5 in lower hsCRP groups) but not in the overweight/obese patients (NNT=6 in higher hsCRP vs. NNT=5 in lower hsCRP). Similarly, a significant interaction effect was observed for the combination of hsCRP and BMI on the procognitive effect of lurasidone, with higher baseline hsCRP levels being associated with improvement in cognitive function for lurasidone (vs placebo) in the normal BMI range subgroup but not in overweight/obese patients. These results suggest that young patients with bipolar depression with normal weight and higher levels of pre-treatment CRP may show a greater placebo-adjusted improvement in depressive symptoms and cognitive performance when treated with lurasidone. If these findings are confirmed in future prospective studies, CRP and BMI may prove to be useful diagnostic and predictive biomarkers in the treatment with lurasidone of children and adolescents with bipolar depression.

    更新日期:2019-12-17
  • Crotoxin down-modulates pro-inflammatory cells and alleviates pain on the MOG35-55-induced experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-13
    N.B. Teixeira; M.B. Sant'Anna; A.C. Giardini; L.P. Araujo; L.A. Fonseca; A.S. Basso; Y. Cury; G. Picolo
    更新日期:2019-12-13
  • In vivo characterization of functional states of cortical microglia during peripheral inflammation
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-11
    Karin Riester, Bianca Brawek, Daria Savitska, Nicole Fröhlich, Elizabeta Zirdum, Nima Mojtahedi, Michael T. Heneka, Olga Garaschuk

    Peripheral inflammation is known to trigger a mirror inflammatory response in the brain, involving brain’s innate immune cells - microglia. However, the functional phenotypes, which these cells adopt in the course of peripheral inflammation, remain obscure. In vivo two-photon imaging of microglial Ca2+ signaling as well as process motility reveals two distinct functional states of cortical microglia during a lipopolysaccharide-induced peripheral inflammation: an early “sensor” state” characterized by dramatically increased intracellular Ca2+ signaling but ramified morphology and a later “effector state” characterized by slow normalization of intracellular Ca2+ signaling but hypertrophic morphology, substantial IL-1β production in a subset of cells as well as increased velocity of directed process extension and loss of coordination between individual processes. Thus, lipopolysaccharide-induced microglial Ca2+ signaling might represent the central element connecting receptive and executive functions of microglia.

    更新日期:2019-12-11
  • NADPH oxidase 2 as a potential therapeutic target for protection against cognitive deficits following systemic inflammation in mice
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-10
    Wan-Yu Huang, Ko-Hung Liu, Shankung Lin, Ting-Yu Chen, Chien-Yu Tseng, Hsuan-Ying Chen, Hung-Ming Wu, Kuei-Sen Hsu

    Background Research indicates that sepsis increases the risk of developing cognitive impairment. After systemic inflammation, a corresponding activation of microglia is rapidly induced in the brain, and multiple neurotoxic factors, including inflammatory mediators (e.g., cytokines) and reactive oxygen species (e.g., superoxide), are also released that contribute to neuronal injury. NADPH oxidase (NOX) enzymes play a vital role in microglial activation through the generation of superoxide anions. We hypothesized that NOX isoforms, particularly NOX2, could exhibit remarkable abilities in developing cognitive deficits induced by systemic inflammation. Methods Mice with deficits of NOX2 organizer p47phox (p47phox-/-) and wild-type (WT) mice treated with the NOX inhibitor diphenyleneiodonium (DPI) were used in this study. Intraperitoneal lipopolysaccharide (LPS) injection was used to induce systemic inflammation. Spatial learning and memory were compared among treatment groups using the radial arm maze task. Brain tissues were collected for evaluating the transcript levels of proinflammatory cytokines, whereas immunofluorescence staining and immunoblotting were conducted to determine the percentage of activated glia (microglia and astroglia) and damaged neurons and the expression of synaptic proteins and BDNF. Results Cognitive impairment induced by systemic inflammation was significantly attenuated in the p47phox-/- mice compared to that in the WT mice. The p47phox-/- mice exhibited reduced microglial and astroglial activation and neuronal damage and attenuated the induction of multiple proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and CCL2. Similar to that observed in the p47phox-/- mice, the administration of DPI significantly attenuated the cognitive impairment, reduced the glial activation and brain cytokine concentrations, and restored the expression of postsynaptic proteins (PSD-95) and BDNF in neurons and astrocytes, compared to those in the vehicle-treated controls within 10 days after LPS injection. Conclusions This study clearly demonstrates that NOX2 contributes to glial activation with subsequent reduction in the expression of BDNF, synaptic dysfunction, and cognitive deficits after systemic inflammation in an LPS-injected mouse model. Our results provide evidence that NOX2 might be a promising pharmacological target that could be used to protect against synaptic dysregulation and cognitive impairment following systemic inflammation.

    更新日期:2019-12-11
  • The effect of blueberry interventions on cognitive performance and mood: A systematic review of randomized controlled trials
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-04-15
    Nikolaj Travica, Nathan M. D'Cunha, Nenad Naumovski, Katherine Kent, Duane D. Mellor, Joseph Firth, Ekavi N. Georgousopoulou, Olivia M. Dean, Amy Loughman, Felice Jacka, Wolfgang Marx

    Blueberries are rich in polyphenols that may be beneficial to cognitive performance and mood. The aim of this systematic review was to evaluate randomized controlled trials investigating the effects of blueberries and blueberry products on measures of cognition and mood. In total, eleven articles (that included 12 studies) were identified using freeze-dried blueberries (n = 9 studies), whole blueberries (n = 2) and blueberry concentrate (n = 1). These studies were conducted in children (n = 5), young adults (n = 1), and older people with either no known cognitive impairment (n = 4) or indicated cognitive impairment (n = 2). Eight studies reported blueberry consumption or supplementation at various doses and time lengths to improve measures of cognitive performance, particularly short- and long-term memory and spatial memory. For mood, one study reported significant between-group improvements in positive affect from blueberry products, whereas four studies reported no improvement. Low risk of bias were observed across all studies. Based on the current evidence, blueberries may improve some measures of cognitive performance. However, considerable differences in study design, dosages, and anthocyanin content hinder between-study comparison. The use of standardized blueberry interventions, consideration of placebo formulations, and consistently reported cognitive performance tools are recommended in future trials. PROSPERO registration no. CRD42018100888.

    更新日期:2019-12-09
  • Early life adversity exposure and circulating markers of inflammation in children and adolescents: A systematic review and meta-analysis
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-04-15
    Kate R. Kuhlman, Sarah R. Horn, Jessica J. Chiang, Julienne E. Bower

    This study provides a comprehensive review of the published research on the association between early life adversity and markers of inflammation in children and adolescents. We conducted a systematic review of the published literature on the association between early life adversity and markers of inflammation in pediatric populations. To date, 27 studies have been published in this area representing a wide range of global populations and diverse methods of which nearly half were prospective, longitudinal studies. Of these 27, only 13 studies shared an inflammatory outcome with 4 or more other studies; 9 for CRP, and 7 for IL-6. The association between early life adversity and both CRP, z = 0.06 [−0.01, 0.14], and IL-6, z = 0.06 [−0.17, 0.30], was small and non-significant when subjected to meta-analysis, although comparable in magnitude to the effects observed in adult samples. Descriptively, the association between early life adversity and CRP appeared to be stronger in studies conducted in infants and adolescents compared with middle childhood. There was minimal evidence of publication bias for studies measuring CRP, but evidence of publication bias for studies using IL-6. Eight studies have looked at the association between early life adversity and stimulated inflammatory cytokines in vitro, and both the methods and results of these studies were mixed; the majority observed exaggerated production of inflammatory cytokines despite mixed methodological approaches that make comparisons across studies difficult. In summary, the evidence supporting an association between early life adversity and inflammation in pediatric samples is limited so far by the number of studies and their heterogeneous methodological approaches. More research that is grounded in a developmental framework and informed by the complexity of the innate immune system is needed in this area.

    更新日期:2019-12-09
  • Altered gut microbiota and endocannabinoid system tone in vitamin D deficiency-mediated chronic pain
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-04-03
    Francesca Guida, Serena Boccella, Carmela Belardo, Monica Iannotta, Fabiana Piscitelli, Francesca De Filippis, Salvatore Paino, Flavia Ricciardi, Dario Siniscalco, Ida Marabese, Livio Luongo, Danilo Ercolini, Vincenzo Di Marzo, Sabatino Maione

    Recent evidence points to the gut microbiota as a regulator of brain and behavior, although it remains to be determined if gut bacteria play a role in chronic pain. The endocannabinoid system is implicated in inflammation and chronic pain processing at both the gut and central nervous system (CNS) levels. In the present study, we used low Vitamin D dietary intake in mice and evaluated possible changes in gut microbiota, pain processing and endocannabinoid system signaling. Vitamin D deficiency induced a lower microbial diversity characterized by an increase in Firmicutes and a decrease in Verrucomicrobia and Bacteroidetes. Concurrently, vitamin D deficient mice showed tactile allodynia associated with neuronal hyperexcitability and alterations of endocannabinoid system members (endogenous mediators and their receptors) at the spinal cord level. Changes in endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were also observed in the duodenum and colon. Remarkably, the anti-inflammatory anandamide congener, palmitoylethanolamide, counteracted both the pain behaviour and spinal biochemical changes in vitamin D deficient mice, whilst increasing the levels of Akkermansia, Eubacterium and Enterobacteriaceae, as compared with vehicle-treated mice. Finally, induction of spared nerve injury in normal or vitamin D deficient mice was not accompanied by changes in gut microbiota composition. Our data suggest the existence of a link between Vitamin D deficiency – with related changes in gut bacterial composition – and altered nociception, possibly via molecular mechanisms involving the endocannabinoid and related mediator signaling systems.

    更新日期:2019-12-09
  • Gastrointestinal (Non-systemic) Antibiotic Rifaximin Differentially Affects Chronic Stress-induced Changes in Colon Microbiome and Gut Permeability without Effect on Behavior
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-07
    Dániel Kuti, Zsuzsanna Winkler, Krisztina Horváth, Balázs Juhász, Melinda Paholcsek, Anikó Stágel, Gabriella Gulyás, Levente Czeglédi, Szilamér Ferenczi, Krisztina J. Kovács

    Chronic stress is often accompanied by gastrointestinal symptoms, which might be due to stress-induced shift of gut microbiome to pathogenic bacteria. It has been hypothesized that stress alters gut permeability and results in mild endotoxemia which exaggerates HPA activity and contributes to anxiety and depression. To reveal the relationship between microbiome composition, stress-induced gastrointestinal functions and behavior, we treated chronically stressed mice with non-absorbable antibiotic, rifaximin. The “two hits” stress paradigm was used, where newborn mice were separated from their mothers for 3 hours daily as early life adversity (maternal separation, MS) and exposed to 4 weeks chronic variable stress (CVS) as adults. 16S rRNA based analysis of gut microbiome revealed increases of Bacteroidetes and Proteobacteria and more specifically, Clostridium species in chronically stressed animals. In mice exposed to MS+CVS, we found extenuation of colonic mucosa, increased bacterial translocation to mesenteric lymph node, elevation of plasma LPS levels and infiltration of F4/80 positive macrophages into the colon lamina propria. Chronically stressed mice displayed behavioral signs of anxiety-like behavior and neophobia. Rifaximin treatment decreased Clostridium concentration, gut permeability and LPS plasma concentration and increased colonic expression of tight junction proteins (TJP1,TJP2) and occludin. However, these beneficial effects of rifaximin in chronically stressed mice was not accompanied by positive changes in behavior. Our results suggest that non-absorbable antibiotic treatment alleviates stress-induced local pathologies, however, does not affect stress-induced behavior.

    更新日期:2019-12-07
  • The Role of the Microbiota in Acute Stress-Induced Myeloid Immune Cell Trafficking
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-05
    Marcel van de Wouw, Joshua M. Lyte, Marcus Boehme, Marzia Sichetti, Gerard Moloney, Michael S. Goodson, Nancy Kelley-Loughnane, Timothy G. Dinan, Gerard Clarke, John F. Cryan

    There has been a growing recognition of the involvement of the gastrointestinal microbiota in the development of stress-related disorders. Acute stress leads to activation of the neuroendocrine systems, which in turn orchestrate a large-scale redistribution of innate immune cells. Both these response systems are independently known to be primed by the microbiota, even though much is still unclear about the role of the gastrointestinal microbiota in acute stress-induced immune activation. In this study, we investigated whether the microbiota influences acute stress-induced changes in innate immunity using conventionally colonised mice, mice devoid of any microbiota (i.e. germ-free, GF), and colonised GF mice (CGF). We also explored the kinetics of stress-induced immune cell mobilisation in the blood, the spleen and mesenteric lymph nodes (MLNs). Mice were either euthanised prior to stress or underwent restraint stress and were then euthanised at various time points (i.e. 0, 45- and 240-minutes) post-stress. Plasma adrenaline and noradrenaline levels were analysed using ELISA and immune cell levels were quantified using flow cytometry. GF mice had increased baseline levels of adrenaline and noradrenaline, of which adrenaline was normalised in CGF mice. In tandem, GF mice had decreased circulating levels of LY6Chi and LY6Cmid, CCR2+ monocytes, and granulocytes, but not LY6C-, CX3CR1+ monocytes. These deficits were normalised in CGF mice. Acute stress decreased blood LY6Chi and LY6Cmid, CCR2+ monocytes while increasing granulocyte levels in all groups 45 minutes post-stress. However, only GF mice showed stress-induced changes in LY6Chi monocytes and granulocytes 240 minutes post-stress, indicating impairments in the recovery from acute stress-induced changes in levels of specific innate immune cell types. LY6C-, CX3CR1+ monocytes remained unaffected by stress, indicating that acute stress impacts systemic innate immunity in a cell-type-specific manner. Overall, these data reveal novel cell-type-specific changes in the innate immune system in response to acute stress, which in turn are impacted by the microbiota. In conclusion, the microbiota influences the priming and recovery of the innate immune system to an acute stressor and may inform future microbiota-targeted therapeutics aimed at modulating stress-induced immune activation in stress-related disorders.

    更新日期:2019-12-05
  • Peptides of neuron specific enolase as potential ASD biomarkers: from discovery to epitope mapping
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-05
    Alexandra Ramirez-Celis, Elizabeth Edmiston, Joseph Schauer, Tam Vu, Judy Van de Water

    Autism spectrum disorder (ASD) is an important health issue and affects 1 in 59 children in the US. Prior studies determined that maternal autoantibody related (MAR) autism is thought to be associated with ∼23% of ASD cases. We previously identified seven MAR-specific autoantigens including CRMP1, CRMP2, GDA, LDHA, LDHB, STIP1, and YBX1. We subsequently described the epitope peptide sequences recognized by maternal autoantibodies for each of the seven ASD-specific autoantigens. The aim of the current study was to expand upon our previous work and identify additional antigens recognized by the ASD-specific maternal autoantibodies, as well as to map the unique ASD-specific epitopes using microarray technology. Fetal Rhesus macaque brain tissues were separated by molecular weight and a fraction containing bands between 37 and 45 kDa was analyzed using 2-D gel electrophoresis, followed by peptide mass mapping using MALDI-TOF MS and TOF/TOF tandem MS/MS. Using this methodology, Neuron specific enolase (NSE) was identified as a target autoantigen and selected for epitope mapping. The full NSE sequence was translated into 15-mer peptides with an overlap of 14 amino acids onto microarray slides and probed with maternal plasma from mothers with an ASD child and from mothers with a Typically Developing child (TD) (ASD= 27 and TD=21). The resulting data were analyzed by T-test. We found 16 ASD-specific NSE-peptide sequences for which four sequences were statistically significant (p<0.05) using both the t-test and SAM t-test: DVAASEFYRDGKYDL (p=0.047; SAM score 1.49), IEDPFDQDDWAAWSK (p=0.049; SAM score 1.49), ERLAKYNQLMRIEEE (p=0.045; SAM score 1.57), and RLAKYNQLMRIEEEL (p=0.017; SAM score 1.82). We further identified 5 sequences that were recognized by both ASD and TD antibodies suggesting a large immunodominant epitope (DYPVVSIEDPFDQDDWAAW). While maternal autoantibodies against the NSE protein are present both in mothers with ASD and mothers of TD children, there are several ASD-specific epitopes that can potentially be used as MAR ASD biomarkers. Further, studies including analysis of NSE as a target protein in combination with the previously identified MAR ASD autoantigens are currently underway.

    更新日期:2019-12-05
  • Association of Exposure to Toxoplasma gondii, Epstein-Barr Virus, Herpes Simplex Virus Type 1 and Cytomegalovirus with New-Onset Depressive and Anxiety Disorders: an 11-year follow-up study
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-12-04
    Niina Markkula, Maija Lindgren, Robert H. Yolken, Jaana Suvisaari

    Background Some prevalent infections have been associated with common mental disorders, but there are few longitudinal studies, and results are inconsistent. We aimed to assess whether serological evidence of exposure to Toxoplasma gondii (T. gondii), Epstein-Barr Virus (EBV), Herpes Simplex virus Type 1 (HSV-1) and Cytomegalovirus (CMV) predict development of new-onset depressive and anxiety disorders. Methods In a nationally representative sample of the Finnish adult population aged 30 and over (BRIF8901, n=8028), IgG antibodies for T. gondii, EBV, HSV-1 and CMV were measured in plasma samples. The population was followed up for 11 years and new-onset depressive and anxiety disorders were diagnosed with the Composite International Diagnostic Interview. Associations were analysed controlling for sex, age, educational level, region of residence and marital status, and in separate analyses also for C-reactive protein level. Results Seropositivity and serointensity of the four infectious agents were not associated with an increased risk of new-onset depressive or anxiety disorders. Seropositivity for CMV at baseline was associated with a lower risk of new-onset generalized anxiety disorder (adjusted OR 0.43, 95% CI 0.22-0.86 for CMV positive persons). Conclusion The results of this large, nationally representative longitudinal study suggest that common viral infections are not significant risk factors for common mental disorders. The association of CMV with a lower risk of generalized anxiety disorder warrants further investigation.

    更新日期:2019-12-04
  • Childhood Trauma, HPA Axis Activity and Antidepressant Response in Patients with Depression
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-30
    Naghmeh Nikkheslat, Anna P. McLaughlin, Caitlin Hastings, Zuzanna Zajkowska, Maria A. Nettis, Nicole Mariani, Daniela Enache, Giulia Lombardo, Linda Pointon, Philip J. Cowen, Jonathan Cavanagh, Neil A. Harrison, Edward T. Bullmore, Carmine M. Pariante, Valeria Mondelli

    Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n=42), treatment non-responder (n=80) and untreated depressed (n=41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment.

    更新日期:2019-12-02
  • Repeated Stress Induces a Pro-inflammatory State, Increases Amygdala Neuronal and Microglial Activation, and Causes Anxiety in Adult Male Rats
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-27
    Soumyabrata Munshi, Maxine K. Loh, Nicole Ferrara, M. Regina DeJoseph, Alexandra Ritger, Mallika Padival, Matthew J. Record, Janice H. Urban, J. Amiel Rosenkranz

    A link exists between immune function and psychiatric conditions, particularly depressive and anxiety disorders. Psychological stress is a powerful trigger for these disorders and stress influences immune state. However, the nature of peripheral immune changes after stress conflicts across studies, perhaps due to the focus on few measures of pro-inflammatory or anti-inflammatory processes. The basolateral amygdala (BLA) is critical for emotion, and plays an important role in the effects of stress on anxiety. As such, it may be a primary central nervous system (CNS) mediator for the effects of peripheral immune changes on anxiety after stress. Therefore, this study aimed to delineate the influence of stress on peripheral pro-inflammatory and anti-inflammatory aspects, BLA immune activation, and its impact on BLA neuron activity. To produce a more encompassing view of peripheral immune changes, this study used a less restrictive approach to categorize and group peripheral immune changes. We found that repeated social defeat stress in adult male Sprague-Dawley rats increased the frequencies of mature T-cells positive for intracellular type 2-like cytokine and serum pro-inflammatory cytokines. Principal component analysis and hierarchical clustering was used to guide grouping of T-cells and cytokines, producing unique profiles. Stress shifted the balance towards a specific set that included mostly type 2-like T-cells and pro-inflammatory cytokines. Within the CNS component, repeated stress caused an increase of activated microglia in the BLA, increased anxiety-like behaviors across several assays, and increased BLA neuronal firing in vivo that was prevented by blockade of microglia activation. Because repeated stress can trigger anxiety states by actions in the BLA, and altered immune function can trigger anxiety, these results suggest that repeated stress may trigger anxiety-like behaviors by inducing a pro-inflammatory state in the periphery and the BLA. These results begin to uncover how stress may recruit the immune system to alter the function of brain regions critical to emotion.

    更新日期:2019-11-28
  • Accumulation of affective symptoms and midlife cognitive function: the role of inflammation
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-27
    Amber John, Jennifer Rusted, Marcus Richards, Darya Gaysina

    Background The aim of the present study was to test whether C-Reactive Protein (CRP), a proxy measure of inflammation, is elevated in people with higher child and adulthood affective symptoms and whether elevated CRP predicts midlife cognitive function. Methods Data were used from the National Child Development Study (n = 6276). Measures of memory, verbal fluency, information processing speed and accuracy were available in midlife (age 50). Affective symptoms were assessed in childhood (ages 7, 11, 16) and in adulthood (ages 23, 33, 42, 50). The level of plasma CRP was measured at age 44. Pathway models, unadjusted and fully adjusted for sex, education, childhood socioeconomic position, childhood cognitive ability and affective symptoms at age 50, were fitted to test direct associations between affective symptoms and midlife cognitive function, and indirect associations via the inflammatory pathway (CRP level). Results In a fully adjusted model, there were significant indirect associations between adult affective symptoms and immediate memory (β=-0.01, SE=0.003, p=.03) and delayed memory (β=-0.01, SE=0.004, p=.03) via CRP. In addition, there were significant indirect associations between affective symptoms in childhood and immediate memory (β=-0.001, SE=0.00, p=.03) and delayed memory (β=-0.001, SE=0.001, p=.03), via adult affective symptoms and associated CRP. Independent of CRP, there was a significant direct association between adult affective symptoms and information processing errors (β=0.47, SE=0.21, p=.02). There were no direct or indirect associations between affective symptoms and verbal fluency or information processing speed. Conclusions CRP at age 44 is elevated in people with higher affective symptoms from age 7 to 42, and elevated CRP is associated with poorer immediate and delayed memory at age 50.

    更新日期:2019-11-28
  • Prenatal low-dose penicillin results in long-term sex-specific changes to murine behaviour, immune regulation, and gut microbiota
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-27
    Kevin Champagne-Jorgensen, M. Firoz Mian, Sebastian Kay, Hila Hanani, Oren Ziv, Karen-Anne McVey Neufeld, Omry Koren, John Bienenstock

    Growing evidence suggests that environmental disruptors of maternal microbes may have significant detrimental consequences for the developing fetus. Antibiotic exposure during early life can have long-term effects on neurodevelopment in mice and humans. Here we explore whether exposure to low-dose penicillin during only the last week of gestation in mice has long-term effects on offspring behaviour, brain, immune function, and gut microbiota. We found that this treatment had sex-specific effects in the adult mouse offspring. Female, but not male, mice demonstrated decreased anxiety-like behaviours, while male, but not female, mice had abnormal social behaviours which correlated with altered brain expression of AVPR1A, AVPR1B, and OXTR, and decreases in the balance of splenic FOXP3+ regulatory T cells. Prenatal penicillin exposure also led to distinct microbiota compositions that clustered differently by sex. These data suggest that exposure of pregnant mice to even a low dose of penicillin through only the last week before birth is nonetheless sufficient to induce long-term sex-specific developmental changes in both male and female offspring.

    更新日期:2019-11-28
  • Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-27
    Pernille M. Madsen, Haritha L. Desu, Juan Pablo de Rivero Vaccari, Yoleinny Florimon, Ditte G. Ellman, Robert W. Keane, Bettina H. Clausen, Kate L. Lambertsen, Roberta Brambilla

    The pleotropic cytokine tumor necrosis factor (TNF) is involved in the pathophysiology of multiple sclerosis (MS). In various models of MS, including experimental autoimmune encephalomyelitis (EAE), the membrane-bound form of TNF (tmTNF), which signals primarily via TNFR2, mediates protective and reparative effects, whereas the soluble form (solTNF), which signals primarily via TNFR1, promotes pro-inflammatory and detrimental functions. In this study, we investigated the role of TNFR2 expressed in the oligodendrocyte in the early phase of EAE pathogenesis. We demonstrated that mice with specific ablation of oligodendroglial TNFR2 displayed early onset and higher peak of motor dysfunction when subjected to EAE, in advance of which accelerated infiltration of immune cells was observed as early as 10 days post EAE induction. The immune cell influx was preceded by microglial activation and increased blood brain barrier permeability. Lack of oligodendroglial TNFR2 accelerated the expression of inflammatory cytokines as well as expression and activation of the inflammasome. Gene expression profiling of oligodendrocytes sorted from the spinal cord 14 days post EAE induction showed robust upregulation of inflammatory genes, some of which were elevated in cells lacking TNFR2 compared to controls. Together, our data demonstrate that oligodendrocytes are directly involved in inflammation and immune modulation in CNS disease and this function is regulated, at least in part, by TNFR2.

    更新日期:2019-11-28
  • The association between obesity and lower working memory is mediated by inflammation: Findings from a nationally representative dataset of U.S. adults
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-27
    Yingkai Yang, Grant S. Shields, Qian Wu, Yanling Liu, Hong Chen, Cheng Guo

    Obesity is often accompanied by lower working memory (e.g., a lower ability to keep goal-relevant information in mind) relative to healthy weight individuals. Understanding this relative working memory impairment has important clinical implications, as working memory is thought to facilitate adherence to weight management programs. Theoretical models of obesity, self-regulation, and inflammation suggest that inflammation plays a role in obesity-related working memory impairments, but to date no study has tested this prediction. Therefore, the current study examined whether inflammation statistically mediated the relationship between obesity and working memory in a nationally representative dataset of U.S. adults from Wave IV of The National Longitudinal Study of Adolescent to Adult Health (N=11,546, age range 25–34). Inflammation was quantified via C-reactive protein (CRP) level, and working memory was assessed using a modified digit span backward task. As expected, cross-sectional analyses showed that a body mass index (BMI) indicative of obesity—as well as greater BMI when BMI was analyzed continuously—and greater CRP were each related to lower working memory. Critically, we found that CRP levels statistically mediated the relationships between obesity/greater BMI and working memory, with CRP accounting for 44.1% of the variance explained in working memory by BMI. Moreover, these findings held both with and without controlling for relevant covariates, including demographic characteristics (e.g., age), socioeconomic status, and behavioral factors (e.g., smoking). Our results therefore point to inflammation as playing an important role in the relationship between obesity and working memory, and suggest that interventions aimed at reducing inflammation may help lessen the cognitive burden of obesity.

    更新日期:2019-11-28
  • Biological motion during inflammation in humans
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-27
    J. Lasselin, T. Sundelin, P.M. Wayne, M.J. Olsson, S. Paues Göranson, J. Axelsson, M. Lekander

    Biological motion is a powerful perceptual cue that can reveal important information about the inner state of an individual. Activation of inflammatory processes likely leads to changes in gait, posture, and mobility patterns, but the specific characteristics of inflammation-related biological motion have not been characterized. The aim of this study was to determine the effect of inflammation on gait and motion in humans. Systemic inflammation was induced in 19 healthy volunteers with an intravenous injection of lipopolysaccharide (2 ng/kg body weight). Biological motion parameters (walking speed, stride length and time, arm, leg, head, and shoulder angles) were assessed during a walking paradigm and the timed-up-and-go test. Cytokine concentrations, body temperature, and sickness symptoms were measured. During inflammation, compared to placebo, participants exhibited shorter, slower, and wider strides, less arm extension, less knee flexion, and a more downward-tilting head while walking. They were also slower and took shorter first steps in the timed-up-and-go test. Higher interleukin-6 concentrations, stronger sickness symptoms, and lower body temperature predicted the inflammation-related alterations in biological motion. These findings show that biological motion contains clear information about the inflammatory status of an individual, and may be used by peers or artificial intelligence to recognize that someone is sick or contagious.

    更新日期:2019-11-28
  • Loss of tissue-nonspecific alkaline phosphatase (TNAP) enzyme activity in cerebral microvessels is coupled to persistent neuroinflammation and behavioral deficits in late sepsis
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-25
    Divine C. Nwafor, Sreeparna Chakraborty, Allison L. Brichacek, Sujung Jun, Catheryne A. Gambill, Wei Wang, Elizabeth B. Engler-Chiurazzi, Duaa Dakhlallah, Anthony B. Pinkerton, José Luis Millán, Stanley A. Benkovic, Candice M. Brown

    Sepsis is a host response to systemic inflammation and infection that may lead to multi-organ dysfunction and eventual death. While acute brain dysfunction is common among all sepsis patients, chronic neurological impairment is prevalent among sepsis survivors. The brain microvasculature has emerged as a major determinant of sepsis-associated brain dysfunction, yet the mechanisms that underlie its associated neuroimmune perturbations and behavioral deficits are not well understood. An emerging body of data suggests that inhibition of tissue-nonspecific alkaline phosphatase (TNAP) enzyme activity in cerebral microvessels may be associated with changes in endothelial cell barrier integrity. The objective of this study was to elucidate the connection between alterations in cerebrovascular TNAP enzyme activity and brain microvascular dysfunction in late sepsis. We hypothesized that the disruption of TNAP enzymatic activity in cerebral microvessels would be coupled to the sustained loss of brain microvascular integrity, elevated neuroinflammatory responses, and behavioral deficits. Male mice were subjected to cecal ligation and puncture (CLP), a model of experimental sepsis, and assessed up to seven days post-sepsis. All mice were observed daily for sickness behavior and underwent behavioral testing. Our results showed a significant decrease in brain microvascular TNAP enzyme activity in the somatosensory cortex and spinal cord of septic mice but not in the CA1 and CA3 hippocampal regions. Furthermore, we showed that loss of cerebrovascular TNAP enzyme activity was coupled to a loss of claudin-5 and increased perivascular IgG infiltration in the somatosensory cortex. Analyses of whole brain myeloid and T-lymphoid cell populations also revealed a persistent elevation of infiltrating leukocytes, which included both neutrophil and monocyte myeloid derived suppressor cells (MDSCs). Regional analyses of the somatosensory cortex, hippocampus, and spinal cord revealed significant astrogliosis and microgliosis in the cortex and spinal cord of septic mice that was accompanied by significant microgliosis in the CA1 and CA3 hippocampal regions. Assessment of behavioral deficits revealed no changes in learning and memory or evoked locomotion. However, the hot plate test uncovered a novel anti-nociceptive phenotype in our septic mice, and we speculate that this phenotype may be a consequence of sustained GFAP astrogliosis and loss of TNAP activity in the somatosensory cortex and spinal cord of septic mice. Taken together, these results demonstrate that the loss of TNAP enzyme activity in cerebral microvessels during late sepsis is coupled to sustained neuroimmune dysfunction which may underlie, in part, the chronic neurological impairments observed in sepsis survivors.

    更新日期:2019-11-26
  • Adolescent microglia play a role in executive function in male mice exposed to perinatal high fat diet
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-23
    Brittany L. Smith, Collin J. Laaker, Kelsey R. Lloyd, Adam R. Hiltz, Teresa M. Reyes

    In humans, excessive gestational weight gain during pregnancy is associated with an increased risk for executive function deficits in the offspring. Our previous work has confirmed this finding in mice, as offspring from dams fed a 60% high fat (HF) diet during breeding, gestation, and lactation demonstrate impulsive-like behavior in the 5 choice serial reaction time task (5CSRTT). Because the prefrontal cortex (PFC), which plays a key role in executive function, undergoes substantial postnatal adolescent pruning and microglia are actively involved in synaptic refinement, we hypothesized that microglia may play a role in mediating changes in brain development after maternal HF diet, with a specific focus on microglial activity during adolescence. Therefore, we treated male and female offspring from HF or control diet (CD) dams with PLX3397-formulated diet (PLX) to ablate microglia during postnatal days 23-45. After PLX removal and microglial repopulation, adult mice underwent testing to evaluate executive function. Adolescent PLX treatment did increase the control male dropout rate in learning the basic FR1 task, but otherwise had a minimal effect on behavior in control offspring. In males, HF offspring learned faster and performed better on a simple operant task (fixed ratio 1) without an effect of PLX. However, in HF offspring this increase in FR1 responding was associated with more impulsive errors in the 5CSRTT while PLX eliminated this association and decreased impulsive errors specifically in HF offspring. This suggests that adolescent PLX treatment improves executive function and particularly impulsive behavior in adult male HF offspring, without an overall effect of perinatal diet. In females, maternal HF diet impaired reversal learning but PLX had no effect on performance. We then measured gene expression in adult male PFC, nucleus accumbens (NAC), and amygdala (AMG), examining targets related to synaptic function, reward, and inflammation. Maternal HF diet increased PFC synaptophysin and AMG psd95 expression. PFC synaptophysin expression was correlated with more impulsive errors in the 5CSRTT in the HF offspring only and PLX treatment eliminated this correlation. These data suggest that adolescent microglia may play a critical role in mediating executive function after perinatal high fat diet in males.

    更新日期:2019-11-26
  • Prenatal Opioid Exposure: The Next Neonatal Neuroinflammatory Disease
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-22
    Lauren L. Jantzie, Jessie R. Maxwell, Jessie C. Newville, Tracylyn R. Yellowhair, Yuma Kitase, Nethra Madurai, Sindhu Ramachandra, Ludmila N. Bakhireva, Frances J. Northington, Gwendolyn Gerner, Aylin Tekes, Lorraine A. Milio, Jonathan L. Brigman, Shenandoah Robinson, Andrea Allan

    The rates of opioid use disorder during pregnancy have more than quadrupled in the last decade, resulting in numerous infants suffering exposure to opioids during the perinatal period, a critical period of central nervous system (CNS) development. Despite increasing use, the characterization and definition of the molecular and cellular mechanisms of the long-term neurodevelopmental impacts of opioid exposure commencing in utero remains incomplete. Thus, in consideration of the looming public health crisis stemming from the multitude of infants with prenatal opioid exposure entering school age, we undertook an investigation of the effects of perinatal methadone exposure in a novel preclinical model. Specifically, we examined the effects of opioids on the developing brain to elucidate mechanisms of putative neural cell injury, to identify diagnostic biomarkers and to guide clinical studies of outcome and follow-up. We hypothesized that methadone would induce a pronounced inflammatory profile in both dams and their pups, and be associated with immune system dysfunction, sustained CNS injury, and altered cognition and executive function into adulthood. This investigation was conducted using a combination of cellular, molecular, biochemical, and clinically translatable biomarker, imaging and cognitive assessment platforms. Data reveal that perinatal methadone exposure increases inflammatory cytokines in the neonatal peripheral circulation, and reprograms and primes the immune system through sustained peripheral immune hyperactivity. In the brain, perinatal methadone exposure not only increases chemokines and cytokines throughout a crucial developmental period, but also alters microglia morphology consistent with activation, and upregulates TLR4 and MyD88 mRNA. This increase in neuroinflammation coincides with reduced myelin basic protein and altered neurofilament expression, as well as reduced structural coherence and significantly decreased fractional anisotropy on diffusion tensor imaging. In addition to this microstructural brain injury, adult rats exposed to methadone in the perinatal period have significant impairment in associative learning and executive control as assessed using touchscreen technology. Collectively, these data reveal a distinct systemic and neuroinflammatory signature associated with prenatal methadone exposure, suggestive of an altered CNS microenvironment, dysregulated developmental homeostasis, complex concurrent neural injury, and imaging and cognitive findings consistent with clinical literature. Further investigation is required to define appropriate therapies targeted at the neural injury and improve the long-term outcomes for this exceedingly vulnerable patient population.

    更新日期:2019-11-22
  • Feeling Needed: Effects of A Randomized Generativity Intervention on Well-Being and Inflammation in Older Women
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-20
    Mona Moieni, Michael R. Irwin, Teresa E. Seeman, Theodore F. Robles, Matthew D. Lieberman, Elizabeth C. Breen, Stephanie Okimoto, Clara Lengacher, Jesusa M. G. Arevalo, Richard Olmstead, Steven W. Cole, Naomi I. Eisenberger

    Generativity, or concern for and contribution to the well-being of younger generations, plays an important role in successful aging. The purpose of this study was to develop a novel, writing-based intervention to increase feelings of generativity and test the effect of this intervention on well-being and inflammation in a sample of older women. Participants in this study (n=73; mean age = 70.9 years, range 60-86 years) were randomly assigned to a 6-week generativity writing condition (writing about life experiences and sharing advice with others) or a control writing condition (neutral, descriptive writing). Self-reported measures of social well-being, mental health, and physical health, as well as objective measures of systemic and cellular levels of inflammation (plasma pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α; genome-wide RNA transcriptional profiling), were assessed pre- and post-intervention. The generativity intervention led to significant improvements across multiple domains, including increases in participation in social activities, decreases in psychological distress, more positive expectations regarding aging in the physical health domain, and decreases in pro-inflammatory gene expression. Thus, this study provides preliminary evidence for the ability of a novel, low-cost, low-effort intervention to favorably impact inflammation and well-being in older women.

    更新日期:2019-11-20
  • Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/ chronic fatigue syndrome
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-20
    Akiko Eguchi, Sanae Fukuda, Hirohiko Kuratsune, Junzo Nojima, Yasuhito Nakatomi, Yasuyoshi Watanabe, Ariel E. Feldstein

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.

    更新日期:2019-11-20
  • Do upsetting life events explain the relationship between low socioeconomic status and systemic inflammation in childhood? Results from a longitudinal study
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-19
    Theodora Kokosi, Eirini Flouri, Emily Midouhas

    Background Children from families of low socioeconomic status (SES) are more likely to be exposed to upsetting situations and stressors. Such exposures have, in turn, been linked to inflammation in some studies. In this study we explore if low SES is related to inflammation in children via such stressful life events. Methods Data on 4,525 children of the Avon Longitudinal Study of Parents and Children, a general population birth cohort, were used to explore associations between SES at ages 0-3 years, upsetting life events at ages 3-9 years and inflammatory markers [interleukin 6 (IL-6) and C-reactive protein (CRP)] at age 9 years. Confounders included body mass index, gender, financial problems, and upsetting life events at ages 0-3 years. Results Using Structural Equation Modelling, we found that early socioeconomic disadvantage predicted higher levels of IL-6 (β=0.034, 95% CI=0.063, 0.005) even after adjusting for confounders. This association was partially mediated by upsetting life events (β=0.003, 95% CI=0.011, 0.001). Conclusions In the general child population, low SES is associated with increased exposure to stressful life events, in turn associated with later inflammation. These findings highlight the role of stressors associated with poverty and disadvantage in the development of inflammation among children in the general population.

    更新日期:2019-11-19
  • Deletion of equilibrative nucleoside transporter-2 protects against lipopolysaccharide-induced neuroinflammation and blood-brain barrier dysfunction in mice
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-18
    Kuo-Chen Wu, Chih-Yu Lee, Fang-Yi Chou, Yijuang Chern, Chun-Jung Lin

    Neuroinflammation is a common pathological feature of many brain diseases and is a key mediator of blood-brain barrier (BBB) breakdown and neuropathogenesis. Adenosine is an endogenous immunomodulator, whose brain extracellular level is tightly controlled by equilibrative nucleoside transporters-1 (ENT1) and ENT2. This study was aimed to investigate the role of ENTs in the modulation of neuroinflammation and BBB function. The results showed that mRNA level of Ent2 was significantly more abundant than that of Ent1 in the brain (hippocampus, cerebral cortex, striatum, midbrain, and cerebellum) of wild-type (WT) mice. Ent2-/- mice displayed higher extracellular adenosine level in the hippocampus than their littermate controls. Repeated lipopolysaccharide (LPS) treatment induced microglia activation, astrogliosis and upregulation of proinflammatory cytokines, along with aberrant BBB phenotypes (including reduced tight junction protein expression, pericyte loss, and immunoglobulin G extravasation) and neuronal apoptosis in the hippocampus of WT mice. Notably, Ent2-/- mice displayed significant resistance to LPS-induced neuroinflammation, BBB breakdown, and neurotoxicity. These findings suggest that Ent2 is critical for the modulation of brain adenosine tone and deletion of Ent2 confers protection against LPS-induced neuroinflammation and neurovascular-associated injury.

    更新日期:2019-11-19
  • Are we all the same? The critical role of translational brain, behavior, and immunity research in East Asia
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-07-11
    Kuan-Pin Su

    Traditional Chinese medicine (TCM) is founded on the idea that the “Mind and Body” are all interconnected. When you have a difficult time or disturbing lifestyle and experience a series of somatic and psychological symptoms mimicking inflammation-induced sickness behaviors, the TCM practitioners would be very likely to give you a diagnosis of “On Fire” and prescribe specific food intervention and herbal medicine, which might be considered anti-inflammatory to “cool you down.” Psychoneuroimmunology has been long stemmed in ancient medicine.

    更新日期:2019-11-18
  • Inhibition of CD147 improves oligodendrogenesis and promotes white matter integrity and functional recovery in mice after ischemic stroke
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-07-26
    Shan Liu, Rong Jin, Adam Y. Xiao, Wei Zhong, Guohong Li

    White matter damage is an important contributor to long-term neurological deficit after stroke. Our previous study has shown that inhibition of CD147 ameliorates acute ischemic stroke in mice. In this study, we aimed to investigate whether inhibition of CD147 promotes white matter repair and long-term functional recovery after ischemic stroke. Male adult C57BL/6 mice were subjected to transient (1-h) middle cerebral artery occlusion (tMCAO). Anti-CD147 function–blocking antibody (αCD147) was injected intravenously once daily for 3 days beginning 4 h after onset of ischemia. Sensorimotor and cognitive functions were evaluated up to 28 days after stroke. We found that αCD147 treatment not only prevented neuronal and oligodendrocyte cell death in the acute phase, but also profoundly protected white matter integrity and reduced brain atrophy and tissue loss in the late phase, leading to improved sensorimotor and cognitive functions for at least 28 days after stroke. Mechanistically, we found that αCD147 treatment increased the number of proliferating NG2(+)/PDGFRα(+) oligodendrocyte precursor cells (OPCs) and newly generated mature APC(+)/Sox10(+) oligodendrocytes after stroke, possibly through upregulation of SDF-1/CXCR4 axis in OPCs. In conclusion, inhibition of CD147 promotes long-term functional recovery after stroke, at least in part, by enhancing oligodendrogenesis and white matter repair.

    更新日期:2019-11-18
  • Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-07-26
    Zinah Zamil Al-Ghezi, Philip Brandon Busbee, Hasan Alghetaa, Prakash S. Nagarkatti, Mitzi Nagarkatti

    Currently, a combination of marijuana cannabinoids including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is used as a drug to treat muscle spasticity in patients with Multiple Sclerosis (MS). Because these cannabinoids can also suppress inflammation, it is unclear whether such patients benefit from suppression of neuroinflammation and if so, what is the mechanism through which cannabinoids act. In the currently study, we used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to study the role of gut microbiota in the attenuation of clinical signs of paralysis and inflammation caused by cannabinoids. THC + CBD treatment attenuated EAE and caused significant decrease in inflammatory cytokines such as IL-17 and IFN-γ while promoting the induction of anti-inflammatory cytokines such as IL-10 and TGF-β. Use of 16S rRNA sequencing on bacterial DNA extracted from the gut revealed that EAE mice showed high abundance of mucin degrading bacterial species, such as Akkermansia muciniphila (A. muc), which was significantly reduced after THC + CBD treatment. Fecal Material Transfer (FMT) experiments confirmed that THC + CBD-mediated changes in the microbiome play a critical role in attenuating EAE. In silico computational metabolomics revealed that LPS biosynthesis, a key component in gram-negative bacteria such as A. muc, was found to be elevated in EAE mice which was confirmed by demonstrating higher levels of LPS in the brain, while treatment with THC + CBD reversed this trend. EAE mice treated with THC + CBD also had significantly higher levels of short chain fatty acids such as butyric, isovaleric, and valeric acids compared to naïve or disease controls. Collectively, our data suggest that cannabinoids may attenuate EAE and suppress neuroinflammation by preventing microbial dysbiosis seen during EAE and promoting healthy gut microbiota.

    更新日期:2019-11-18
  • A proinflammatory diet is associated with inflammatory gene expression among healthy, non-obese adults: Can social ties protect against the risks?
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-07-26
    Avelina C. Padin, James R. Hébert, Alex Woody, Stephanie J. Wilson, Nitin Shivappa, Martha A. Belury, William B. Malarkey, John F. Sheridan, Janice K. Kiecolt-Glaser

    The Western diet, characterized by high intake of saturated fat, sugar, and salt, is associated with elevated inflammation and chronic disease risk. Few studies have investigated molecular mechanisms linking diet and inflammation; however, a small number of randomized controlled trials suggest that consuming an anti-inflammatory diet (i.e., a primarily plant-based diet rich in monounsaturated fat and lean protein) decreases proinflammatory gene expression. The current study investigated the association between everyday diet and proinflammatory gene expression, as well as the extent to which central adiposity and social involvement modulate risk. Participants were healthy middle-aged and older adults (N = 105) who completed a food frequency questionnaire and reported how many close social roles they have. Anthropometric measurements and blood samples also were collected; gene expression data were analyzed from LPS-stimulated peripheral blood mononuclear cells for interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. The inflammatory potential of each participant’s diet was calculated using the Dietary Inflammatory Index (DII®). Participants with higher DII® scores, indicating a more proinflammatory diet, had greater IL-6 (b = −0.02, SE = 0.008, p = .01), IL-1β (b = −0.01, SE = 0.006, p = .03), and TNF-α (b = −0.01, SE = 0.005, p = .04) gene expression if they had a smaller sagittal abdominal diameter (SAD); effects were not seen among those with higher SADs. Social involvement served a protective role, such that participants with smaller SADs had greater IL-6 (b = 0.01, SE = 0.004, p = .049) and IL-1β (b = 0.01, SE = 0.003, p = .045) gene expression only if they had less social involvement; there was no effect of diet on gene expression among those who reported greater social participation. Results are the first to demonstrate a link between self-reported diet and proinflammatory gene expression. Importantly, the effect of diet on gene expression depended upon both body fat composition and social participation, both of which have previously been linked directly with proinflammatory gene expression and inflammation.

    更新日期:2019-11-18
  • Complement activation sustains neuroinflammation and deteriorates adult neurogenesis and spatial memory impairment in rat hippocampus following sleep deprivation
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-08-10
    Meetu Wadhwa, Amit Prabhakar, Jag Pravesh Anand, Koushik Ray, Dipti Prasad, Bhuvnesh Kumar, Usha Panjwani

    Background An association between neuroinflammation, reduced adult neurogenesis, and cognitive impairment has been established in sleep deprivation (SD). Complement receptors are expressed on neuronal and glial cells, thus, regulate the neuroinflammation, neurogenesis and learning/memory. However, understanding of the effect of SD on the brain-immune system interaction associated with cognitive dysfunction and its mechanisms is obscure. We hypothesized that complement activation induced changes in inflammatory and neurogenesis related proteins might be involved in the cognitive impairment during SD. Methodology Adult male Sprague Dawley rats were used. Rats were sleep deprived for 48 h using a novel automated SD apparatus. Dosage of BrdU (50 mg/kg/day, i.p. in 0.07 N NaOH), complement C3a receptor antagonist (C3aRA; SB290157; 1 mg/kg/day, i.p.) in 1.16% v/v PBS and complement C5a receptor antagonist (C5aRA; W-54011; 1 mg/kg/day, i.p.) in normal saline were used. Rats were subjected to spatial memory evaluation following SD. Hippocampal tissue was collected for biochemical, molecular, and immunohistochemical studies. T-test and ANOVA were used for the statistical analysis. Results An up-regulation in the levels of complement components (C3, C5, C3a, C5a) and receptors (C3aR and C5aR) in hippocampus, displayed the complement activation during SD. Selective antagonism of C3aR/C5aR improved the spatial memory performance of sleep-deprived rats. C3aR antagonist (C3aRA) or C5aR antagonist (C5aRA) treatment inhibited the gliosis, maintained inflammatory cytokines balance in hippocampus during SD. Complement C3aR/C5aR antagonism improved hippocampal adult neurogenesis via up-regulating the BDNF level following SD. Administration of C3aRA and C5aRA significantly maintained synaptic homeostasis in hippocampus after SD. Gene expression analysis showed down-regulation in the mRNA levels of signal transduction pathways (Notch and Wnt), differentiation and axogenous proteins, which were found to be improved after C3aRA/C5aRA treatment. These findings were validated at protein and cellular level. Changes in the corticosterone level and ATP-adenosine-NO pathway were established as the key mechanisms underlying complement activation mediated consequences of SD. Conclusion Our study suggests complement (C3a-C3aR and C5a-C5aR) activation as the novel mechanism underlying spatial memory impairment via promoting neuroinflammation and adult neurogenesis decline in hippocampus during SD, thereby, complement (C3aR/C5aR) antagonist may serve as the novel therapeutics to improve the SD mediated consequences.

    更新日期:2019-11-18
  • Contribution of individual psychological and psychosocial factors to symptom severity and time-to-recovery after naturally-occurring acute infective illness: The Dubbo Infection Outcomes Study (DIOS)
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-07-31
    Erin Cvejic, Hui Li, Ian B. Hickie, Denis Wakefield, Andrew R. Lloyd, Uté Vollmer-Conna

    Background Substantial heterogeneity exists in both the severity of symptoms experienced as part of the sickness response to naturally-occurring infections, and the time taken for individuals to recover from these symptoms. Although contributing immunological and genetic factors have been previously been explored, less is known about the role of individual psychological and psychosocial factors, which may modulate the host immune response, or contribute independently, to symptom severity and duration. Methods Longitudinally-collected data from 484 Caucasian participants (mean age: 33.5 years; 51% women) experiencing a naturally-occurring acute infective illness enrolled in the prospective Dubbo Infection Outcome Study (DIOS) were analysed. At intake and subsequent follow-up assessments, self-report questionnaires were used to ascertain individual psychological and psychosocial characteristics and symptom information. Principal component analysis was applied to symptom data to derive endophenotype severity scores representing discrete symptom domains (fatigue, mood, pain, neurocognitive difficulties) and an overall index of severity. The contribution of individual psychological (trait neuroticism, locus of control, and illness behaviours) and psychosocial factors (relative socioeconomic advantage) to endophenotype severity at baseline were examined using multivariable linear regression models; interval-censored flexible parametric proportional hazards survival models were used to explore time to recovery (defined using within-sample negative threshold values). Results After controlling for time since symptom onset, greater levels of trait neuroticism consistently predicted greater symptom severity across all symptom domains (all p’s < 0.015). Similarly, greater relative socioeconomic disadvantage was significantly associated with greater severity across all endophenotypes (p’s < 0.025) except neurocognitive disturbance. Locus of control and illness behaviours contributed differentially across endophenotypes. Reduced likelihood of recovery was significantly predicted by greater initial symptom severity for all endophenotypes (all p’s < 0.001), as well as higher levels of trait neuroticism. Conclusions Individual psychological and psychosocial factors contribute to the initial severity and to the prolonged course of symptoms after naturally-occurring infective illnesses. These factors may play an independent role, represent a bias in symptom reporting, or reflect increased stress responsivity and a heightened inflammatory response. Objective metrics for severity and recovery are required to further elucidate their roles.

    更新日期:2019-11-18
  • Mold inhalation causes innate immune activation, neural, cognitive and emotional dysfunction
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-18
    Cheryl F. Harding, Carolyn L. Pytte, Kimberly G. Page, Kelly J. Ryberg, Edna Normand, Gregory J. Remigio, Richard A. DeStefano, David B. Morris, Julia Voronina, Ariel Lopez, Lauren A. Stalbow, Erin P. Williams, ohely Abreu

    Individuals living or working in moldy buildings complain of a variety of health problems including pain, fatigue, increased anxiety, depression, and cognitive deficits. The ability of mold to cause such symptoms is controversial since no published research has examined the effects of controlled mold exposure on brain function or proposed a plausible mechanism of action. Patient symptoms following mold exposure are indistinguishable from those caused by innate immune activation following bacterial or viral exposure. We tested the hypothesis that repeated, quantified doses of both toxic and nontoxic mold stimuli would cause innate immune activation with concomitant neural effects and cognitive, emotional, and behavioral symptoms. We intranasally administered either 1) intact, toxic Stachybotrys spores; 2) extracted, nontoxic Stachybotrys spores; or 3) saline vehicle to mice. As predicted, intact spores increased interleukin-1β immunoreactivity in the hippocampus. Both spore types decreased neurogenesis and caused striking memory deficits in young mice, while decreasing pain thresholds and enhancing auditory-cued memory in older mice. Nontoxic spores also increased anxiety-like behavior. Levels of hippocampal immune activation correlated with decreased neurogenesis, contextual memory deficits, and/or enhanced auditory-cued fear memory. Innate-immune activation may explain how both toxic mold and nontoxic mold skeletal elements caused cognitive and emotional dysfunction.

    更新日期:2019-11-18
  • Epigenetic upregulation of hippocampal CXCL12 contributes to context spatial memory-associated morphine conditioning
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-11-18
    Guan-Xi Liu, Jia-You Wei, Meng Liu, Wen-Jing Shi, Liang-Huan Song, Shang Li, Shi-Qi Zhu, Wen-Jun Xin, Xue-Qin Zhang

    Conditioned place preference (CPP) is a learned behavior, in which animals learn to associate environmental contexts with rewarding effects. The formation of CPP is an integrated outcome of multiple learning processes. Although multiple anatomical substrates underlying this contextual learning have been proposed, it remains unknown whether a specific molecular signaling pathway within CA1 mediates context learning associated with morphine conditioning. Here, we showed that repeated context learning associated with morphine conditioning significantly increased CXCL12 levels in hippocampal CA1 neurons, and the inhibition of CXCL12 expression ameliorated the CPP behavior following context exposure with morphine conditioning. Additionally, repeated context exposure with morphine conditioning increased the phosphorylation of STAT3 and the acetylation of histone H4 in CXCL12-expressing neurons in CA1. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that repeated context exposure with morphine conditioning increased the binding of STAT3 to the CXCL12 gene promoter and the interaction between STAT3 and p300, which contributed to the enhanced transcription of CXCL12 by increasing the acetylation of histone H4 in the CXCL12 gene promoter. The inhibition of STAT3 by intrathecal injection of S3I-201 suppressed the acetylation of histone H4. These data demonstrated the epigenetic upregulation of CXCL12 following repeated context exposure with morphine conditioning, which potentially contributed to the spatial memory consolidation associated with conditioned place preference induced by morphine conditioning.

    更新日期:2019-11-18
  • Circadian and circannual timescales interact to generate seasonal changes in immune function
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-07-24
    Kenneth G. Onishi, Andrew C. Maneval, Erin C. Cable, Mary Claire Tuohy, Andrew J. Scasny, Evelina Sterina, Jharnae A. Love, Jonathan P. Riggle, Leah K. Malamut, Aashna Mukerji, Jennifer S. Novo, Abena Appah-Sampong, Joseph B. Gary, Brian J. Prendergast

    Annual changes in day length enhance or suppress diverse aspects of immune function, giving rise to seasonal cycles of illness and mortality. The daily light–dark cycle also entrains circadian rhythms in immunity. Most published reports on immunological seasonality rely on measurements or interventions performed only at one point in the day. Because there can be no perfect matching of circadian phase across photoperiods of different duration, the manner in which these timescales interact to affect immunity is not understood. We examined whether photoperiodic changes in immune function reflect phenotypic changes that persist throughout the daily cycle, or merely reflect photoperiodic shifts in the circadian phase alignment of immunological rhythms. Diurnal rhythms in blood leukocyte trafficking, infection induced sickness responses, and delayed-type hypersensitivity skin inflammatory responses were examined at high-frequency sampling intervals (every 3 h) in Siberian hamsters (Phodopus sungorus) following immunological adaptation to summer or winter photoperiods. Photoperiod profoundly enhanced or suppressed immune function, in a trait-specific manner, and we were unable to identify a phase alignment of diurnal waveforms which eliminated these enhancing and suppressing effects of photoperiod. These results support the hypothesis that seasonal timescales affect immunity via mechanisms independent of circadian entrainment of the immunological circadian waveform.

    更新日期:2019-11-18
  • S-adenosyl-l-methionine (SAMe), cannabidiol (CBD), and kratom in psychiatric disorders: Clinical and mechanistic considerations
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-07-10
    M. Taylor Levine, Jin Gao, Senthil Kumaran Satyanarayanan, Sarah Berman, Jack T. Rogers, David Mischoulon

    Given the limitations of prescription antidepressants, many individuals have turned to natural remedies for the management of their mood disorders. We review three selected natural remedies that may be of potential use as treatments for depressive disorders and other psychiatric or neurological conditions. The best studied and best supported of these three remedies is S-adenosyl-l-methionine (SAMe), a methyl donor with a wide range of physiological functions in the human organism. With the increasing legalization of cannabis-related products, cannabidiol (CBD) has gained popularity for various potential indications and has even obtained approval in the United States and Canada for certain neurological conditions. Kratom, while potentially useful for certain individuals with psychiatric disorders, is perhaps the most controversial of the three remedies, in view of its greater potential for abuse and dependence. For each remedy, we will review indications, doses and delivery systems, potential anti-inflammatory and immunomodulatory action, adverse effects, and will provide recommendations for clinicians who may be considering prescribing these remedies in their practice.

    更新日期:2019-11-18
  • Brain eicosapentaenoic acid metabolism as a lead for novel therapeutics in major depression
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-07-03
    Richard P. Bazinet, Adam H. Metherel, Chuck T. Chen, Saame Raza Shaikh, Agnes Nadjar, Corinne Joffre, Sophie Layé

    The results of several meta-analyses suggest that eicosapentaenoic acid (EPA) supplementation is therapeutic in managing the symptoms of major depression. It was previously assumed that because EPA is extremely low in the brain it did not cross the blood-brain barrier and any therapeutic effects it exerted would be via the periphery. However, more recent studies have established that EPA does enter the brain, but is rapidly metabolised following entry. While EPA does not accumulate within the brain, it is present in microglia and homeostatic mechanisms may regulate its esterification to phospholipids that serve important roles in cell signaling. Furthermore, a variety of signaling molecules from EPA have been described in the periphery and they have the potential to exert effects within the brain. If EPA is confirmed to be therapeutic in major depression as a result of adequately powered randomized clinical trials, future research on brain EPA metabolism could lead to the discovery of novel targets for treating or preventing major depression.

    更新日期:2019-11-18
  • Altered gut microbiota and mucosal immunity in patients with schizophrenia
    Brain Behav. Immun. (IF 6.170) Pub Date : 2019-06-27
    Ruihuan Xu, Bingbing Wu, Jingwen Liang, Fusheng He, Wen Gu, Kang Li, Yi Luo, Jianxia Chen, Yongbo Gao, Ze Wu, Yongqiang Wang, Wenhao Zhou, Mingbang Wang

    Evidence shows that gut microbiota may play important roles in schizophrenia pathogenesis via the “gut-brain” axis, but the mechanisms remain unclear. Here, eighty-four patients with schizophrenia and 84 sex- and age-matched healthy controls were enrolled. Shotgun metagenomic sequencing and 16S rRNA sequencing were performed, and the gut microbiota-associated epitopes (MEs) were predicted, which, together with IgA content, were used to determine the gut microbiota composition associated with gut immune status. Patients with schizophrenia had significantly reduced gut microbiota richnesses compared with those of the healthy controls, and the gut microbiota compositions clearly distinguished the patients with schizophrenia from the healthy controls. Based on two-stage metagenomic-wide association studies, nineteen gut microbiota taxonomies were associated with schizophrenia, and the microbial dysbiosis (MD) index was calculated based on the abundance of differential taxonomies. We found that MD index was positively correlated with MEs diversity and gut IgA levels, and negatively correlated with gut microbiota richness. Glutamate synthase (GOGAT) was more active in the guts of patients with schizophrenia than in those of healthy controls, and high GOGAT activity was associated with altered gut microbiota taxonomies associated with gut IgA levels. Our results may imply a role of the microbiome in the etiology of schizophrenia and contribute to the development of microbiome targeted interventions for schizophrenia.

    更新日期:2019-11-18
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