The risk for behavioural deficits is determined by the maternal immune response to prenatal immune challenge in a neurodevelopmental model

BackgroundSchizophrenia is a highly disabling psychiatric disorder with a proposed neurodevelopmental basis. One mechanism through which genetic and environmental risk factors might act is by triggering persistent brain inflammation, as evidenced by long-lasting neuro-immunological disturbances in patients. Our goal was to investigate whether microglia activation is a neurobiological correlate to the altered behaviour in the maternal immune activation (MIA) model, a well-validated animal model with relevance to schizophrenia. A recent observation in the MIA model is the differential maternal body weight response to the immune stimulus, correlated with a different behavioural outcome in the offspring. Although it is generally assumed that the differences in maternal weight response reflect differences in cytokine response, this has not been investigated so far. Our aim was to investigate whether (i) the maternal weight response to MIA reflects differences in the maternal cytokine response, (ii) the differential behavioural phenotype of the offspring extends to depressive symptoms such as anhedonia and (iii) there are changes in chronic microglia activation dependent on the behavioural phenotype.MethodsBased on a dose–response study, MIA was induced in pregnant rats by injecting 4 mg/kg Poly I:C at gestational day 15. Serum samples were collected to assess the amount of TNF-α in the maternal blood following MIA. MIA offspring were divided into weight loss (WL; n = 14) and weight gain (WG; n = 10) groups, depending on the maternal body weight response to Poly I:C. Adult offspring were behaviourally phenotyped for prepulse inhibition, locomotor activity with and without amphetamine and MK-801 challenge, and sucrose preference. Finally, microglia activation was scored on CD11b- and Iba1-immunohistochemically stained sections.ResultsPregnant dams that lost weight following MIA showed increased levels of TNF-α compared to controls, unlike dams that gained weight following MIA. Poly I:C WL offspring showed the most severe behavioural outcome. Poly I:C WG offspring, on the other hand, did not show clear behavioural deficits. Most interestingly a reduced sucrose preference indicative of anhedonia was found in Poly I:C WL but not Poly I:C WG offspring compared to controls. Finally, there were no significant differences in microglia activation scores between any of the investigated groups.ConclusionsThe individual maternal immune response to MIA is an important determinant of the behavioural outcome in offspring, including negative symptoms such as anhedonia. We failed to find any significant difference in the level of microglia activation between Poly I:C WL, Poly I:C WG and control offspring.     

Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: Amelioration by COX-2 inhibition

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4 mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31–33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3 mg/kg) in adulthood (PND > 90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31–33 (105%, p = 0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p = 0.027, and 31% p = 0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p = 0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.     

Positive modulation of α5 GABAA receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide

We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with α5 GABA_A receptors (α5GABA_ARs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of α5GABA_ARs in offspring’s preadolescence (from postnatal day 22–28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 μg/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of α5GABA_ARs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of α5GABA_ARs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.     

Maternal immune activation in late gestation increases neuroinflammation and aggravates experimental autoimmune encephalomyelitis in the offspring

Multiple sclerosis (MS) is characterized by an autoimmune response against myelin antigens driven by autoreactive T cells. Several lines of evidence indicate that environmental factors, such as previous infection, can influence and trigger autoimmune responses. However, the importance of the gestational period, particularly under inflammatory conditions, on the modulation of MS and related neuroinflammation by the offspring is unknown. This study aimed to evaluate the impact of prenatal exposure to lipopolysaccharide (LPS) during late gestation on the neuroinflammatory response in primary mixed glial cultures and on the progression of experimental autoimmune encephalomyelitis (EAE, an animal model of MS) in the offspring. LPS (Escherichia coli 0127:B8, 120 μg/kg) was administered intraperitoneally to pregnant C57BL/6J mice on gestational day 17, and the offspring were assigned to two experiments: (1) mixed glial cultures generated using the brain of neonates, stimulated in vitro with LPS, and (2) adult offspring immunized with MOG_35–55. The EAE clinical symptoms were followed for 30 days. Different sets of animals were sacrificed either during the onset (7 days post-immunization [p.i.]), when spleen and lymph nodes were collected, or the peak of disease (20 days p.i.), when CNS were collected for flow cytometry, cytokine production, and protein/mRNA-expression analysis. The primary CNS cultures from the LPS-treated group produced exaggerated amounts of IL-6, IL-1β and nitrites after in vitro stimulus, while IL-10 production was lowered compared to the data of the control group. Prenatal exposure to LPS worsened EAE disease severity in adult offspring, and this worsening was linked to increased CNS-infiltrating macrophages, Th1 cells and Th17 cells at the peak of EAE severity; additionally, exacerbated gliosis was evidenced in microglia (MHC II) and astrocytes (GFAP protein level and immunoreactivity). The IL-2, IL-6 and IL-17 levels in the spleen and lymph nodes were increased in the offspring of the LPS-exposed dams. Our results indicate that maternal immune activation during late gestation predispose the offspring to increased neuroinflammation and potentiate the autoimmune response and clinical manifestation of EAE.     

Primary murine microglia are resistant to nitric oxide inhibition of indoleamine 2,3-dioxygenase

Indoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing enzyme that is activated by proinflammatory cytokines, including interferon-γ (IFNγ), and metabolizes tryptophan along the kynurenine pathway. Activation of murine macrophages induces not only IDO but also nitric oxide synthase (iNOS), and the ensuing production of nitric oxide (NO) inhibits IDO. To determine the sensitivity of primary cultures of murine microglia to NO, microglia were stimulated with recombinant murine IFNγ (1 ng/ml) and lipopolysaccharide (LPS) (10 ng/ml). This combination of IFNγ + LPS synergized to produce maximal amounts of nitrite as early as 16 h. Steady-state mRNAs for both iNOS and IDO were significantly increased by IFNγ + LPS at 4 h post-treatment, followed by an increase in IDO enzymatic activity at 24 h. Murine microglia (>95% CD11b⁺) were pretreated with the iNOS inhibitor, L-NIL hydrochloride, at a dose (30 μM) that completely abrogated production of nitrite. L-NIL had no effect on IDO mRNA at 4 h or IDO enzymatic activity at 24 h following stimulation with IFNγ + LPS. These data establish that IDO regulation in murine microglia is not restrained by NO, thereby permitting the accumulation of kynurenine and its downstream metabolites in the central nervous system.     

Brief postpartum separation from offspring promotes resilience to lipopolysaccharide challenge-induced anxiety and depressive-like behaviors and inhibits neuroinflammation in C57BL/6J dams

Emerging evidence indicates an important role for neuroinflammation in depression. Brief maternal separation promotes resilience to depression in offspring, but relatively little is known about the effects of different durations of postpartum separation (PS) from offspring on anxiety and depressive-like behaviors in dams following immune challenge. Lactating C57BL/6J mice were subjected to no separation (NPS), brief PS (15 min/day, PS15) or prolonged PS (180 min/day, PS180) from postpartum day (PPD) 1 to PPD21 and then injected with lipopolysaccharide (LPS). Behavioral tests, including the open field test (OFT) and forced swimming test (FST), were carried out at 24 h after the injection. LPS resulted in anxiety and depressive-like behaviors in NPS dams and activated ionized calcium-binding adaptor molecule (Iba1), an important biomarker of microglia, in the hippocampus. However, compared with NPS + LPS dams, PS15 + LPS dams spent significantly more time in the center of the OFT (anxiety-like behavior) and exhibited lower immobility time in the FST (depressive-like behavior), which indicated a phenomenon of resilience. Furthermore, the activation of neuroinflammation was inhibited in PS15 dams. Specifically, levels of the Iba1 mRNA and protein were decreased, while the mRNA expression of NLR family pyrin domain containing 3 (NLRP3) inflammasome/interleukin-18 (IL-18)/nuclear factor kappa-B (NF-κB) was decreased in the hippocampus. Furthermore, positive linear correlations were observed between microglial activation and LPS-induced depressive-like behaviors in dams. Collectively, the findings of this study confirm that brief PS from offspring promotes resilience to LPS immune challenge-induced behavioral deficits and inhibits neuroinflammation in dams separated from their offspring during lactation.     

Menstrual cycle and reproductive aging alters immune reactivity,NGF expression,antioxidant enzyme activities,and intracellular signaling pathways in the peripheral blood mononuclear cells of healthy women

Reproductive senescence in women is a process that begins with regular menstrual cycles and culminates in menopause followed by gradual development of diseases such as autoimmune diseases, osteoporosis, neurodegenerative diseases, and hormone-dependent cancers. The age-associated impairment in the functions of neuroendocrine system and immune system results in menopause which contributes to subsequent development of diseases and cancer. The aim of this study is to characterize the alterations in immune responses, compensatory factors such as nerve growth factor (NGF) and antioxidant enzyme activities, and the molecular mechanisms of actions in the peripheral blood mononuclear cells (PBMCs) of young (follicular and luteal phases), middle-aged, and old healthy women. Peripheral blood mononuclear cells were isolated from young women in follicular and luteal phases of the menstrual cycle (n = 20; 22.6 ± 2.9 yrs), middle-aged women (n = 19; 47.1 ± 3.8 yrs; perimenopausal) and old (n = 16; 63.2 ± 4.7 yrs; post-menopausal) women and analyzed for Concanavalin (Con A)-induced proliferation of lymphocytes and cytokine (IL-2 and IFN-γ) production, expression of NGF, p-NF-κB, p-ERK, p-CREB, and p-Akt, antioxidant enzymes [superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), glutathione-S-transferase (GST)], extent of lipid peroxidation, and nitric oxide (NO) production. Serum gonadal hormones (17β-estradiol and progesterone) were also measured. A characteristic age- and menstrual cycle-related change was observed in the serum gonadal hormone secretion (estrogen and progesterone), T lymphocyte proliferation and IFN-γ production. Salient features include the age-related decline observed in target-derived growth factors (lymphocyte NGF expression), signaling molecules (p-ERK/ERK and p-CREB/CREB ratios) and compensatory factors such as the activities of plasma and PBMC antioxidant enzymes (SOD and catalase) and NO production. Further, an age-associated increase in p-NF-κB expression and lipid peroxidation was observed. Also, serum 17β-estradiol levels were positively correlated with IFN-γ production, SOD activity and NGF expression in the PBMCs. These results suggest that alterations in the levels of gonadal hormones are associated with immunosenescence characterized by decreased IFN-γ production and proliferation of T lymphocytes, decline in NGF expression, SOD and catalase activities, NO production, and signaling mechanisms and thus, may increase the incidence of diseases and cancer in women.     

Elevated ratio of arachidonic acid to long-chain omega-3 fatty acids predicts depression development following interferon-alpha treatment: Relationship with interleukin-6

Cross-sectional studies have found that an elevated ratio of arachidonic acid to omega-3 fatty acid is associated with depression, and controlled intervention studies have found that decreasing this ratio through administration of omega-3 fatty acids can alleviate depressive symptoms. Additionally, arachidonic acid and omega-3 fatty acids have opposing effects on inflammatory signaling. Exogenous administration of the inflammatory cytokine interferon-alpha (IFN-α) can trigger a depressive episode in a subset of vulnerable people, though associated risk factors remain poorly understood. Using a within-subject prospective design of 138 subjects, we examined whether baseline long-chain omega-3 (docosahexaenoic acid – DHA; eicosapentaenoic acid – EPA) and omega-6 (arachidonic acid – AA; di-homo-gamma-linolenic acid – DGLA) fatty acid status was associated with depression vulnerability in hepatitis C patients treated with IFN-α. Based on the literature, we had specific a priori interest in the AA/EPA + DHA ratio. Lower baseline DHA predicted depression incidence (p = 0.04), as did elevated DGLA (p = 0.02) and an elevated AA/EPA + DHA ratio (p = 0.007). The AA/EPA + DHA ratio predicted depression even when controlling for other critical variables such as sleep quality and race. A higher AA/EPA + DHA ratio was positively associated with both increasing Montgomery-Asperg Depression Rating Scores over time (F = 4.0; p < 0.05) as well as interleukin-6 levels (F = 107.4; p < 0.05) but not C-reactive protein. Importantly, omega-3 and omega-6 fatty acid status was not associated with sustained viral response to IFN-α treatment. These prospective data support the role of fatty acid status in depression vulnerability and indicate a potential role for omega-3 fatty acids in the prevention of inflammation-induced depression.     

Evaluation of periodontitis in hospital outpatients with major depressive disorder. A focus on gingival and circulating cytokines

An imbalance in stimulated cytokine production is associated with the etiopathogenesis of numerous diseases such as major depressive disorder (MDD) and periodontal disease. Increased cytokine levels have been reported in the gingival crevicular fluid (GCF) of patients with MDD. Thirty-six outpatients with MDD participated in this study. Each outpatient was age-matched (±3 years) with a healthy control (n = 36). The patients were controlled for race and smoking habits. Unstimulated and stimulated interleukin 6 (IL-6), interleukin 1β (IL-1β), and interferon-γ (INF-γ) production in whole blood culture (WBC) and IL-6 and IL-1β levels in the GCF were evaluated. Circulating levels of IL-6 and IL-1β (unstimulated) as well as GCF IL-1β were modestly lower in MDD patients, compared to the levels in age-matched controls (Mann–Whitney, p = 0.002, 0.0075, ANCOVA, p = 0.025, respectively). In the unstimulated group, there was no correlation between the levels of circulating IL-6 and GCF IL-6 (r = 0.07, p = 0.67), and between the levels of circulating IL-1β and the IL-1β level in the CGF (r = −0.08, p = 0.63). In the LPS stimulation group, there was no correlation between the levels of circulating levels of IL-6 and GCF IL-6 (r = 0. 02, p = 0.91) or between the circulating IL-1β and GCF IL-1β (r = 0.13, p = 0.42). We observed modest immunosuppression in MDD patients (evaluated by no stimulation whole blood culture [WBC]), especially in patients with melancholic depression, chronic depression, and severe depression.     

Effects of voluntary wheel running on LPS-induced sickness behavior in aged mice

Peripheral stimulation of the innate immune system with LPS causes exaggerated neuroinflammation and prolonged sickness behavior in aged mice. Regular moderate intensity exercise has been shown to exert anti-inflammatory effects that may protect against inappropriate neuroinflammation and sickness in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced sickness behavior and proinflammatory cytokine gene expression in ∼22-month-old C57BL/6 J mice. Mice were housed with a running wheel (VWR), locked-wheel (Locked), or no wheel (Standard) for 10 weeks, after which they were intraperitoneally injected with LPS across a range of doses (0.02, 0.08, 0.16, 0.33 mg/kg). VWR mice ran on average 3.5 km/day and lost significantly more body weight and body fat, and increased their forced exercise tolerance compared to Locked and Shoebox mice. VWR had no effect on LPS-induced anorexia, adipsia, weight-loss, or reductions in locomotor activity at any LPS dose when compared to Locked and Shoebox groups. LPS induced sickness behavior in a dose-dependent fashion (0.33 > 0.02 mg/kg). Twenty-four hours post-injection (0.33 mg/kg LPS or Saline) we found a LPS-induced upregulation of whole brain TNFα, IL-1β, and IL-10 mRNA, and increased IL-1β and IL-6 in the spleen and liver; these effects were not attenuated by VWR. We conclude that VWR does not reduce LPS-induced exaggerated or prolonged sickness behavior in aged animals, or 24 h post-injection (0.33 mg/kg LPS or Saline) brain and peripheral proinflammatory cytokine gene expression. The necessity of the sickness response is critical for survival and may outweigh the subtle benefits of exercise training in aged animals.     

Prenatal maternal anxiety predicts reduced adaptive immunity in infants

Prenatal anxiety has been linked with altered immune function in offspring in animal studies, but the relevance for human health is unknown. We examined prenatal maternal anxiety as a predictor of adaptive immunity in infants at 2 and 6 months of age as part of a prospective longitudinal study. The humoral immune response to hepatitis B vaccine was assessed at 2 months (n = 80) and 6 months (n = 76) of age. Prenatal anxiety predicted lower hepatitis B antibody titers at 6 months of age independent of obstetric and socio-demographic covariates; the effects were limited to those infants who had not completed the 3-dose vaccine series (for transformed titer values, r = −.36, p < .05). Cell-mediated immune responses at 2 (n = 56) and 6 (n = 54) months of age were examined by ELISpot assays for interferon(IFN)-γ, interleukin(IL)-2, and IL-4 responder cell frequencies to three antigens: hepatitis B surface antigen, tetanus toxoid, and phytohaemagglutinin (PHA). Prenatal maternal anxiety was associated with reduced IFN-γ and increased IL-4 responder cell frequencies at 6 months of age, independent of obstetric and socio-demographic covariates. No effect of prenatal anxiety was found on adaptive immunity at 2 months of age. The findings provide the first demonstration in humans that prenatal anxiety alters adaptive immunity in the infant.     

Role of brain macrophages on IL-1β and fatigue following eccentric exercise-induced muscle damage

Fatigue associated with recovery from muscle damage has recently been linked to increases in brain and muscle proinflammatory cytokines. However, little is known regarding the origin of these cytokines. Since macrophage-like cells in the brain are a primary source of cytokines, we used a brain specific macrophage depletion technique involving liposome encapsulated clodronate (CLD) to examine the role of macrophages on brain IL-1β and fatigue following eccentric exercise-induced muscle damage. Mice were assigned to six groups: Downhill saline (DWNSAL), downhill clodronate (DWNCLD), uphill saline (UPSAL), uphill clodronate (UPCLD), non-running saline (CONSAL) or non-running clodronate (CONCLD). Mice were given intracerebroventricular (ICV) (10 μL) injections of clodronate-filled liposomes (CLD) to deplete macrophages, or saline-filled liposomes (SAL) and run on a treadmill at 22 m/min and ?14% (DWN) or 14% (UP) grade for 150 min. A subset of uphill and downhill running mice (n = 40) was then run to fatigue on a treadmill at 36 m/min, 8% grade at 24 h after the uphill and downhill runs. A second subset of uphill, downhill, and control mice (n = 30) was sacrificed 24 h after the run for analysis of brain IL-1β concentration. Histological examination confirmed previous reports that CLD administration reduced perivascular and meningeal macrophage subsets in the brain. CLD reduced IL-1β concentration in the cortex of DWN mice (P < 0.05), which was associated with enhanced treadmill performance 24 h after both uphill and downhill runs (P < 0.05) although the magnitude was greater following the downhill run. These results suggest that brain macrophages can contribute to the increase in brain IL-1β and fatigue that are associated with recovery from exercise-induced muscle damage.     

Tetramethylpyrazine accelerates the function recovery of traumatic spinal cord in rat model by attenuating inflammation

In the present study, we explored the effects of tetramethylpyrazine (TMP), an alkaloid extracted from the Chinese herbal medicine Ligusticum wallichii Franchat (chuanxiong), on a rat model of contusion spinal cord injury (SCI). The contusion SCI model was induced in rats by a modified Allen's weight-drop method with a severity of 5 g × 50 mm impacting on the T10 segment. In the TMP treatment group, rats were injected intraperitoneally (i.p.) with TMP (200 mg/kg), every 24 h for 5 days, starting half an hour after contusion SCI. The control group was treated with saline. Compared with the control group, the TMP group significantly ameliorated the recovery of hindlimb function of rats. TMP treatment significantly reduced the expression of macrophage migration inhibitory factor, nuclear factor κappa B, pro-inflammatory cytokine interleukin-18 and neutrophil infiltration. On the other hand, TMP enhanced the expression of inhibitor κappa B and anti-inflammation cytokine interleukin-10. In conclusion, our results demonstrate that TMP inhibits the development of inflammation and tissue injury associated with spinal cord contusion in rats which may improve the rats' hindlimb function.     

Behaviour and hippocampus-specific changes in spiny mouse neonates after treatment of the mother with the viral-mimetic Poly I:C at mid-pregnancy

Epidemiological studies have suggested a link between prenatal exposure to bacterial or viral infections and subsequent development of mental disorders such as schizophrenia and autism. Animal models to study the prenatal origin of such outcomes of pregnancy have largely used conventional rodents which are immature at birth compared to the human neonate, and doses of the infective agent (i.e., lipopolysaccharide, Poly I:C) have been large enough to cause sickness behaviour in the mother. In this study we have used the spiny mouse (Acomys cahirinus) whose offspring have completed organogenesis at birth, and a single subcutaneous injection of a low (0.5 mg/kg) dose of polyriboinosinic–polyribocytidilic acid (Poly I:C) at mid gestation (20 days, term is 39 days). The treatment had no effect on maternal, fetal or neonatal survival, or postnatal growth of the offspring. However, offspring showed significant impairments in non-spatial memory and learning tasks, and motor activity. Brain histology examined at 1 and 100 days of age revealed significant decreases in reelin, increased GFAP expression, and increased numbers of activated microglia, specifically in the hippocampus. This study provides evidence that a prenatal subclinical infection can have profound effects on brain development that are long-lasting.     

Neurocognitive disturbances associated with acute infectious mononucleosis,Ross River fever and Q fever: A preliminary investigation of inflammatory and genetic correlates

Disturbances in neurocognitive performance are a core feature of the acute sickness response to infection; however the underlying mechanisms remain unclear. The current study used a computerised battery to assess neurocognitive functioning in subjects enrolled in the Dubbo Infection Outcomes Study (n = 107) – a prospective cohort of subjects followed from documented acute infection with Epstein Barr virus, Ross River virus, or Coxiella burnetii until recovery. Subjects were assessed when ill, and a subset again after complete recovery. Associations between sickness-related cognitive disturbances and single nucleotide polymorphisms (SNPs) in cytokine (interleukin [IL]-6, IL-10, tumor necrosis factor-α and interferon-γ) and neurobehavioral genes (serotonin transporter and catechol-O-methyltransferase) were explored.During acute infection, subjects exhibited slower matching-to-sample responses (p = 0.03), poorer working memory capacity (p = 0.014), mental planning (p = 0.045), and dual attention task performance (p = 0.02), and required longer to complete discordant Stroop trials (p = 0.01) compared to recovery. Objective impairments correlated significantly with self-reported symptoms (p < 0.05) as well as levels of the inflammation marker, C-reactive protein (p = 0.001). Linear regression analysis identified an association between neurocognitive disturbance during acute illness and functional polymorphisms in inflammatory cytokine genes. Specifically, the high cytokine producing G allele of the IL-6-174G/C SNP was associated with poorer neurocognitive performance when subjects were ill (p = 0.027).These findings confirm that acute infection impacts on neurocognitive performance, manifesting as slowed responses and impaired performance on complex tasks requiring higher-order functioning which has important real-world implications. The data provide the first preliminary evidence for a role of a genetic predisposition to more intense inflammatory responses in objective neurocognitive disturbances during acute infections. These associations require replication in a larger sample size.     

Modality and sex differences in pain sensitivity during human endotoxemia

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8 ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6 ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8 ng/kg dose being −64 ± 30 kPa P = .04; with the 0.6 ng/kg dose −58 ± 55 kPa, P < .01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P’s > .70). Suprathreshold noxious pain was not affected by LPS in men (P’s ⩾ .15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P = .01), and showed a tendency to rate noxious cold pain as more painful (P = .06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P < .01, for men P = .27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women’s pain perception and modulation is more sensitive to immune activation than men’s.     

The pro-inflammatory cytokine interferon-gamma is an important driver of neuropathology and behavioural sequelae in experimental pneumococcal meningitis

Interferon-gamma is known to play a complex modulatory role in immune defence during microbial infections. Its actions in pneumococcal meningitis, however, remain ill-defined. Here, a pathological role for IFN-γ was demonstrated using a murine model of pneumococcal meningitis, in that C57BL/6J mice deficient in this pro-inflammatory cytokine (IFN-γ^−/−) showed less severe acute and long-term neuropathology following intracerebral challenge with Streptococcus pneumoniae. The absence of IFN-γ significantly lengthened the survival of mice that otherwise would have developed fatal clinical signs within two days of CNS infection. Compared to their wild-type counterparts, IFN-γ^−/− mice showed a diminished inflammatory response (attenuated levels of pro-inflammatory cytokines in the cerebrospinal fluid) and milder brain pathologies (less BBB permeability to protein and brain haemorrhage) during the acute phase of disease. Following a full regime of antibiotic treatment, we found substantial brain injuries in the wild-type mice 10 days after infection. IFN-γ^−/− mice, however, showed decreased neuronal damage in both hippocampus and cortex. In the longer term (≈10 weeks p.i.), the wild-type mice that had survived meningitis due to antibiotic treatment had neurobehavioural abnormalities including diurnal hypoactivity, nocturnal hyperactivity and impaired performance in a discrimination reversal task. IFN-γ^−/− mice, concomitantly tested in the automated IntelliCage platform, had reduced behavioural and cognitive disorders compared to wild-type mice. Both IFN-γ^−/− and wild-type survivors of pneumococcal meningitis showed impaired working memory in the IntelliCage-based complex patrolling task. These observations indicate an association between IFN-γ-driven acute brain pathology and the long-term neurological sequelae resulting from pneumococcal meningitis.     

Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia

Background & aims: To elucidate the brain mechanisms underlying inflammation-induced visceral hyperalgesia in humans, in this functional magnetic resonance imaging (fMRI) study we tested if intravenous administration of lipopolysaccharide (LPS) involves altered central processing of visceral pain stimuli. Methods: In this randomized, double-blind, placebo-controlled fMRI study, 26 healthy male subjects received either an intravenous injection of low-dose LPS (N = 14, 0.4 ng/kg body weight) or placebo (N = 12, control group). Plasma cytokines (TNF-α, IL-6), body temperature, plasma cortisol and mood were assessed at baseline and up to 6 h post-injection. At baseline and 2 h post-injection (test), rectal pain thresholds and painful rectal distension-induced blood oxygen level-dependent (BOLD) responses in brain regions-of-interest were assessed. To address specificity for visceral pain, BOLD responses to non-painful rectal distensions and painful somatic stimuli (i.e., punctuate mechanical stimulation) were also analyzed as control stimuli. Results: Compared to the control group, LPS-treated subjects demonstrated significant and transient increases in TNF-α, IL-6, body temperature and cortisol, along with impaired mood. In response to LPS, rectal pain thresholds decreased in trend, along with enhanced up-regulation of rectal pain-induced BOLD responses within the posterior insula, dorsolateral prefrontal (DLPFC), anterior midcingulate (aMCC) and somatosensory cortices (all FWE-corrected p < 0.05). Within the LPS group, more pronounced cytokine responses correlated significantly with enhanced rectal pain-induced neural activation in DLPFC and aMCC. No significant LPS effects were observed on neural responses to non-painful rectal distensions or mechanical stimulation. Conclusions: These findings support that peripheral inflammatory processes affect visceral pain thresholds and the central processing of sensory-discriminative aspects of visceral pain.     

Cytokine-induced depression during IFN-α treatment: The role of IL-6 and sleep quality

Depressive symptoms, poor sleep quality, and systemic markers of inflammation (e.g., interleukin (IL)-6) are frequently associated. Interferon-alpha (IFN-α) therapy results in Major Depressive Disorder (MDD) in some people, offering the possibility to elucidate the relationship of MDD to sleep and inflammation during treatment. In particular, delineating the temporal relations among these factors could help inform their causal relationships. To this end, a cohort of 95 non-depressed hepatitis C patients was followed prospectively for four consecutive months during IFN-α therapy. We found that higher pre-treatment levels of circulating IL-6 predicted incidence of MDD (X²(1) = 7.7; p < 0.05). Time-lagged mixed-effect analyses supported uni-directional associations in which IL-6 predicted next month’s PSQI scores (F(47, 11.6) = 78.4; p < 0.0005), and PSQI scores predicted next month’s depressive Beck Depression Inventory-II (BDI) scores (F(16, 22.6) = 3.4; p < 0.005). In addition, on any given month of treatment, IL-6 levels predicted BDI symptoms the following month (F(16, 97.5) = 7.3; p < 0.0005), and conversely BDI predicted next month’s IL-6 (F(14, 7.4) = 5.2; p < 0.05) – providing evidence for a positive feedback relationship between depressive symptoms and systemic inflammation. These data provide further evidence that high levels of inflammation and poor sleep quality may be risk factors for IFN-α induced depression. Furthermore, these findings highlight the complex temporal relationships that exist among sleep, depression, and inflammation, and support the need for further prospective investigations to elucidate the dynamics that underlie depression during IFN-α treatment.