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The acute-phase response (APR) is an adaptive emergency life-history stage, wherein vertebrates exhibit fever and anorexia to survive an infection. However, induced immune responses are energetically costly, and sick animals may reduce physical activity to compensate. Tests of this predicted energetic trade-off in free-ranging animals are rare due to difficulties in measuring individual physiology and behaviour under immune challenge in natural settings. However, recent advances in biologging technology now make such studies possible. We surgically implanted heart rate/temperature loggers in free-ranging adult male Arctic ground squirrels, fitted the squirrels with collar-mounted accelerometers and light/temperature loggers, and injected animals with lipopolysaccharide (LPS) to simulate an immune challenge. LPS-injected squirrels exhibited approximately 1°C overnight fevers accompanied by slightly elevated (10 bpm) heart rates; LPS-injected squirrels also spent 19% less of their time aboveground the following day and reduced overall movement by 40% compared with saline-injected controls. Thus, we found support for an energetic trade-off between functional immune responses (fever and anorexia) and lethargic sickness behaviour within the APR of a free-ranging mammal. Moreover, our results suggest animal-borne devices can play an important role in future studies of vertebrate immunity and disease dynamics.

Sickness-associated anorexia, the reduction in appetite seen during infection, is a widely conserved and well-recognized symptom of acute infection, yet there is very little understanding of its functional role in recovery. Anorexic sickness behaviours can be understood as an evolutionary strategy to increase tolerance to pathogen-mediated illness. In this review we explore the evidence for mechanisms and potential metabolic benefits of sickness-associated anorexia. Energy intake can impact on the immune response, control of inflammation and tissue stress, and on pathogen fitness. Fasting mediators including hormone-sensitive lipase, peroxisome proliferator-activated receptor-alpha (PPAR-α) and ketone bodies are potential facilitators of infection recovery through multiple pathways including suppression of inflammation, adaptation to lipid utilising pathways, and resistance to pathogen-induced cellular stress. However, the effect and benefit of calorie restriction is highly heterogeneous depending on both the infection and the metabolic status of the host, which has implications regarding clinical recommendations for feeding during different infections., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Peripheral inflammation is closely related to the pathogenesis of sickness behaviors and psychiatric disorders such as anxiety and depression. The circumventricular organs (CVOs) are important brain sites to perceive peripheral inflammatory signals, but few studies have reported their role in inflammation-induced anxiety or depression. Using a mouse model of lipopolysaccharide (LPS)-induced inflammation, we identified a previously unreported role of the subfornical organ (SFO), one of the CVOs, in combating inflammation-induced anxiety. LPS treatment induced anxiety-like and sickness behaviors in mice. Although both the SFO and the organum vasculosum of the lamina terminalis (a CVO) neurons were activated after LPS treatment, only manipulating SFO neurons modulated LPS-induced anxiety-like behaviors. Activating or inhibiting SFO neurons alleviated or aggravated LPS-induced anxiety-like behaviors. In addition, SFO exerted this effect through glutamatergic projections to the bed nucleus of the stria terminalis. Manipulating SFO neurons did not affect LPS-induced sickness behaviors. Thus, we uncovered an active role of SFO neurons in counteracting peripheral inflammation-induced anxiety.

Selection for group living has occurred across taxa, despite inherent risk of disease transmission. Behavioral and immune responses to sickness affect social interactions and can be altered by social contexts. However, the majority of research on sickness behavior has focused on species that do not form selective social relationships. Prairie voles (Microtus ochrogaster) form selective social relationships with mates and peers and provide a useful study system to examine effects of sickness on social seeking in established relationships. We used peripheral injections of lipopolysaccharide (LPS) of E. coli to stimulate the innate immune system and verified effects on activity, core temperature, and corticosterone concentrations for 6 h following treatment. We demonstrated that male and female same-sex pairs of prairie voles increase social contact when sick and that this increase persists when contact is initiated by the sick vole. Finally, we assessed social motivation following immune challenge using operant choice chambers equipped with two levers and side chambers. Voles worked to gain access to chambers with social and non-social rewards. While overall effort decreased following LPS injection, only immune-challenged voles worked significantly harder for their companion than for a non-social chamber. LPS treatment also increased proportion of rewards earned for the partner versus a stranger and again led to increased huddling behavior. Prior studies in other rodent species have shown decreased social interaction when sick; the present results demonstrate an alternative outcome of sickness in the context of dyadic bonds and lay the foundation for future work in peer companions., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Systemic inflammation elicits sickness behaviors and fever by engaging a complex neuronal circuitry that begins in the preoptic area of the hypothalamus. Ectotherms such as teleost fish display sickness behaviors in response to infection or inflammation, seeking warmer temperatures to enhance survival via behavioral fever responses. To date, the hypothalamus is the only brain region implicated in sickness behaviors and behavioral fever in teleosts. Yet, the complexity of neurobehavioral manifestations underlying sickness responses in teleosts suggests engagement of higher processing areas of the brain. Using in vivo models of systemic inflammation in rainbow trout, we find canonical pyrogenic cytokine responses in the hypothalamus whereas in the telencephalon and the optic tectum il-1b and tnfa expression is decoupled from il-6 expression. Polyamine metabolism changes, characterized by accumulation of putrescine and decreases in spermine and spermidine, are recorded in the telencephalon but not hypothalamus upon systemic injection of bacteria. While systemic inflammation causes canonical behavioral fever in trout, blockade of bacterial polyamine metabolism prior to injection abrogates behavioral fever, polyamine responses, and telencephalic but not hypothalamic cytokine responses. Combined, our work identifies the telencephalon as a neuronal substrate for brain responses to systemic inflammation in teleosts and uncovers the role of polyamines as critical chemical mediators in sickness behaviors., Competing Interests: Competing interests statement:The authors declare no competing interest.

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 (r s =.26, p <.05); sex and ESR (r s =.29, p <.05); age and IL-6 (r s =.29, p <.05) and IL-8 (r s =.30, p <.05); BMI and IL-6 (r s =.50, p <.001), CRP (r s =.63, p <.001) and ESR (r s =.42, p <.001). Ratings of depression were positively and significantly related to ratings of sickness behavior and anxiety (β =.32 and β =.40, respectively), explaining 49 % of the total variance in depression ratings. Insomnia was positively and significantly related to sickness behavior (β =.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., Competing Interests: Declaration of Competing Interest No conflict., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Administration of low-dose lipopolysaccharide (LPS) to healthy humans is a translational approach to analyze the effects of acute systemic inflammation and sickness behavior. Although studies documented that LPS-induced inflammation can alter social behavior, its impact on empathy remains poorly understood. In this double-blind, placebo-controlled study, 52 healthy female volunteers received an intravenous injection of either LPS (0.4 ng/kg body weight) or placebo and completed the Social Interaction Empathy Task (SIET) two hours after injection. Physiological responses (blood pressure, heart rate, body temperature, cytokines, cortisol) were analyzed along with sickness symptoms and mood before and after LPS or placebo administration. LPS application led to significant increases in plasma cytokines and sickness symptoms as well as low mood. Moreover, volunteers receiving LPS showed significantly less empathy for other's psychological pain than those who received placebo. Furthermore, LPS-injected volunteers with more severe sickness symptoms displayed higher pain ratings in the first-person perspective. Thus, low-grade inflammation reduces empathy for other's psychological pain which might reflect an adaptive strategy to save energy by not responding empathetically when sick oneself., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Infections frequently cause behavioral changes, known as sickness behavior. In a recent study, 1 Yipp and collaborators discovered a sensory circuit that is activated by a bacterial lipopolysaccharide during lung infection and drives sickness behaviors independent of inflammation. Biofilm-producing bacteria, however, avoid activating this lung-brain circuit, resulting in infection without sickness behavior., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Historically, the fields of ecoimmunology, psychoneuroimmunology and disease ecology have taken complementary yet disparate theoretical and experimental approaches, despite sharing critical common themes. Researchers in these areas have largely worked independently of one another to understand mechanistic immunological responses, organismal level immune performance, behavioral changes, and host and parasite/disease population dynamics, with few bridges across disciplines. Although efforts to strengthen and expand these bridges have been called for (and occasionally heeded) over the last decade, more integrative studies are only now beginning to emerge, with critical gaps remaining. Here, we briefly discuss the origins of these key fields, and their current state of integration, while highlighting several critical directions that we suggest will strengthen their connections into the future. Specifically, we highlight three key research areas that provide collaborative opportunities for integrative investigation across multiple levels of biological organization, from mechanisms to ecosystems: (1) parental effects of immunity, (2) microbiome and immune function and (3) sickness behaviors. By building new bridges among these fields, and strengthening existing ones, a truly integrative approach to understanding the role of host immunity on individual and community fitness is within our grasp., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

The capacity to rapidly detect and avoid sick people may be adaptive. Given that faces are reliably available, as well as rapidly detected and processed, they may provide health information that influences social interaction. Prior studies used faces that were manipulated to appear sick (e.g., editing photos, inducing inflammatory response); however, responses to naturally sick faces remain largely unexplored. We tested whether adults detected subtle cues of genuine, acute, potentially contagious illness in face photos compared to the same individuals when healthy. We tracked illness symptoms and severity with the Sickness Questionnaire and Common Cold Questionnaire. We also checked that sick and healthy photos were matched on low-level features. We found that participants (N = 109) rated sick faces, compared to healthy faces, as sicker, more dangerous, and eliciting more unpleasant feelings. Participants (N = 90) rated sick faces as more likely to be avoided, more tired, and more negative in expression than healthy faces. In a passive-viewing eye-tracking task, participants (N = 50) looked longer at healthy than sick faces, especially the eye region, suggesting people may be more drawn to healthy conspecifics. When making approach-avoidance decisions, participants (N = 112) had greater pupil dilation to sick than healthy faces, and more pupil dilation was associated with greater avoidance, suggesting elevated arousal to threat. Across all experiments, participants' behaviors correlated with the degree of sickness, as reported by the face donors, suggesting a nuanced, fine-tuned sensitivity. Together, these findings suggest that humans may detect subtle threats of contagion from sick faces, which may facilitate illness avoidance. By better understanding how humans naturally avoid illness in conspecifics, we may identify what information is used and ultimately improve public health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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-1β), 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., (© 2022. The Author(s).)

Background: Systemic inflammation is accompanied by unspecific physical and psychological symptoms of sickness, including pain and affective symptoms. These symptoms (commonly called "sickness behavior") are mediated by the central nervous effects of immune messengers such as pro-inflammatory cytokines. While adaptive during acute inflammation, sickness symptoms can have detrimental effects on quality of life during chronic inflammation and may contribute to comorbidity in chronic pain conditions. Despite the high clinical relevance of sickness behavior, psychological interventions aiming to modulate sickness symptoms have hardly been investigated. One approach could be the use of expectation effects, since positive and negative expectations (placebo or nocebo effects) have been shown to have an influence on pain and affect-related symptoms., Objectives: Herein, we summarize immunological and psychobiological factors that contribute to pain in the context of sickness behavior, with a major focus on findings from experimental endotoxemia. Against this background, we discuss how expectations could help to improve immune-mediated sickness symptoms and outline potential psychological and psychobiological mechanisms underlying this putative effect., (© 2021. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Almishri, Swain, D’Mello, Le, Urbanski and Nguyen.)

Aims: During illnesses caused by infectious diseases, a suite of brain-mediated responses called sickness syndrome occurs, triggering behavioral and physiological changes. This study investigated whether ghrelin modulates sickness syndrome induced by systemic administration of lipopolysaccharide (LPS)., Main Methods: Male Wistar rats were pretreated with vehicle or [D-lys3]-GHRP-6, a ghrelin receptor GHS-R1 antagonist (20 nmol, i.c.v), 30 min before injection of LPS (200 μg/kg, i.p.) or sterile saline. We investigated the behavioral effects in male rats after LPS administration by screening for depressive-like behavior, locomotor activity alterations, and corticosterone release. Changes in body temperature were measured using a biotelemetry probe preimplanted in the peritoneal cavity to evaluate the effect of ghrelin on the thermoregulatory response during immunological challenge., Key Findings: Pretreatment with [D-lys3]-GHRP-6 blunted most of the assessed parameters related to sickness syndrome, including social withdrawal, anhedonia, depressive-like behavior, and anorexia, reduced the activation of the HPA axis, but did not alter LPS-induced fever., Significance: Our findings suggest that ghrelin centrally mediates the sickness behavior and activation of HPA, as a ghrelin receptor antagonist attenuates social withdrawal, anhedonia, depressive-like behavior, anorexia, and HPA activation in response to LPS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Many instances of sickness critically involve the immune system. The immune system talks to the brain in a bidirectional loop. This discourse affords the immune system immense control, such that it can influence behavior and optimize recovery from illness. These behavioral responses to infection are called sickness behaviors and can manifest in many ways, including changes in mood, motivation, or energy. Fascinatingly, most of these changes are conserved across species, and most organisms demonstrate some form of sickness behaviors. One of the most interesting sickness behaviors, and not immediately obvious, is altered sociability. Here, we discuss how the immune system impacts social behavior, by examining the brain regions and immune mediators involved in this process. We first outline how social behavior changes in response to infection in various species. Next, we explore which brain regions control social behavior and their evolutionary origins. Finally, we describe which immune mediators establish the link between illness and social behavior, in the context of both normal development and infection. Overall, we hope to make clear the striking similarities between the mechanisms that facilitate changes in sociability in derived and ancestral vertebrate, as well as invertebrate, species., (© 2021 S. Karger AG, Basel.)

Along with its many advantages, social roosting imposes a major risk of pathogen transmission. How social animals reduce this risk is poorly documented. We used lipopolysaccharide challenge to imitate bacterial infection in both a captive and a free-living colony of an extremely social, long-lived mammal-the Egyptian fruit bat. We monitored behavioral and physiological responses using an arsenal of methods, including onboard GPS to track foraging, acceleration sensors to monitor movement, infrared video to record social behavior, and blood samples to measure immune markers. Sick-like (immune-challenged) bats exhibited an increased immune response, as well as classic illness symptoms, including fever, weight loss, anorexia, and lethargy. Notably, the bats also exhibited behaviors that would reduce pathogen transfer. They perched alone and appeared to voluntarily isolate themselves from the group by leaving the social cluster, which is extremely atypical for this species. The sick-like individuals in the open colony ceased foraging outdoors for at least two nights, thus reducing transmission to neighboring colonies. Together, these sickness behaviors demonstrate a strong, integrative immune response that promotes recovery of infected individuals while reducing pathogen transmission inside and outside the roost, including spillover events to other species, such as humans., (© 2021 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced mobility and depressive behaviors. Dimethyl fumarate (DMF) is an immunomodulatory and anti-oxidative molecule commonly used for the symptomatic treatment of multiple sclerosis and psoriasis. In this study, we investigated the potential use of DMF against microglial NLRP3 inflammasome activation both in vitro and in vivo . For in vitro studies, LPS- and ATP-stimulated N9 microglial cells were used to induce NLRP3 inflammasome activation. DMF's effects on inflammasome markers, pyroptotic cell death, ROS formation, and Nrf2/NF-κB pathways were assessed. For in vivo studies, 12-14 weeks-old male BALB/c mice were treated with LPS, DMF + LPS and ML385 + DMF + LPS. Behavioral tests including open field, forced swim test, and tail suspension test were carried out to see changes in lipopolysaccharide-induced sickness behavior. Furthermore, NLRP3 and Caspase-1 expression in isolated microglia were determined by immunostaining. Here we demonstrated that DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia via Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels via Nrf2 activation. Additionally, we showed that DMF pretreatment decreased miR-146a and miR-155 both in vivo and in vitro . Our results proved the effectiveness of DMF on the amelioration of microglial NLRP3 inflammasome activation. We anticipate that this study will provide the foundation consideration for further studies aiming to suppress NLRP3 inflammasome activation associated with in many diseases and a better understanding of its underlying mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tastan, Arioz, Tufekci, Tarakcioglu, Gonul, Genc and Genc.)

Fevers are considered an adaptive response by the host to infection. For gregarious animals, however, fever and the associated sickness behaviors may signal a temporary loss of capacity, offering other group members competitive opportunities. We implanted wild vervet monkeys ( Chlorocebus pygerythrus ) with miniature data loggers to obtain continuous measurements of core body temperature. We detected 128 fevers in 43 monkeys, totaling 776 fever-days over a 6-year period. Fevers were characterized by a persistent elevation in mean and minimum 24-h body temperature of at least 0.5 °C. Corresponding behavioral data indicated that febrile monkeys spent more time resting and less time feeding, consistent with the known sickness behaviors of lethargy and anorexia, respectively. We found no evidence that fevers influenced the time individuals spent socializing with conspecifics, suggesting social transmission of infection within a group is likely. Notably, febrile monkeys were targeted with twice as much aggression from their conspecifics and were six times more likely to become injured compared to afebrile monkeys. Our results suggest that sickness behavior, together with its agonistic consequences, can carry meaningful costs for highly gregarious mammals. The degree to which social factors modulate the welfare of infected animals is an important aspect to consider when attempting to understand the ecological implications of disease., Competing Interests: The authors declare no competing interest.

The use of endotoxin, such as lipopolysaccharide (LPS) as a model of sickness behavior, has attracted recent attention. To objectively investigate sickness behavior along with its pain-like behaviors in LPS-treated mice, the behavioral measurement requires accurate methods, which reflects clinical relevance. While reflexive pain response tests have been used for decades for pain assessment, its accuracy and clinical relevance remain problematic. Hence, we used automated home-cage monitoring LABORAS to evaluate spontaneous locomotive behaviors in LPS-induced mice. LPS-treated mice displayed sickness behaviors including pain-like behaviors in automated home-cage monitoring characterized by decreased mobile behaviors (climbing, locomotion, rearing) and increased immobility compared to that of the control group in both short- and long-term locomotive assessments. Here, in short-term measurement, both in the open-field test and automated home-cage monitoring, mice demonstrated impaired locomotive behaviors. We also assessed 24 h long-term locomotor activity in the home-cage system, which profiled the diurnal behaviors of LPS-stimulated mice. The results demonstrated significant behavioral impairment in LPS-stimulated mice compared to the control mice in both light and dark phases. However, the difference is more evident in the dark phase compared to the light phase owing to the nocturnal activity of mice. In addition, the administration of indomethacin as a pharmacological intervention improved sickness behaviors in the open-field test as well as automated home-cage monitoring, confirming that automated home-cage monitoring could be potentially useful in pharmacological screening. Together, our results demonstrate that automated home-cage monitoring could be a feasible alternative to conventional methods, such as the open-field test and combining several behavioral assessments may provide a better understanding of sickness behavior and pain-like behaviors in LPS-treated mice., Competing Interests: The authors have declared that no competing interests exist.

Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism's ability to respond to environmental threats in order to survive. We describe how the immune system relays information to the nervous system and how cytokine signalling occurs in neurons. We also speculate on how the brain may be hardwired to receive and process information from the immune system. Finally, we propose a unified theory depicting a co-evolution of the immune system and host behaviour in response to the evolutionary pressure of pathogens., (© 2021. Springer Nature Limited.)

Sickness symptoms exerted via inflammatory responses occur in several infectious and chronic diseases. A growing body of evidence suggests that altered nutrient availability and metabolism are tightly coupled to inflammatory processes. However, the relationship between metabolic shifts and the development of the sickness response has not been explored fully. Therefore, we aimed to evaluate metabolic phenotypes with a mouse model showing sickness symptoms via systemic administration of lipopolysaccharide (LPS) in the present study. LPS injection elevated the lipid utilization and circulating levels of fatty acids. It also increased the levels of β-hydroxybutyric acid, a ketone body produced from fatty acids. We confirmed the functional connectivity between nutrient utilization and inflammatory responses and demonstrated enhanced lipid utilization in the hypothalamus providing insights into hypothalamic control of sickness responses. Collectively, these findings could help develop new therapeutic strategies to treat patients with severe sickness symptoms associated with infectious and chronic human diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Exposure to light at night (LAN) can disrupt the circadian system, thereby altering neuroimmune reactivity and related behavior. Increased exposure to LAN affects people of all ages - and could have particularly detrimental effects during early-life and adolescence. Despite this, most research on the behavioral and physiological effects of LAN has been conducted in adult animals. Here we evaluated the effects of dim LAN during critical developmental windows on adulthood neuroimmune function and affective/sickness behaviors. Male and female C57BL/6 J mice were exposed to dim LAN [12:12 light (150 lx)/dim (15 lx) cycle] during early life (PND10-24) or adolescence (PND30-44) [control: 12:12 light (150 lx)/dark (0 lx) cycle]. Behaviors were assessed during juvenile (PND 42-44) and adult (PND60) periods. Contrary to our hypothesis, juvenile mice that were exposed to dim LAN did not exhibit changes in anxiety- or depressive-like behaviors. By adulthood, adolescent LAN-exposed female mice showed a modest anxiety-like phenotype in one behavioral task but not another. Adolescent LAN exposure also induced depressive-like behavior in a forced swim task in adulthood in both male and female mice. Additionally, developmental LAN exacerbated the hippocampal cytokine response (IL-1β) following peripheral LPS in female, but not male mice. These results suggest female mice may be more susceptible to developmental LAN than male mice: LAN female mice had a modest anxiety-like phenotype in adulthood, and upon LPS challenge, higher hippocampal IL-1β expression. Taken together, developmental LAN exposure in mice promotes a modest increase in susceptibility to anxiety- and depressive-like symptoms., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the topical glaucoma eye drops adherence prevalence and its association with beliefs and illness perceptions about glaucoma in Turkey. We also aimed to explore the factors linked to patients' total, voluntary, and involuntary non-adherence to medication in different patient attitudes., Material and Methods: A prospective study with cross-sectional design which included a total of 317 glaucoma patients who completed questionnaires. We assessed the adherence to medication, illness perceptions, and the beliefs about the glaucoma treatment by the "Reported Adherence to Medication scale," "the Brief Illness Perception Questionnaire," and "the Beliefs about Medicine-Specific Questionnaire," respectively. According to the RAM scale, voluntary and involuntary non-adherence scores were also distinguished. Different adherence categories in RAM scale were compared with perception and belief measures. Patient attitudes were assessed from the BMQ. We also performed attitudinal type comparisons with different adherence groups., Results: The full adherence prevelance to glaucoma medication was 40%. The proportion of voluntary and involuntary non-adherence was 26% and 57%, respectively. The adherence groups were similar in terms of belief measures but statistically different according to illness perceptions (consequences (p = 0.002), timeline (p = 0.008), personal control (p = 0.001), identity (p = 0.019), concerns (p = 0.003)), and attitude types (ambivalent (p = 0.030) and accepting (p = 0.029))., Conclusion: New strategies are required to improve patient adherence to glaucoma medication in Turkey. The beliefs about the glaucoma treatment and illness perceptions are also needed to be enhanced.

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: As the fight against the COVID-19 epidemic continues, medical workers may have allostatic load., Objective: During the reopening of society, medical and nonmedical workers were compared in terms of allostatic load., Methods: An online study was performed; 3,590 Chinese subjects were analyzed. Socio-demographic variables, allostatic load, stress, abnormal illness behavior, global well-being, mental status, and social support were assessed., Results: There was no difference in allostatic load in medical workers compared to nonmedical workers (15.8 vs. 17.8%; p = 0.22). Multivariate conditional logistic regression revealed that anxiety (OR = 1.24; 95% CI 1.18-1.31; p < 0.01), depression (OR = 1.23; 95% CI 1.17-1.29; p < 0.01), somatization (OR = 1.20; 95% CI 1.14-1.25; p < 0.01), hostility (OR = 1.24; 95% CI 1.18-1.30; p < 0.01), and abnormal illness behavior (OR = 1.49; 95% CI 1.34-1.66; p < 0.01) were positively associated with allostatic load, while objective support (OR = 0.84; 95% CI 0.78-0.89; p < 0.01), subjective support (OR = 0.84; 95% CI 0.80-0.88; p < 0.01), utilization of support (OR = 0.80; 95% CI 0.72-0.88; p < 0.01), social support (OR = 0.90; 95% CI 0.87-0.93; p < 0.01), and global well-being (OR = 0.30; 95% CI 0.22-0.41; p < 0.01) were negatively associated., Conclusions: In the post-COVID-19 epidemic time, medical and nonmedical workers had similar allostatic load. Psychological distress and abnormal illness behavior were risk factors for it, while social support could relieve it., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Vasopressin (AVP) cells in the paraventricular nucleus of the hypothalamus (PVN) are activated during sickness and project to multiple nuclei responsible for the anxiety, social and motivated behaviours affected during sickness, suggesting that these cells may play a role in sickness behaviours, typically expressed as reduced mobility, increased anxiety, anhedonia and social withdrawal. In the present study, we selectively ablated AVP neurones in the PVN of male and female mice (Mus musculus) and induced sickness behaviour via injection of bacterial lipopolysaccharide (LPS). We found that PVN AVP ablation increased the effects of LPS, specifically by further decreasing sucrose preference in males and females and decreasing the social preference of males, monitored within 24 hours of LPS injection. These results suggest that PVN AVP contributes to the change in motivated behaviours during sickness and may help promote recovery from infection.., (© 2020 British Society for Neuroendocrinology.)

This study investigated the influence of illness on sexual risk behavior in adolescence and the transition to adulthood, both directly and through moderation of the impact of social disadvantage. We hypothesized positive effects for social disadvantages and illness on sexual risk behavior, consistent with the development of faster life history strategies among young people facing greater life adversity. Using the first two waves of the National Longitudinal Study of Adolescent to Adult Health, we developed a mixed-effects multinomial logistic regression model predicting sexual risk behavior in three comparisons: risky nonmonogamous sex versus safer nonmonogamous sex, versus monogamous sex, and versus being sexually inactive, by social characteristics, illness, interactions thereof, and control covariates. Multiple imputation was used to address a modest amount of missing data. Subjects reporting higher levels of illness had lower odds of having safer nonmonogamous sex (OR = 0.84, p < .001), monogamous sex (OR = 0.82, p < .001), and being sexually inactive (OR = 0.74, p < .001) versus risky nonmonogamous sex, relative to subjects in better health. Illness significantly moderated the sex (OR = 0.88, p < .01), race/ethnicity (e.g., OR = 1.21, p < .001), and childhood SES (OR = 0.94; p < .01) effects for the sexually inactive versus risky nonmonogamous sex comparison. Substantive findings were generally robust across waves and in sensitivity analyses. These findings offer general support for the predictions of life history theory. Illness and various social disadvantages are associated with increased sexual risk behavior in adolescence and the transition to adulthood. Further, analyses indicate that the buffering effects of several protective social statuses against sexual risk-taking are substantially eroded by illness.

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.

Objective: To evaluate the involvement of nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in schizophrenia-like behaviour in young animals exposed to maternal immune activation (MIA)., Methods: To this aim, on the 15th gestational day, the females received an injection of lipopolysaccharides. When the animals completed 7, 14 and 45 postnatal days, they were killed and the whole brain was dissected for biochemical analysis. Animals with 45 postnatal days were submitted to behavioural tests of locomotor activity, social interaction and stereotyped movements., Results: It was observed that the animals presented schizophrenia-like behaviour at 45 postnatal days associated with the increase of NLRP3 inflammasome expression and IL-1β levels on 7, 14 and 45 postnatal days., Conclusion: This study shows that MIA may be associated with a schizophrenia-like behaviour. This behaviour can be induced to a neuroinflammatory profile in the brain. These evidences may base future studies on the relationship between neuroinflammation and psychiatric disorders.

Objectives: It is well known that mental health problems can recur even after effective treatment, leading to an understandable fear of illness recurrence (FIR) and mental health anxiety (MHA). These may themselves contribute to the process of relapse. This study aims to examine whether people recovering from psychosis have greater FIR than those recovering from common mental health problems or healthy controls. The study also hypothesized that there will be a relationship between FIR and MHA and that both these constructs will be associated with maladaptive coping behaviours. Finally, the relationship between mental defeat with FIR and psychological distress (anxiety and depression) will be examined., Method: A cross-sectional questionnaire design was employed. Thirty-nine participants in recovery from psychosis, eighty-two in recovery from other mental health difficulties, and sixty-one healthy controls aged 18-73 were recruited from NHS services and via social media. Self-report questionnaires measured mental defeat, mental health anxiety, fear of illness recurrence, maladaptive coping behaviours, and psychological distress., Results: Those recovering from psychosis were found to more negatively evaluate the likely consequences of relapse than those recovering from common mental health problems or healthy controls. However, the levels of FIR in common mental health problems were also significantly elevated when compared to healthy controls. There were no other differences between these groups (in terms of mental defeat, anxiety, depression, social functioning, and maladaptive coping behaviours). The hypothesized relationship between FIR and MHA was also found, and both were associated with maladaptive coping behaviours. Mental defeat was associated with FIR and psychological distress (anxiety and depression)., Conclusions: This study found that those with psychosis experienced higher FIR than those with common mental health problems. Furthermore, people defining themselves as in recovery are worried about relapse and the extent of this is linked to mental health anxiety. Given that such responses may contribute to actual relapse, it is important that these issues are better understood and interventions developed to ameliorate them., Practitioner Points: Following recovery, fear of relapse may be particularly high in those with experience of psychosis; it is also present in those with common mental health problems The importance of this observation lies in the issue that anxiety about relapse may initiate a self-fulfilling process, with increased anxiety worsening symptoms and vice versa. Cognitive-behavioural therapy for health anxiety may be beneficial to those experiencing high levels of mental health anxiety. Cognitions related to relapse need to be explored and addressed both in further research and, when clearly identified, may be a target during relapse-prevention planning., (© 2020 The Authors. British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

During infection, sickness behaviors, such as a hunched stance with piloerection, can facilitate host resistance by supporting the generation and maintenance of fever. Fever, in turn, is mediated by hypothalamic neuroimmune signaling. Sickness behaviors, however, can also be influenced by social stimuli. In this study, guinea pig pups were injected with lipopolysaccharide to simulate a bacterial infection and then exposed to a novel, threatening environment while either with their mother or alone. We found that the presence of the mother suppressed sickness behavior, but enhanced fever, and had no measureable effect on gene expression of hypothalamic mediators of fever. This 3-way dissociation induced by the mother's presence is interpreted in terms of the differential adaptive consequences of behavioral and febrile responses for pups in this situation. The results contribute to a growing literature linking immunological and social processes., (© 2020 Wiley Periodicals, Inc.)

The purpose of current study was to evaluate the effect of curcumin (CUR) loaded lipid-core nanocapsules (CUR-LNC) treatment on neuroinflammatory and behavioral alterations in a model of sickness behavior induced by lipopolysaccharide (LPS) in rats. Rats were treated with CUR-LNC and CUR daily for 14 days. After the last treatments, sickness behavior was induced with LPS. Sickness behavior LPS-induced was confirmed by behavioral tests, an increase in levels of proinflammatory cytokines, decrease in levels of IL-10, overexpression of IDO-1 and IDO-2. In conclusion, CUR-LNC treatment attenuated the neuroinflammatory and behavioral changes caused in sickness behavior model., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1β (25 µg/kg) but not prevented in IL-1RI -/- mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1β synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation. SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1β trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus "bioenergetic stress" drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium., (Copyright © 2020 Kealy, Murray et al.)

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.

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.

Background: Production of inflammatory mediators by reactive microglial cells in the brain is generally considered the primary mechanism underlying the development of symptoms of sickness in response to systemic inflammation., Methods: Depletion of microglia was achieved in C57BL/6 mice by chronic oral administration of PLX5622, a specific antagonist of colony stimulating factor-1 receptor, and in rats by a knock-in model in which the diphtheria toxin receptor was expressed under the control of the endogenous fractalkine receptor (CX3CR1) promoter sequence. After successful microglia depletion, mice and rats were injected with a sickness-inducing dose of lipopolysaccharide according to a 2 (depletion vs. control) × 2 (LPS vs. saline) factorial design. Sickness was measured by body weight loss and decreased locomotor activity in rats and mice, and reduced voluntary wheel running in mice., Results: Chronic administration of PLX5622 in mice and administration of diphtheria toxin to knock-in rats depleted microglia and peripheral tissue macrophages. However, it did not abrogate the inducible expression of proinflammatory cytokines in the brain in response to LPS and even exacerbated it for some of the cytokines. In accordance with these neuroimmune effects, LPS-induced sickness was not abrogated, rather it was exacerbated when measured by running wheel activity in mice., Conclusions: These findings reveal that the sickness-inducing effects of acute inflammation can develop independently of microglia activation.

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., (© 2019 Wiley Periodicals, Inc.)

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.

Individual differences in premorbid behaviors and in those exhibited in the course of an infection disease may be useful to explain the individual susceptibility to infections, the underlying neuroimmunological mechanisms and be helpful to design patient oriented treatments with better prediction of pharmacological reactivity/outcome. Age (old) and gender (male) are also considered vulnerability factors. In the present study, the motor, emotional, anxious-like and social phenotypes of adult (6-month-old) and old (18-month-old) male C57BL/6 × 129Sv mice were determined using both a transversal and longitudinal designs prior to the analysis of LPS (150 mg/kg, i.p.)-induced sickness behavior and mortality. The results show: i) Individual premorbid behavioral phenotype had short- and long-term predictive value of hours of survival; ii) Persistence of behavioral traits from adulthood to old age and predictive value on hours of survival; iii) First signs of sickness behavior were also predicting mortality, mostly in old animals; iv) LPS-sickness behavior was the same at both ages but adult animals were able to show attempts of motor recovery; v) The mortality rate over 96 h was 100% in both ages, but old animals showed shorter survival times. In summary, these results confirm the relevance of age/aging but also individual behavioral differences in the premorbid phenotype and the morbidity response to the LPS-induced-sepsis that correlate with the individual's mortality. Thus, this work supports the translational scenarios to study personalized evaluation of risks factors and psycho-neuro-immunological mechanisms relevant for better interventions and prognosis in the critically ill young but specially aged patient population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

Neuropeptide Y (NPY) has been demonstrated to exert stress buffering effects and promote resilience. Non-invasive intranasal (IN) application of NPY to rodents is able to mitigate traumatic stress-induced behavioral changes as well as dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is unknown whether IN NPY could prevent the behavioral, pro-inflammatory and neurochemical responses to peripheral immune activation by the Toll-like receptor 4 (TLR4) stimulant lipopolysaccharide (LPS). Therefore, we analyzed the effects of IN NPY (100 μg) on the behavioral sickness response (reduced locomotion and exploration) and the underlying molecular mechanisms, 3 h and 21 h after intraperitoneal injections of LPS (0.03 mg/kg) in male C57BL/6N mice. The acute behavioral sickness response was significantly dampened by pretreatment with IN NPY 3 h after LPS injection. This effect was accompanied by diminished weight loss and lowered plasma corticosterone (CORT) levels 21 h after LPS injection. In contrast, acute circulating cytokine levels and hypothalamic cytokine mRNA expression remained unaltered by IN NPY, which indicates that the peripheral and cerebral immune response to LPS was left undisturbed. Our findings are in agreement with the reported activity of NPY to dampen the response of the HPA axis to stress. We propose that IN NPY ablates sickness behavior at a site beyond the peripheral and cerebral cytokine response, an action that is associated with reduced activity of the HPA axis as determined by decreased plasma CORT.These results indicate that IN NPY administration may be relevant to the management of neuropsychiatric disorders arising from immune-induced neuroendocrine dysfunction.

Objective: Social relationships can both influence and be influenced by immune processes. Past work implicates two distinct pathways along which this interaction may occur: inflammatory processes and antiviral processes. This article reviews how social behavior is modulated by these two immune processes and how such processes may in turn regulate social behavior., Methods: This narrative review outlines existing work on social behavior and both inflammatory and antiviral processes. We propose an evolutionary framework that aims to integrate these findings. Specifically, social isolation has evolutionarily increased the likelihood of wounding and therefore increased the need for inflammation, which works to promote healing. Conversely, broader social networks provide protection from physical threats but also lead to increased pathogen exposure, necessitating a more robust antiviral response., Results: This review highlights that social adversity, such as social exclusion or loneliness, is associated with increased inflammation, whereas social contact is associated with increased antiviral immunity. Furthermore, increased inflammation leads to sensitivity to social stimuli, presumably to avoid hostile conspecifics and approach allies who may provide care while vulnerable. Individuals with inadequate antiviral immunity engage in behaviors that minimize pathogen exposure, such as reduced affiliative behavior., Conclusions: This review suggests that adverse social experiences (social isolation, perceived social threat) may induce inflammatory responses while suppressing antiviral immunity, whereas positive experiences of social connection may reduce inflammation and bolster antiviral responses. Although acutely elevated inflammation would be adaptive under conditions where wounding is likely, chronic inflammation related to continued social adversity may have detrimental health consequences.

Objectives: The study aimed to investigate if South African individuals with psychogenic nonepileptic seizures (PNES) differ from individuals with epileptic seizures (ES) and other nonepileptic seizures (oNES) in terms of demographic and seizure characteristics, personality traits, illness behaviors, and depression, anxiety, and posttraumatic stress disorder (PTSD) comorbidity in statistically significant ways; and if so, to test if these differences can be utilized in raising suspicion of PNES as the differential diagnosis to epilepsy and oNES in practice., Methods: Data were analyzed from 29 adults with seizure complaints recruited using convenience sampling from a private and a government hospital with video-electroencephalography (vEEG) technology. A quantitative double-blind convenient sampling comparative design was used. A demographic and seizure questionnaire, the NEO Five Factor Inventory-3 (NEO-FFI-3), an abbreviated version of Illness Behavior Questionnaire (IBQ), and the Beck Anxiety Inventory - Primary Care (BAI-PC) were administered. Cronbach's alphas, analysis of variance (ANOVA), cross-tabulation, Fisher exact test, and receiver operating characteristic (ROC) analyses were performed on the dataset., Results: The total sample consisted of 29 participants, of which 5 had PNES (17%), 21 ES (73%), and 3 oNES (10%). The final sample was comprised of 24 participants from the private hospital and 5 from the government hospital. The group with PNES was found to be significantly more male, to experience significantly more monthly seizures, and chronic pain when comparing the PNES with the ES group, and the PNES with the combined ES and oNES group in both private only sample, as well as the private and government hospital combined sample. Patients with PNES also had a higher level of education compared with the group with ES in the combined private and government hospital sample, something that was not evident in the private hospital only sample. No significant differences between groups were found in either sample in terms of age, population group, language, age at first seizure, and the NEO-FFI-3 subscales. All three groups scored above the cutoff point of 5 exhibiting depression, anxiety, and PTSD symptoms on the BAI-PC in both samples. However, the group with PNES tended to score significantly higher than the group with ES and the combined ES and oNES group in the private hospital sample. A cutoff point of 12 on the BAI-PC was found to predict PNES in this seizure population with 80% sensitivity and 89% specificity. However, once the analysis was repeated on the combined private and government hospital sample, significance in BAI-PC scores between groups was lost. All scales showed good reliability in our study, with the exception of the "Openness to Experience" subscale of the NEO-FFI-3 once reliability analysis was carried out on the combined private and government hospital group., Conclusions: This study provides an important stepping stone in the understanding of demographic and seizure factors, personality domains, abnormal illness behaviors, and psychiatric comorbidity in the South African population with PNES. The study also reported on a cutoff score of 12 on the BAI-PC predicting PNES with 80% sensitivity and 89% specificity in a private hospital sample., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It is well-established that bacterial lipopolysaccharides (LPS) can promote neuroinflammation through receptor Toll-like 4 activation and induces sickness behavior in mice. This phenomenon triggers changes in membranes lipid dynamics to promote the intracellular cell signaling. Desorption electrospray ionization mass spectrometry (DESI-MS) is a powerful technique that can be used to image the distribution of lipids in the brain tissue directly. In this work, we characterize the LPS-induced neuroinflammation and the lipid dynamics in C57BL/6 mice at 3 and 24 h after LPS injection. We have observed that intraperitoneal administration of LPS (5 mg/kg body weight) induces sickness behavior and triggers a peripheral and cerebral increase of pro- and anti-inflammatory cytokine levels after 3 h, but only IL-10 was upregulated after 24 h. Morphological analysis of hypothalamus, cortex and hippocampus demonstrated that microglial activation was present after 24 h of LPS injection, but not at 3 h. DESI-MS revealed a total of 14 lipids significantly altered after 3 and 24 h and as well as their neuroanatomical distribution. Multivariate statistical analyzes have shown that ions associated with phosphatidylethanolamine [PE(38:4)] and docosatetraenoic acid [FA (22:4)] could be used as biomarkers to distinguish samples from the control or LPS treated groups. Finally, our data demonstrated that monitoring cerebral lipids dynamics and its neuroanatomical distribution can be helpful to understand sickness behavior and microglial activation after LPS administration., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Illness behaviors-or responses to bodily symptoms-predict individuals' recovery and functioning; however, there has been little research on the early life personality antecedents of illness behavior. This study's primary aims were to evaluate (a) childhood temperament traits (i.e., emotionality and sociability) as predictors of adult illness behaviors, independent of objective health; and (b) adult temperament traits for mediation of childhood temperament's associations., Method: Participants included 714 (53% male; 350 adoptive family and 364 control family) children and siblings from the Colorado Adoption Project (CAP; Plomin & DeFries, 1983). Structural regression analyses evaluated paths from childhood temperament to illness behavior (i.e., somatic complaints, sick days, and medication use) at two adulthood assessments (CAP years 21 and 30). Analyses controlled for participant age, sex, family type (adoptive or control), adopted status, parent education/occupation, and middle childhood illnesses, doctor visits, and life events stress., Results: Latent illness behavior factors were established across 2 adulthood assessments. Multilevel path analyses revealed that higher emotionality (fearfulness) in adulthood-but not childhood temperament-predicted higher levels of illness behavior at both assessments. Lastly, lower emotionality-fearfulness partially mediated the effect of higher childhood sociability on adult illness behavior., Conclusions: Results suggest the importance of childhood illness experiences and adult emotionality (fearfulness) in shaping illness behavior in early adulthood. They also suggest a small, protective role of childhood sociability on reduced trait fearfulness in adulthood. These findings broaden our understanding of the prospective links between temperament and illness behavior development, suggesting distinct associations from early life illness experiences. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

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.

Background: Ischemic stroke results in a robust inflammatory response within the central nervous system. As the immune-inhibitory CD200-CD200 receptor 1 (CD200R1) signaling axis is a known regulator of immune homeostasis, we hypothesized that it may play a role in post-stroke immune suppression after stroke., Methods: In this study, we investigated the role of CD200R1-mediated signaling in stroke using CD200 receptor 1-deficient mice. Mice were subjected to a 60-min middle cerebral artery occlusion and evaluated at days 3 and 7, representing the respective peak and early resolution stages of neuroinflammation in this model of ischemic stroke. Infarct size and behavioral deficits were assessed at both time points. Central and peripheral cellular immune responses were measured using flow cytometry. Bacterial colonization was determined in lung tissue homogenates both after acute stroke and in an LPS model of systemic inflammation., Results: In wild-type (WT) animals, CD200R1 was expressed on infiltrating monocytes and lymphocytes after stroke but was absent on microglia. Early after ischemia (72 h), CD200R1-knockout (KO) mice had significantly poorer survival rates and an enhanced susceptibility to spontaneous bacterial colonization of the respiratory tract compared to wild-type (WT) controls, despite no difference in infarct or neurological deficits. While the CNS inflammation was resolved by day 7 post-stroke in WT mice, brain-resident microglia and monocyte activation persisted in CD200R1-KO mice, accompanied by a delayed, augmented lymphocyte response. At this time point, CD200R1-KO mice displayed greater weight loss, more severe neurological deficits, and impaired motor function compared to WT. Systemically, CD200R1-KO mice exhibited signs of persistent infection including lymphopenia, T cell activation and memory conversion, and narrowing of the TCR repertoire. These findings were confirmed in a second model of acute neuroinflammation induced by systemic endotoxin challenge., Conclusion: This study defines an essential role of CD200-CD200R1 signaling in stroke. Loss of CD200R1 led to high mortality, increased rates of post-stroke infection, and enhanced entry of peripheral leukocytes into the brain after ischemia, with no increase in infarct size. This suggests that the loss of CD200 receptor leads to enhanced peripheral inflammation that is triggered by brain injury.