Associations between sickness behavior, but not inflammatory cytokines, and psychiatric comorbidity in chronic pain.

OBJECTIVES: Approximately one in five adults experiences chronic pain, often in co-occurrence with depression, insomnia, anxiety, and lower self-rated health. Elevated levels of cytokines, e.g. tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10), have been identified in patients with chronic pain. Depression, insufficient sleep, poor self-rated health, and pain intensity have also been associated with inflammatory biomarkers. This study aimed to investigate the interrelationships between inflammatory biomarkers and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity in patients with chronic pain. METHODS: Self-report questionnaires and blood samples analyzed for plasma levels of inflammatory biomarkers were collected from 80 adult patients with chronic pain. Associations between inflammatory biomarkers (TNF-α, IL-6, IL-8, IL-10, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity, were analyzed using bivariate Spearman rank correlation coefficients and regression analyses. RESULTS: Participants were mainly women (72.5 %), with a mean age of 50.8 years, and a reported mean pain duration of 16.7 years. There were significant correlations between insomnia and CRP (rs =.26, p <.05); sex and ESR (rs =.29, p <.05); age and IL-6 (rs =.29, p <.05) and IL-8 (rs =.30, p <.05); BMI and IL-6 (rs =.50, p <.001), CRP (rs =.63, p <.001) and ESR (rs =.42, p <.001). Ratings of depression were positively and significantly related to ratings of sickness behavior and anxiety (ß =.32 and ß =.40, respectively), explaining 49 % of the total variance in depression ratings. Insomnia was positively and significantly related to sickness behavior (ß =.37) explaining 31 % of the total variance in insomnia ratings. Inflammatory biomarkers, however, did not contribute significantly to the models. CONCLUSIONS: Participants reported high levels of symptoms, yet the associations between these ratings and the inflammatory biomarkers were either absent or weak. Also, despite high levels of self-reported sickness behavior, overall the inflammatory status remained within the normal range. Ratings of sickness behavior contributed more than inflammatory markers in explaining ratings of depression and insomnia. The present results point to the complexity of chronic pain, and the challenges of identifying biomarkers that explain symptomatology.

Lipopolysaccharide-induced sickness behavior is not altered in male Fmr1-deficient mice.

OBJECTIVES: Fragile X syndrome is the main monogenetic cause of intellectual disability and autism. Alterations in the immune system are commonly found in these developmental disorders. We and others have demonstrated that Fmr1 mutant mice present an altered response to immune stimuli. However, whether this altered immune response can influence the Fmr1 mutant behavioral outcomes in response to inflammation has not been fully investigated. MATERIALS AND METHODS: In the current study, we examine the behavioral sickness response of male wildtype and knockout  mice to the innate immune stimulus lipopolysaccharide (LPS) (0.1 mg/kg) to determine if Fmr1 mutants have altered sickness behavior. We used an enzyme-linked immunosorbent assay (ELISA) to measure changes in the cytokine interleukin-6 (IL-6) to determine that inflammation was induced in the mice. Sickness behavior was assessed in a wheel-running paradigm, and a tail suspension test was used to assess the depressive-like phenotype that follows sickness behavior in response to LPS. RESULTS: The ELISA using blood serum confirmed a significant increase in IL-6 in mice that were treated with LPS. Treated Fmr1 mutants exhibited decreased distance traveled in the wheel running after LPS administration, similar to treated controls. Another cohort of animals treated with LPS were tested in the tail suspension test and exhibited no alterations in immobility time in response to LPS. CONCLUSION: Together, our data suggest that Fmr1 mutant mice do not have altered sickness behavior in response to a low dose of LPS.

Putative involvement of sirtuin modulators in LPS-induced sickness behaviour in mice.

NAD+-dependent histone deacetylases (sirtuins 1-7) have been shown to be involved in various pathophysiological conditions including their involvement in cardiovascular, cancerous, neurodegenerative, immune dysregulation and inflammatory conditions. This study investigates the inflammomodulatory potential of resveratrol (RES), a sirtuin activator and sirtinol (SIR), a sirtuin inhibitor in lipopolysaccharide (LPS)-induced model of sickness behaviour in mice. Male Swiss albino mice were divided into five groups (n = 6) consisting of saline (SAL), LPS, RES, SIR, and fluoxetine (FLU) respectively, each group except LPS was prepared by intraperitoneally (i.p.) administration of SAL (10 mL/kg), RES (50 mg/kg), SIR (2 mg/kg) and FLU (10 mg/kg). Thirty minutes after the treatments, all the groups, except SAL were administered LPS (2 mg/kg, i.p.). The behavioural assays including, open field test, forced swim test, and tail suspension tests were conducted 1 h after LPS challenge. LPS administration significantly reduced the locomotor activity along with inducing a state of high immobility and that was prevented by pretreatment with RES and SIR. Further, various proinflammatory cytokines (TNF-α, IL-6, and IL-1ß), and oxidative stress markers (MDA and GSH) were found to be significantly elevated in the brain homogenates after LPS treatment. SIR pretreatment abrogated the LPS-induced neuroinflammatory and oxidative stress changes, whereas RES was only effective in reducing the oxidative stress and TNF-α levels. The results of this study speculate that the role of SIRT modulators in neuroinflammatory conditions could vary with their dose, regimen and chemical properties. Further studies with detailed molecular and pharmacokinetic profiling will be needed to explore their therapeutic potentials.

ADAM Metalloproteinase Domain 17 Regulates Cholestasis-Associated Liver Injury and Sickness Behavior Development in Mice.

Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a ubiquitously expressed membrane-bound enzyme that mediates shedding of a wide variety of important regulators in inflammation including cytokines and adhesion molecules. Hepatic expression of numerous cytokines and adhesion molecules are increased in cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), however, the pathophysiological role of ADAM17 in regulating these conditions remains unknown. Therefore, we evaluated the role of ADAM17 in a mouse model of cholestatic liver injury due to bile duct ligation (BDL). We found that BDL enhanced hepatic ADAM17 protein expression, paralleled by increased ADAM17 bioactivity. Moreover, inhibition of ADAM17 bioactivity with the specific inhibitor DPC 333 significantly improved both biochemical and histological evidence of liver damage in BDL mice. Patients with cholestatic liver disease commonly experience adverse behavioral symptoms, termed sickness behaviors. Similarly, BDL in mice induces reproducible sickness behavior development, driven by the upregulated expression of cytokines and adhesion molecules that are in turn regulated by ADAM17 activity. Indeed, inhibition of ADAM17 activity significantly ameliorated BDL-associated sickness behavior development. In translational studies, we evaluated changes in ADAM17 protein expression in liver biopsies obtained from patients with PBC and PSC, compared to normal control livers. PSC and PBC patients demonstrated increased hepatic ADAM17 expression in hepatocytes, cholangiocytes and in association with liver-infiltrating immune cells compared to normal controls. In summary, cholestatic liver injury in mice and humans is associated with increased hepatic ADAM17 expression. Furthermore, inhibition of ADAM17 activity improves both cholestatic liver injury and associated sickness behavior development, suggesting that ADAM17 inhibition may represent a novel therapeutic approach for treating patients with PBC/PSC.

Voluntary wheel running ameliorates select paclitaxel chemotherapy-induced sickness behaviors and associated melanocortin signaling.

While chemotherapy remains a common cancer treatment, it is associated with debilitating side effects (e.g., anorexia, weight loss, and fatigue) that adversely affect patient quality of life and increase mortality. However, the mechanisms underlying taxane chemotherapy-induced side effects, and effective treatments to ameliorate them, are not well-established. Here, we tested the longitudinal relationship between a clinically-relevant paclitaxel regimen, inflammation, and sickness behaviors (loss of body mass, anorexia, fever, and fatigue) in adult, female mice. Furthermore, we sought to identify the extent to which voluntary exercise (wheel running) attenuates paclitaxel-induced sickness behaviors and underlying central pathways. Body mass and food intake decreased following six doses of chemotherapy treatment relative to vehicle controls, lasting less than 5 days after the last dose. Paclitaxel treatment also transiently decreased locomotion (open field test), voluntary wheel running, home-cage locomotion, and core body temperature without affecting motor coordination (rotarod task). Circulating interleukin (IL)-6 and hypothalamic Il1b gene expression remained elevated in chemotherapy-treated mice at least 3 days after the last dose. Exercise intervention did not ameliorate fatigue or inflammation, but hastened recovery from paclitaxel-induced weight loss. Body mass recovery was associated with the wheel running-induced recovery of body composition, paclitaxel-induced alterations to hypothalamic melanocortin signaling, and associated peripheral circulating hormones (ghrelin and leptin). The present findings demonstrate the benefits of exercise on faster recovery from paclitaxel-induced body mass loss and deficits in melanocortin signaling and suggests the development of therapies targeting the melanocortin pathway to reduce paclitaxel-induced weight loss.

Infectious disease and sickness behaviour: tumour progression affects interaction patterns and social network structure in wild Tasmanian devils.

Infectious diseases, including transmissible cancers, can have a broad range of impacts on host behaviour, particularly in the latter stages of disease progression. However, the difficulty of early diagnoses makes the study of behavioural influences of disease in wild animals a challenging task. Tasmanian devils (Sarcophilus harrisii) are affected by a transmissible cancer, devil facial tumour disease (DFTD), in which tumours are externally visible as they progress. Using telemetry and mark-recapture datasets, we quantify the impacts of cancer progression on the behaviour of wild devils by assessing how interaction patterns within the social network of a population change with increasing tumour load. The progression of DFTD negatively influences devils' likelihood of interaction within their network. Infected devils were more active within their network late in the mating season, a pattern with repercussions for DFTD transmission. Our study provides a rare opportunity to quantify and understand the behavioural feedbacks of disease in wildlife and how they may affect transmission and population dynamics in general.

Prenatal LPS induces sickness behaviour and decreases maternal and predatory behaviours after an LPS challenge.

Purpose: The influence of a challenge dose of lipopolysaccharide (LPS) on the behavioural selection between maternal (MB) and predatory behaviours (PB) of female rats prenatally treated with the same endotoxin or saline solution (F1 generation) were studied.Material and methods: Thus, in adult age, these female rats were mated and, at lactation days 5 or 6, the following groups were formed: (1) LPS + LPS group-female rats prenatally treated with LPS and received an LPS challenge dose; (2) S + LPS group-female rats prenatally treated with saline solution and received a challenge LPS dose (3) S + S group-females rats prenatally treated with saline which received a saline injection. MB, PB to cockroaches, exploratory behaviour, periaqueductal grey (PAG) expression of the astrocytic biomarker glial fibrillary acidic protein (GFAP), and corticosterone and TNF-alpha serum levels were evaluated.Results: Showed that: (1) relative to the S + S group, the LPS + S group showed decreased MB and slightly increased PB, without inducing sickness behaviour; (2) the LPS + LPS group showed decreased MB but few effects on PB; (3) there was increased sickness behaviour associated with increased TNF-alpha serum levels in the LPS + LPS group; (4) a significant increase in GFAP expression was observed in both LPS groups, which was greater in the LPS + LPS group and (5) no differences in the corticosterone of all groups.Conclusions: Prenatal LPS impaired the switch from MB to PB in female rats of the LPS + LPS group by increased sickness behaviour as well as an increase in plasmatic TNF-alpha levels inducing PAG astrogliosis.

Psychological Distress and Illness Perceptions in Thyroid Cancer Survivors: Does Age Matter?

Purpose: To examine the role of differentiated thyroid cancer (DTC) patients' age in illness perceptions and psychological distress, and the potential moderating role of age in the relationship between illness perceptions and psychological distress. Methods: We used the Netherlands Cancer Registry to select all patients diagnosed with thyroid cancer between 1990 and 2008 (n = 568). Patients filled out the Hospital Anxiety and Depression Scale (HADS) and Brief Illness Perception Questionnaire. Levels of psychological distress and illness perceptions were compared between the different DTC survivor age groups (adolescents and young adults [AYAs; 18-39 years], middle-aged adults [40-64 years], and older survivors [65-84 years]). Results: Among 293 respondents with DTC, AYAs (n = 84) had more faith in the fact that their treatment can help them, and reported a stronger belief in understanding their illness compared to middle-aged (n = 172) and older adults (n = 37). No differences regarding age were seen on the other six illness perception subscales. AYAs did report significantly less distress (HADS caseness = 13.8%) compared to middle-aged (28.7%) and older adults (22.2%). Most illness perception subscales were associated with distress and the associations with age were mixed. AYAs and older patients who believed that their illness would continue for a long time reported more distress, but this association was not found for the middle-aged group. Conclusion: Illness perceptions play a key role in the experience of distress years after diagnosis and this is related to age. AYA and older cancer patients may be particularly vulnerable to distress related to maladaptive cancer-related beliefs/perceptions.

Sickness Behavior Score Is Associated with Neuroinflammation and Late Behavioral Changes in Polymicrobial Sepsis Animal Model.

The use of reliable scores is a constant development in critical illness. According to Sepsis-3 consensus, the use of Sequential Organ Failure Assessment (SOFA) score of 2 or more is associated with a higher mortality of sepsis patients. In experimental research, due murine animal model limitations, the use of a score systems can be an alternative to assess sepsis severity. In this work, we suggest a sickness behavior score (SBS) that uses physiological variables to assess sepsis severity and mortality. Animals were evaluated daily by the presence of six indicators of sickness behavior: temperature alteration, preference of water/sucrose, liquid intake, food intake, body weight, and movimentation. Male adult Wistar rats were evaluated daily after sepsis induction by cecal ligation and puncture (CLP) or laparotomy only (sham) for determination of SBS. Oxidative stress, IL-6, and HPA axis markers (corticosterone and adrenal gland weight) were evaluated 24 h after CLP to determine the correlation with the acute SBS and neuroinflammation. Also, BDNF and four cognitive behavioral tests were correlated with the chronic SBS, i.e., sum of 8 days after surgery. In result, septic rats presented higher SBS than sham animals. Sepsis severity markers were associated with acute and chronic SBS. Also, SBS was negative correlated with the cognitive tests. In conclusion, SBS shows to be reliable score to predict sepsis severity and mortality. The use of score system provides the analysis of global sickness behavior, beyond evaluation of each parameter individually.

Early life stress sensitizes individuals to the psychological correlates of mild fluctuations in inflammation.

BACKGROUND: Early life stress (ELS) has been linked to health disparities across the human lifespan, particularly increased risk for depression and its recurrence. In this study we explore two plausible and competing pathways through which ELS may lead to depression via inflammation. METHODS: Participants (ages 18-22; n = 41) completed the Early Trauma Inventory as a measure of ELS. Participants then completed consecutive daily diaries of mood and other sickness behavior for the 7 days prior to and 7 days after receiving the annual influenza vaccine. Circulating concentrations of plasma interleukin-6 (IL-6) were measured immediately before and 24 hr after vaccination. RESULTS: ELS was not associated with the magnitude of change in IL-6 from pre- to post-vaccine, however, exposure to ELS moderated the association between change in IL-6 from pre- to post-vaccine and changes in both cognitive difficulty and depressed mood. Individuals exposed to greater ELS showed greater psychological sensitivity to increases in IL-6. CONCLUSIONS: Exposure to ELS may increase sensitivity to peripheral inflammation in the central nervous system. Future studies elaborating on the impact of ELS on the sensitivity of specific neural circuits and cells to inflammation are needed.

Characterization of Spatial Learning and Sickness Responses in Aging Rats Following Recurrent Lipopolysaccharide Administration.

Infections in older individuals can result in cognitive function decline, yet research is limited on how recurrent infections affect cognitive responses. Activation of the immune system results in sickness responses mediated by cytokines. This pilot study examined effects of a model of recurrent infection in aged, male Brown Norway rats on sickness responses, including spatial learning, and cytokine levels. To model initial and recurrent infection, 300 µg/kg lipopolysaccharide (LPS) or saline was administered 1/day for 2 consecutive days during 2 weeks separated by 16 days. Testing occurred for 6 days during each LPS injection week using the Morris water maze, a measure used to evaluate spatial learning. Directional heading error (DHE) and swim time latency served as spatial learning indices. Retention tests and probe trials assessed memory. Plasma cytokine levels were assessed 5 and 24 hr after each LPS injection during Week 2. While food intake and weight decreased significantly in LPS-injected rats compared to controls during Week 1, both displayed increased DHE. Despite exhibiting lessened sickness behaviors during Week 2, experimental animals still displayed spatial learning deficits. Probe trials revealed memory deficits in LPS-injected animals. Interleukin 6 level was higher in the experimental group 5 and 24 hr after LPS injection on Day 1 compared to Day 2 and higher in the experimental compared to the control group at 5 hr on Day 1. Cognitive effects were dissociated from metabolic effects in aged rats, with recurring LPS exposure resulting in persistent cognitive impairment despite decreased sickness responses. Further research with older individuals is warranted.

Lipocalin-2 is dispensable in inflammation-induced sickness and depression-like behavior.

RATIONALE: While the relationship between inflammation and depression is well-established, the molecular mechanisms mediating this relationship remain unclear. RNA sequencing analysis comparing brains of vehicle- and lipopolysaccharide-treated mice revealed LCN2 among the most dysregulated genes. As LCN2 is known to be an important regulator of the immune response to bacterial infection, we investigated its role in the behavioral response to lipopolysaccharide. OBJECTIVE: To explore the role of LCN2 in modulating behavior following lipopolysaccharide administration using wild type (WT) and lcn2-/- mice. METHODS: Using a within-subjects design, mice were treated with 0.33 mg/kg liposaccharide (LPS) and vehicle. Primary outcome measures included body weight, food consumption, voluntary wheel running, sucrose preference, and the tail suspension test. To evaluate the inflammatory response, 1 week later, mice were re-administered either vehicle or LPS and terminated at 6 h. RESULTS: While lcn2-/- mice had increased baseline food consumption and body weight, they showed a pattern of reduced food consumption and weight loss similar to WT mice in response to LPS. WT and lcn2-/- mice both recovered voluntary activity on the fourth day following LPS. LPS induced equivalent reductions in sucrose preference and TST immobility in the WT and lcn2-/- mice. Finally, there were no significant effects of genotype on inflammatory markers. CONCLUSIONS: Our data demonstrate that lcn2 is dispensable for sterile inflammation-induced sickness and depression-like behavior. Specifically, lcn2-/- mice displayed sickness and immobility in the tail suspension test comparable to that of WT mice both in terms of intensity and duration.

Cannabinoid receptor 2 activation mitigates lipopolysaccharide-induced neuroinflammation and sickness behavior in mice.

RATIONALE AND OBJECTIVES: Cannabinoid receptor 2 (CB2R) signaling in the brain is associated with the pathophysiology of depression. Sickness behavior, characterized by lessened mobility, social interaction, and depressive behavior, is linked with neuroinflammation, oxidative stress, and immune system. The present study was aimed at evaluating 1-phenylisatin (PI), a CB2R agonist, in sickness behavior. METHODS: Influence of acute and 7-day activation of CB2R using PI in lipopolysaccharide (LPS)-induced sickness behavior was assessed in mice. An acute injection of LPS (1.5 mg/kg) produced a fully developed sickness behavior in animals within 1 h of administration. The behavioral paradigm was assessed by open field test, forced swim test, and tail suspension test. Further, tumor necrosis factor-α (TNF-α), antioxidant enzymes, and lipid peroxidation were measured in the brain to correlate neuroinflammation and oxidative stress with sickness behavior. Both treatments, PI (20 mg/kg) and imipramine (15 mg/kg), were administered orally (once for acute and once daily for 7-day protocols). RESULTS: LPS elevated the brain TNF-α level, augmented oxidative stress, and induced the sickness behavior in mice. Acute and 7-day treatment of mice with PI significantly reduced the LPS-induced sickness behavior. In addition, PI inhibited the neuroinflammation evidenced by a reduction in brain TNF-α and oxidative stress. CONCLUSION: Our data propose that acute and long-term activation of CB2R might prevent neuroinflammation and oxidative stress-associated sickness behavior.

Sexual activity modulates neuroinflammatory responses in male rats.

Immune activity influences reproduction, however, the extent to which mating experience may inversely alter immune pathways is poorly understood. A few studies in humans suggest that mating triggers a circulating immune and hypothalamic-pituitary-adrenal axis response. In male rats, mating experience enhances neuroplasticity and improves cognitive function and affective-like behavior, independent of the physical activity component. Yet, the extent to which mating experience may influence immune responses in the brain remain unexplored. Here, we hypothesized that recent mating experience in male rats increases neuroinflammatory signaling (via lipopolysaccharide [LPS] stimulation, i.p.) and associated sickness behaviors (i.e., food intake, weight loss) relative to sexually-naïve controls. Virgin male rats were exposed to a sexually non-receptive (control) or sexually-receptive female for 30 min for six consecutive days. Immediately following the last mating experience, rats were administered a saline or LPS injection and euthanized four hours later. Mating increased Tnfα responses to LPS in the brain, which positively correlated with LPS-induced weight loss. Mating also increased peripheral corticosterone among saline-treated rats, but this corticosterone response was attenuated in the most proficient copulators (e.g., shortest latencies). Thus, recent mating experience may be a unique modulator of select stimulated inflammatory signals that are relevant to adaptive neuroimmune responses and behavior.

TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia.

Hypothalamic inflammation is a key component of acute sickness behavior and cachexia, yet mechanisms of inflammatory signaling in the central nervous system remain unclear. Previous work from our lab and others showed that while MyD88 is an important inflammatory signaling pathway for sickness behavior, MyD88 knockout (MyD88KO) mice still experience sickness behavior after inflammatory stimuli challenge. We found that after systemic lipopolysaccharide (LPS) challenge, MyD88KO mice showed elevated expression of several cytokine and chemokine genes in the hypothalamus. We therefore assessed the role of an additional inflammatory signaling pathway, TRIF, in acute inflammation (LPS challenge) and in a chronic inflammatory state (cancer cachexia). TRIFKO mice resisted anorexia and weight loss after peripheral (intraperitoneal, IP) or central (intracerebroventricular, ICV) LPS challenge and in a model of pancreatic cancer cachexia. Compared to WT mice, TRIFKO mice showed attenuated upregulation of Il6, Ccl2, Ccl5, Cxcl1, Cxcl2, and Cxcl10 in the hypothalamus after IP LPS treatment, as well as attenuated microglial activation and neutrophil infiltration into the brain after ICV LPS treatment. Lastly, we found that TRIF was required for Ccl2 upregulation in the hypothalamus and induction of the catabolic genes, Mafbx, Murf1, and Foxo1 in gastrocnemius during pancreatic cancer. In summary, our results show that TRIF is an important inflammatory signaling mediator of sickness behavior and cachexia and presents a novel therapeutic target for these conditions.

Effect of central injection of tumor-necrosis factor-like cytokine 1A and interferons on food intake in chicks.

In mammals, anorexia accompanying infection is thought to be mediated via cytokines including interleukins, interferons (IFNs), and tumor necrosis factor (TNF). However, there is a lack of related knowledge on birds. Therefore, the purpose of the present study was to determine if cytokines are associated with reduced food intake in chicks (Gallus gallus). Specifically, we evaluated the effects of TNF-like cytokine 1A (TL1A), a member of the TNF family, interferon-α (IFN-α), and interferon-γ (IFN-γ) on food intake. Additionally, the effect of lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I:C) on cytokine mRNA expression in the diencephalon and spleen was also measured. Intracerebroventricular (ICV) injection of 0.05 or 0.5 µg TL1A, IFN-α, and IFN-γ had no effect on food intake. However, when 1.0 µg each of these factors was evaluated, TL1A significantly decreased food intake at 180 and 240 min after the injection, but IFN-α and IFN-γ had no effect. When chicks received intraperitoneal (IP) injections of 100 µg LPS or 400 µg poly I:C, their food intake was reduced. Diencephalic mRNA expression of TL1A was significantly decreased following IP injection of LPS or poly I:C. Additionally, diencephalic mRNA expression of IFN-γ mRNA was significantly increased by IP injection of LPS but decreased by IP injection of poly I:C. For the spleen, IP injection of LPS and poly I:C both significantly increased TL1A and IFN-γ mRNA expression. In sum, we have provided evidence that central TL1A but not IFN-α or IFN-γ are related to reduction of food intake in chicks, but the role of these cytokines for mediating anorexia associated with infections may differ from mammals.

Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS-induced sickness and depressive-like behavior in mice.

The communication between the immune and central nervous system (CNS) is affected in many neurological disorders. Peripheral injections of the endotoxin lipopolysaccharide (LPS) are widely used to study this communication: an LPS challenge leads to a biphasic syndrome that starts with acute sickness and is followed by persistent brain inflammation and chronic behavioral alterations such as depressive-like symptoms. In vitro, the response to LPS treatment has been shown to involve enhanced expression of system x c - . This cystine-glutamate antiporter, with xCT as specific subunit, represents the main glial provider of extracellular glutamate in mouse hippocampus. Here we injected male xCT knockout and wildtype mice with a single intraperitoneal dose of 5 mg/kg LPS. LPS-injection increased hippocampal xCT expression but did not alter the mainly astroglial localization of the xCT protein. Peripheral and central inflammation (as defined by cytokine levels and morphological activation of microglia) as well as LPS-induced sickness and depressive-like behavior were significantly attenuated in xCT-deficient mice compared with wildtype mice. Our study is the first to demonstrate the involvement of system x c - in peripheral and central inflammation in vivo and the potential therapeutic relevance of its inhibition in brain disorders characterized by peripheral and central inflammation, such as depression.

The expression of TRPV channels, prostaglandin E2 and pro-inflammatory cytokines during behavioural fever in fish.

A fever, or increased body temperature, is a symptom of inflammation, which is a complex defence reaction of the organism to pathogenic infections. After pathogens enter the body, immune cells secrete a number of agents, the functions of which stimulate the body to develop a functional immune and fever response. In mammals it is known that PGE2 is the principal mediator of fever. The extent to which PGE2 and other pro-inflammatory cytokines such as TNF-α, IL-6, or IL-1ß could be involved in the induction of behavioural fever in fish remains to be clarified. Several members of the transient receptor potential (TRP) family of ion channels have been implicated as transducers of thermal stimuli, including TRPV1 and TRPV2, which are activated by heat. Here we show that members of the TRP family, TRPV1 and TRPV4, may participate in the coordination of temperature sensing during the behavioural fever. To examine the behavioral fever mechanism in Salmo salar an infection with IPNV, infectious pancreatic necrosis virus, was carried out by an immersion challenge with 10 × 105 PFU/mL-1 of IPNV. Behavioural fever impacted upon the expression levels of both TRPV1 and TRPV4 mRNAs after the viral challenge and revealed a juxtaposed regulation of TRPV channels. Our results suggest that an increase in the mRNA abundance of TRPV1 is tightly correlated with a significant elevation in the expression of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and PGE2) in the Pre-Optic Area (POA) and cytokine release in plasma. Together, these data indicate that the reduction of TRPV4 expression during behavioural fever may contribute to the onset of behavioural fever influencing movement toward higher water temperatures. Our data also suggest an effect of TRPV channels in the regulation of behavioural fever through activation of EP3 receptors in the central nervous system by PGE2 induced by plasma-borne cytokines. These results highlight for first time in mobile ectotherms the key role of pro-inflammatory cytokines and TRPV channels in behavioural fever that likely involves a complex integration of prostaglandin induction, cytokine recognition and temperature sensing.

The wake-promoting drug Modafinil prevents motor impairment in sickness behavior induced by LPS in mice: Role for dopaminergic D1 receptor.

The wake-promoting drug Modafinil has been used for many years for treatment of Narcolepsy and Excessive Daytime Sleepiness, due to a dopamine-related psychostimulant action. Recent studies have indicated that Modafinil prevents neuroinflammation in animal models. Thus, the aim of the present study was to evaluate the effect of Modafinil pretreatment in the Lipopolysaccharide (LPS)-induced sickness and depressive-like behaviors. Adult male C57BL/6J mice were pretreated with Vehicle or Modafinil (90mg/Kg) and, 30min later, received a single saline or LPS (2mg/Kg) administration, and were submitted to the open field and elevated plus maze test 2h later. After 24h, mice were subjected to tail suspension test, followed by either flow cytometry with whole brain for CD11b+CD45+ cells or qPCR in brain areas for cytokine gene expression. Modafinil treatment prevented the LPS-induced motor impairment, anxiety-like and depressive-like behaviors, as well as the increase in brain CD11b+CD45high cells induced by LPS. Our results indicate that Modafinil pretreatment also decreased the IL-1ß gene upregulation caused by LPS in brain areas, which is possibly correlated with the preventive behavioral effects. The pharmacological blockage of the dopaminergic D1R by the drug SCH-23390 counteracted the effect of Modafinil on locomotion and anxiety-like behavior, but not on depressive-like behavior and brain immune cells. The dopaminergic D1 receptor signaling is essential to the Modafinil effects on LPS-induced alterations in locomotion and anxiety, but not on depression and brain macrophages. This evidence suggests that Modafinil treatment might be useful to prevent inflammation-related behavioral alterations, possibly due to a neuroimmune mechanism.

Brewer's yeast is a potent inducer of fever, sickness behavior and inflammation within the brain.

Brewer's yeast, derived from the yeast species Saccharomyces cerevisiae (S. cerevisiae), is commonly used for inducing pyrexia in pharmacological studies screening antipyretics in rats. Despite its widespread use, the peripheral and central inflammatory response associated with Brewer's yeast-induced fever and sickness behavior in rats has not been investigated. Thus, we injected male Sprague-Dawley rats (150-200 g) subcutaneously with a high (4 g/kg, n = 9), medium (2 g/kg, n = 5) or low (0.4 g/kg, n = 6) dose of Brewer's yeast solution or saline (0.9%, n = 6) and measured core body temperature, cage activity, food intake and body mass for six days after injection. Blood and brain samples were collected at 2, 8, 18 and 72 h after injection; n = 5-7 per time point. Brewer's yeast administration dose-dependently induced fever, lethargy, anorexia and body mass stunting that was accompanied by increased blood plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and activation of inflammatory transcription factors (nuclear factor (NF) for interleukin-6, signal transducer and activator of transcription (STAT)-3, and NF-κB)) in the hypothalamus and circumventricular organs. The increased activation of transcription factors following Brewer's yeast administration was accompanied by increased hypothalamic mRNA expression of TNF-α, IL-1ß and IL-6 and rate-limiting enzymes for prostaglandin synthesis. Our results show that subcutaneous administration of S. cerevisae induces prolonged fever, anorexia and lethargy that is accompanied by a pronounced increase in the synthesis of pro-inflammatory cytokines, key prostaglandin synthesizing enzymes and transcription factors, in the periphery and brain.