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  • Consequences of early life overfeeding for microglia – perspectives from rodent models
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-02-20
    Alita Soch; Sarah J. Spencer

    The early life period is crucially important to how the individual develops, and environmental and lifestyle challenges during this time can lead to lasting programming effects on the brain and immune system. In particular, poor diet in early development can lead to long-term negative metabolic and cognitive outcomes, with those who over-eat in early development being at risk of obesity and poor learning and memory throughout their adult lives. Current research has identified a neuroinflammatory component to this metabolic and cognitive programming that can potentially be manipulated to restore a healthy phenotype. Thus, early life over-feeding in a rat model leads to microglial priming and an exacerbated microglial response to immune challenge when the rats reach adulthood. Microglial responses to a learning task are also impaired. To specifically investigate the role of microglia in these programming effects our group has developed a novel transgenic rat with a diphtheria toxin receptor insertion in the promoter region for the Cx3cr1 gene, expressed on microglia and monocytes; allowing us to conditionally ablate microglia throughout the brain. With this model we reveal that microglia have a direct role in regulating feeding behavior and modifying cognition, but are not likely to be the sole mechanism by which early life overfeeding confers lasting neuroimmune and cognitive effects. Additional work implicates changes to the hypothalamic-pituitary-adrenal axis in this. Together these data highlight the importance of dietary choices in early life and the potential for positive interventions targeting the neuroimmune and neuroendocrine stress systems to reverse such programming damage.

  • Depression and suicidality: A link to premature T helper cell aging and increased Th17 cells
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-02-14
    Schiweck Carmen; Mireia Valles-Colomer; Volker Arolt; Norbert Müller; Jeroen Raes; Annemarie Wijkhuijs; Stephan Claes; Hemmo Drexhage; Vrieze Elske

    Background Previous research has demonstrated a strong link between immune system abnormalities and Major Depressive Disorder (MDD). High suicide risk is a major complication of MDD and has recently been linked to strong (neuro-)immune alterations, but little is known on the link between circulating immune cell composition and suicidal risk status. Methods Here, we assessed percentages of circulating peripheral blood mononuclear cells with focus on T helper cell subsets (memory T helper cells, Th1, Th2, Th17 and T regulatory cells) in a large and well-matched cohort of 153 patients diagnosed with MDD and 153 age and sex matched controls. We explored the association of these cell populations with suicide risk while accounting for age, gender, BMI, depression severity and childhood trauma. Results Patients with MDD had reduced percentages of NK cells, and higher percentages of B and T cells in line with current literature. Further exploration of T-cells revealed a robustly elevated number of memory T helper cells, regardless of age group. Patients at high risk for suicide had the highest memory T helper cells and additionally showed a robust increase of Th17 cells compared to other suicide risk groups. Conclusions The higher abundance of memory T helper cells points towards premature aging of the immune system in MDD patients, even during young adulthood. Patients at high risk for suicide show the clearest immune abnormalities and may represent a clinically relevant subtype of depression.

  • Sex differences in T cell immune responses, gut permeability and outcome after ischemic stroke in aged mice
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-02-11
    Hilda Ahnstedt; Anthony Patrizz; Anjali Chauhan; Meaghan Roy-O'Reilly; Joseph W. Furr; Monica S. Spychala; John D'Aigle; Frank W. Blixt; Liang Zhu; Javiera Bravo Alegria; Louise D. McCullough

    Introduction Stroke is a sexually dimorphic disease. While women account for more stroke deaths, recent data show that after adjusting for age and pre-stroke functional status, mortality is higher in men. Immune responses are key determinants of stroke outcome and may differ by sex. This study examined sex differences in central and peripheral T cell immune responses, systemic effects on gut permeability and microbiota diversity and behavioral outcomes after stroke in aged mice. We hypothesized that there are sex differences in the immune response to stroke in aged animals. Methods C57BL/6N mice (20-22 months) were subjected to 60 min middle cerebral artery occlusion, or sham surgery. T cells were quantified in brain and blood at 3, 7 and 15 days (d) post-stroke by flow cytometry. Peripheral effects on gut permeability and microbiota diversity, as well as neurological function were assessed up to 14d, and at 21d (cognitive function) post-stroke. Brain glial fibrillary acidic protein (GFAP) expression was evaluated at 42d post-stroke. Results and Discussion Mortality (50% vs 14%, p<0.05) and hemorrhagic transformation (44% vs 0%) were significantly higher in males than in females. No difference in infarct size at 3d were observed. Peripherally, stroke induced greater gut permeability of FITC-dextran in males at d3 (p<0.05), and non-reversible alterations in microbiota diversity in males. Following the sub-acute phase, both sexes demonstrated a time-dependent increase of CD4+ and CD8+ T cells in the brain, with significantly higher levels of CD8+ T cells and Regulatory T cells in males at d15 (p<0.01). Aged males demonstrated greater neurological deficits up to d5 and impaired sensorimotor function up to d15 when assessed by the corner asymmetry test (p<0.001 and p<0.01, respectively). A trend in greater cognitive decline was observed at d21 in males. Increased GFAP expression in the ischemic hemisphere, indicating astroglial activation and gliosis, was demonstrated in both males and females 42d post-stroke. Our findings indicate that despite a similar initial ischemic brain injury, aged male mice experience greater peripheral effects on the gut and ongoing central neuroinflammation past the sub-acute phase after stroke.

  • In-vivo imaging of neuroinflammation in Veterans with Gulf War Illness
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-02-04
    Zeynab Alshelh; Daniel S. Albrecht; Courtney Bergan; Oluwaseun Akeju; Daniel J. Clauw; Lisa Conboy; Robert R. Edwards; Minhae Kim; Yvonne C. Lee; Ekaterina Protsenko; Vitaly Napadow; Kimberly Sullivan; Marco L. Loggia

    Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes. GWI (n=15) and healthy controls (HC, n=33, including a subgroup of healthy Gulf War veterans, HCVET, n=8), were examined using integrated [11C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n=13). Whether compared to the whole HC group, or only the HCVET subgroup, veterans with GWI demonstrated widespread cortical elevations in [11C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [11C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines . Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.

  • N-methyl-D-aspartate Receptor Subunit 2B on Keratinocyte Mediates Peripheral and Central Sensitization in Chronic Post-ischemic Pain in Male Rats
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-02-04
    Xiaohan Xu; Xin Tao; Ping Huang; Feng Lin; Qing Liu; Li Xu; Jijun Xu; Yuguang Huang

    The spinal N-methyl-D-aspartate (NMDA) receptor, and particularly its NR2B subunit, plays a pivotal role in neuropathic pain. However, the role of peripheral NMDA receptor in neuropathic pain is less well understood. We first treated cultured human keratinocytes, HaCaT cells with NMDA or NR2B-specific antagonist, ifenprodil and evaluated the level of total and phosphorylated NR2B at 24h using Western blot. Next, using the chronic post-ischemia pain (CPIP) model, we administered NMDA or ifenprodil subcutaneously into the hind paws of male rats. Nociceptive behaviors were assessed by measuring mechanical and thermal withdrawal thresholds. Expression and phosphorylation of NR2B on keratinocyte were analyzed at 6, 12, 18, and 24 h on day 1 (initiation of pain) as well as day 2, 6, 10 and 14 (development and maintenance of pain) after the ischemia. The level of peripheral sensitization-related proteins (nuclear factor-κB (NF-κB), extracellular regulated protein kinases (ERK), and interleukin-1β (IL-1β)) in epidermis and dorsal root ganglion (DRG) were evaluated by immunofluorescence and western blot. Central sensitization-related C-fos induction, as well as astrocytes and microglia activation in the spinal cord dorsal horn (SDH) were studied using immunofluorescence. Administration of NMDA upregulated NR2B phosphorylation on HaCaT cells. CPIP-induced mechanical allodynia and thermal hyperalgesia were intensified by NMDA and alleviated by ifenprodil. CPIP resulted in an early upregulation of NR2B (peaked at 24h) and late phosphorylation of NR2B (peaked at 14d) in hindpaw keratinocytes. CPIP led to an upregulation and phosphorylation of NF-κB and ERK, as well as an increased IL-1β production in the ipsilateral skin and DRG. CPIP-associated c-fos induction in SDH persisted from acute to chronic stages after ischemia, while microglia and astrocyte activation were only observed in chronic phase. These CPIP-induced changes were also suppressed by ifenprodil administered subcutaneously in the hind paw. Our findings reveal a previously unrecognized role of keratinocyte NMDA receptor subunit 2B in peripheral and central nociceptive sensitization induced by CPIP.

  • Pioglitazone alleviates maternal sleep deprivation-induced cognitive deficits in male rat offspring by enhancing microglia-mediated neurogenesis
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-02-04
    Yue Han; Jiutai Wang; Qiuying Zhao; Xiaofang Xie; Rui Song; Ying Xiao; Xixi Kang; Lijuan Zhang; Yue Zhang; Cheng Peng; Zili You

    Maternal sleep disturbance in pregnancy causes cognitive impairments and emotional disorders in offspring. Microglia-mediated inflammatory processes contribute to prenatal stress-induced neurodevelopmental deficits. Peroxisome proliferator-activated receptor gamma (PPARγ) activation underlies the switching of microglial activation phenotypes, which has emerged as a pharmacological target for regulating neuroinflammatory responses in the treatment of neuropsychiatric disorders. Here we investigated the effects of PPARγ-dependent microglial activation on neurogenesis and cognitive behavioral outcomes in male rat offspring exposed to maternal sleep deprivation (MSD) for 72 h from days 18-21 of pregnancy. In the Morris water maze test, male MSD rat offspring needed more time than control offspring to escape to the hidden platform and spent less time in the target quadrant when the hidden platform was removed. In MSD rat offspring, microglial density as determined by immunofluorescence was higher, microglia showed fewer and shorter processes, and neurogenesis in the hippocampus was significantly reduced. Levels of mRNA encoding pro-inflammatory markers IL-6, TNFα, and IL-1β were higher in male MSD offspring, whereas levels of anti-inflammatory markers Arg1, IL-4, and IL-10 were lower, as was PPARγ expression in the hippocampus. PPARγ activation by pioglitazone (30 mg/kg/day, i.p., 7 d) mitigated these negative effects of MSD, rescuing hippocampal neurogenesis and improving cognitive function. The PPARγ inhibitor GW9662 (1 mg/kg/day, i.p., 7 d) eliminated the effects of pioglitazone. Conditioned medium from pioglitazone-treated microglia promoted proliferation and differentiation of neural progenitor cells. These results suggest that MSD-induced deficits in spatial learning and memory can be ameliorated through PPARγ-dependent modulation of microglial phenotypes.

  • Prenatal and childhood adversity and inflammation in children: A population-based longitudinal study
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-02-03
    Eirini Flouri; Marta Francesconi; Emily Midouhas; Efstathios Papachristou; Glyn Lewis

    Background Stressful life events experienced during childhood and early prenatal development have been associated with inflammation during childhood. However, no study has considered these two exposures jointly, or has investigated the effect of their interaction. Methods In the Avon Longitudinal Study of Parents and Children, a general-population birth cohort, we explored if inflammatory markers [serum C-reactive protein (CRP) and interleukin 6 (IL-6)] at age 9 years were related to early prenatal events (at 18 weeks pregnancy), childhood events (measured on seven occasions at ages 0-9 years) and their interaction (n=3,915). Latent growth curve modelling estimated trajectories of childhood events, and linear regression explored associations of prenatal and childhood events with inflammatory markers. Models controlled for ethnicity, socioeconomic status and body mass index, were stratified by gender and considered both unweighted and weighted (by impact) event exposures. Results Even after adjustment for confounders and prenatal events, both the intercept and the slope of number of childhood events were associated with IL-6, but only in females. The significant effect of the slope held for both weighted (by impact) and unweighted event specifications. Prenatal events were not associated with either inflammatory marker when childhood events were controlled. There was no evidence for synergistic effects of prenatal and childhood events. Conclusion Independently of prenatal adverse life events, the number and increase in number of adverse life events experienced in childhood were associated positively with plasma levels of inflammatory markers, such as IL-6, in girls. This gender specificity warrants further research.

  • let-7g counteracts endothelial dysfunction and ameliorating neurological functions in mouse ischemia/reperfusion stroke model
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-02-01
    David L. Bernstein; Sachin Gajghate; Nancy L. Reichenbach; Malika Winfield; Yuri Persidsky; Nathan A. Heldt; Slava Rom

    Stroke is a debilitating disease, accounting for almost 20% of all hospital visits, and 8% of all fatalities in the United States in 2017. Following an ischemic attack, inflammatory processes originating from endothelial cells within the brain microvasculature can induce many toxic effects into the impacted area, from both sides of the blood brain barrier (BBB). In addition to increased BBB permeability, impacted brain microvascular endothelial cells can recruit macrophages and other immune cells from the periphery and can also trigger the activation of microglia and astrocytes within the brain. We have identified a key microRNA, let-7g, which levels were drastically diminished as consequence of transient middle cerebral artery occlusion (tMCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro ischemia/reperfusion conditions, respectively. We have observed that let-7g* liposome-based delivery is capable of attenuating inflammation after stroke, reducing BBB permeability, limiting brain infiltration by CD3+CD4+ T-cells and Ly6G+ neutrophils, lessening microglia activation and neuronal death. These effects consequently improved clinical outcomes, shown by mitigating post-stroke gait asymmetry and extremity motor function. Due to the role of the endothelium in propagating the effects of stroke and other inflammation, treatments which can reduce endothelial inflammation and limit ischemic damage and improving recovery after a stroke are required. Our findings demonstrate a critical link between the CNS inflammation and the immune system reaction and lay important groundwork for future stroke pharmacotherapies.

  • Excess administration of miR-340-5p ameliorates spinal cord injury-induced neuroinflammation and apoptosis by modulating the P38-MAPK signaling pathway
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-31
    Zhanyang Qian; Jie Chang; Fan Jiang; Dawei Ge; Lei Yang; You Li; Hongtao Chen; Xiaojian Cao

    Spinal cord injury (SCI) is a destructive polyneuropathy that can result in loss of sensorimotor function and sphincter dysfunction, and even death in critical situations. MicroRNAs (miRs) are a series of non-coding RNA molecules that are involved in transcriptional regulation. Previous studies have demonstrated that modulation of multiple miRs is involved in neurological recovery after SCI. However, the functions of miR-340-5p in SCI remain uncertain. Therefore, we probed the therapeutic effect and mechanism of miR-340-5p in microglia in vitro and in vivo in SCI rats. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were employed to examine the alterations in miR-340-5p and P38 levels in SCI rats. miR-340-5p targets in microglia were ascertained using luciferase reporter assays, immunofluorescence analyses, and western blotting. We also established an SCI model and administered miR-340-5p. The effects of miR-340-5p on the amelioration of inflammation, oxidative stress, and apoptosis following SCI were assessed using immunofluorescence, immunohistochemistry, and histological analyses. Finally, locomotor function recovery was determined using the Basso, Beattie, Bresnahan rating scale. In our study, the expression profiles and luciferase assay results clarified that P38 was a target of miR-340-5p, which was associated with activation of the P38-MAPK signaling pathway. Elevation of miR-340-5p decreased P38 expression, subsequently inhibiting the inflammatory reaction. SCI-induced secondary neuroinflammation was relieved under miR-340-5p treatment. Moreover, by controlling neuroinflammation, the increased levels of miR-340-5p might counter oxidative stress and reduce the degree of apoptosis. We also observed decreasing gliosis and glial scar formation and increasing neurotrophin expression at the chronic stage of SCI. Together, these potential effects of miR-340-5p treatment ultimately improved locomotor function recovery in SCI rats.

  • Behavioural and histological changes in cuprizone-fed mice
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-31
    Monokesh K. Sen; Mohammed S.M. Almuslehi; Jens R. Coorssen; David A. Mahns; Peter J. Shortland

    Feeding cuprizone (CPZ) to mice causes demyelination and reactive gliosis in the central nervous system (CNS), hallmarks of some neurodegenerative diseases like multiple sclerosis. However, relatively little is known regarding the behavioural deficits associated with CPZ-feeding and much of what is known is contradictory. This study investigated whether 37 days oral feeding of 0.2% CPZ to young adult mice evoked sensorimotor behavioural changes. Behavioural tests included measurements of nociceptive withdrawal reflex responses and locomotor tests. Additionally, these were compared to histological analysis of the relevant CNS regions by analysis of neuronal and glial cell components. CPZ-fed mice exhibited more foot slips in walking ladder and beam tests compared to controls. In contrast, no changes in nociceptive thresholds to thermal or mechanical stimuli occurred between groups. Histological analysis showed demyelination throughout the CNS, which was most prominent in white matter tracts in the cerebrum but was also elevated in areas such as the hippocampus, basal ganglia and diencephalon. Profound demyelination and gliosis was seen in the deep cerebellar nuclei and brain stem regions associated with the vestibular system. However, in the spinal cord changes were minimal. No loss of oligodendrocytes, neurons or motoneurons occurred but a significant increase in astrocyte staining ensued throughout the white matter of the spinal cord. The results suggest that CPZ differentially affects oligodendrocytes throughout the CNS and induces subtle motor changes such as ataxia. This is associated with deficits in CNS regions associated with motor and balance functions such as the cerebellum and brain stem.

  • Dialing in the Dialogue Between Inflammation and the Brain
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-31
    Keith W. Kelley; Annabelle Réaux-Le Goazigo

    The nervous and immune systems communicate with one another and jointly influence functional responses. To highlight the many advances on this hot topic, Brain, Behavior, and Immunity conceptualized a Special Issue entitled “Dialing in the Dialogue Between Inflammation and the Brain.” Recent advances and exciting developments in understanding communication pathways between the brain and the immune system during both physiological and pathological insults are highlighted.

  • To exclude or not to exclude: considerations and recommendations for C-Reactive Protein values higher than 10 mg/L
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-31
    Naoise Mac Giollabhui; Lauren M. Ellman; Christopher L. Coe; Michelle L. Byrne; Lyn Y. Abramson; Lauren B. Alloy

    This research was supported by National Institute of Mental Health Grants MH079369 and MH101168 awarded to Lauren Alloy, National Institute of Mental Health Grant MH096478 awarded to Lauren Ellman and National Research Service Awards F31MH118808 to Naoise Mac Giollabhui.

  • Zinc, but not paracetamol, prevents depressive-like behavior and sickness behavior, and inhibits interferon-gamma and astrogliosis in rats
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-30
    Thiago B. Kirsten; Danilo Cabral; Marcella C. Galvão; Renan Monteiro; Eduardo F. Bondan; Maria Martha Bernardi

    Considering all mental and addictive disorders, depression is the most responsible for years of life lost due to premature mortality and disability. Antidepressant drugs have limited effectiveness. Depression can be triggered by immune/inflammatory factors. Zinc and paracetamol interfere with immune system and have demonstrated beneficial effects on depression treatment when administered concomitant with antidepressant drugs. The objective of this study was to test zinc and/or paracetamol as treatments of depressive-like behavior, sickness behavior, and anxiety in rats, as well as to understand the central and peripheral mechanisms involved. Sickness behavior and depressive-like behavior were induced in rats with repetitive lipopolysaccharide (LPS, 1 mg/kg for two consecutive days) administrations. Rats received zinc and/or paracetamol for three consecutive days. Sickness behavior (daily body weight and open field general activity); anxiety (light-dark test); depressive-like/antidepressant behavior (forced swim test); plasma corticosterone and interferon (IFN)-gamma levels; and glial fibrillary acidic protein (GFAP) and tyrosine hydroxylase (TH) brain expression were evaluated. LPS induced sickness behavior and depressive-like behavior, as well as elevated IFN-gamma levels and increased GFAP expression. Zinc prevented both behavioral and biochemical impairments. Paracetamol and zinc+paracetamol association induced only slight beneficial effects. Anxiety, corticosterone, and TH do not seem be related with depression and the other behavioral and neuroimmune changes. In conclusion, zinc treatment was beneficial for sickness behavior and depressive-like behavior without concomitant administration of antidepressants. IFN-gamma and GFAP were linked with the expression of sickness behavior and depressive-like behavior and were also involved with the antidepressant effects. Therefore, zinc, IFN-gamma, and GFAP pathways should be considered for depression treatment.

  • Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson’s disease
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-30
    Ruwani S. Wijeyekoon; Deborah Kronenberg-Versteeg; Kirsten M. Scott; Shaista Hayat; Wei-Li Kuan; Jonathan R. Evans; David P. Breen; Gemma Cummins; Joanne L. Jones; Menna R. Clatworthy; R. Andres Floto; Roger A. Barker; Caroline H. Williams-Gray

    The innate immune system is implicated in Parkinson’s disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n=41) stratified according to risk of developing early dementia. ‘Higher Risk’(HR) (n=23) and ‘Lower Risk’ (LR) (n=18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n=95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson’s dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease.

  • Resveratrol alleviates temporomandibular joint inflammatory pain by recovering disturbed gut microbiota
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-27
    Yajing Ma; Sufang Liu; Hui Shu; Joshua Crawford; Ying Xing; Feng Tao

    Patients with temporomandibular disorders (TMDs) often experience persistent facial pain. However, the treatment of TMD pain is still inadequate. In recent years, the disturbance of gut microbiota has been shown to play an important role in the pathogenesis of different neurological diseases including chronic pain. In the present study, we investigated the involvement of gut microbiota in the development of temporomandibular joint (TMJ) inflammation. Intra-temporomandibular joint injection of complete Freund's adjuvant (CFA) was employed to induce TMJ inflammation. Resveratrol (RSV), a natural bioactive compound with anti-inflammatory property, was used to treat the CFA-induced TMJ inflammation. We observed that CFA injection not only induces persistent joint pain, but also causes the reduction of short-chain fatty acids (SCFAs, including acetic acid, propionic acid and butyric acid) in the gut as well as decreases relevant gut bacteria Bacteroidetes and Lachnospiraceae. Interestingly, systemic administration of RSV (i.p.) dose-dependently inhibits CFA-induced TMJ inflammation, reverses CFA-caused reduction of SCFAs and these gut bacteria. Moreover, CFA injection causes blood-brain barrier (BBB) leakage, activates microglia and enhances tumor necrosis factor alpha (TNFα) release in the spinal trigeminal nucleus caudalis (Sp5C). The RSV treatment restores the BBB integrity, inhibits microglial activation and decreases the release of TNFα in the Sp5C. Furthermore, fecal microbiota transplantation with feces from RSV-treated mice significantly diminishes the CFA-induced TMJ inflammation. Taken together, our results suggest that gut microbiome perturbation is critical for the development of TMJ inflammation and that recovering gut microbiome to normal levels could be a new therapeutic approach for treating such pain.

  • Blood-borne and brain-derived microparticles in morphine-induced anti-nociceptive tolerance
    Brain Behav. Immun. (IF 6.170) Pub Date : 2020-01-27
    Deepa Ruhela; Veena M. Bhopale; Ming Yang; Kevin Yu; Eric Weintraub; Aaron Greenblatt; Stephen R. Thom

    We hypothesized that elevations of microparticles (MPs) would occur with morphine administration to mice. Repetitive dosing to induce anti-nociceptive tolerance increases blood-borne MPs by 8-fold, and by 10-fold in deep cervical lymph nodes draining brain glymphatics. MPs express proteins specific to cells including neutrophils, microglia, astrocytes, neurons and oligodendrocytes. Interleukin (IL)-1β content of MPs increases 68-fold. IL-1β antagonist administration diminishes blood-borne and cervical lymph node MPs, and abrogates tolerance induction. Intravenous polyethylene glycol Telomer B, a surfactant that lyses MPs, and intraperitoneal methylnaltrexone also inhibit MPs elevations and tolerance. Critically, neutropenic mice do not develop anti-nociceptive tolerance, elevations of blood-borne or cervical node MPs. Immunohistochemical evidence for microglial activation by morphine does not correlated with the MPs response pattern. Neutrophil-derived MPs appear to be are required for morphine-induced anti-nociceptive tolerance. Further, patients entering treatment for opioid use disorder exhibit similar MPs elevations as do tolerant mice.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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
  • 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.

  • 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
  • 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.

  • 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
  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

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