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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.)

Poor health is associated with an increased risk of tail biting outbreaks in pigs. We propose that this is because illness changes social dynamics either by changing the behaviour of the sick pig towards its penmates, the behaviour of the healthy penmates towards the sick pig, or both. We tested the effect of immune stimulation (lipopolysaccharide (LPS) injection: O111:B4; 1.5 μg kg -1 IV) on social behaviour in gilts housed in triplets in a cross-over experiment. Each pen was subjected to the control treatment (all three pigs injected with saline) and then LPS treatment (one pig injected with LPS, two injected with saline), or vice versa. LPS injected pigs had a shift in social motivation and performed more tail- and ear- directed behaviour than saline pigs two days after injection. They seemed to fit the description of 'sick and grumpy'. This change was seen about 40 h after the signs of acute illness dissipated and was not accompanied by a similar increase in activity. We discuss possible mechanisms for this behavioural change in light of changes in neurotransmitter levels at three days after LPS injection described in a previous experiment., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Most of us have experienced deterioration of mood while ill. In humans, immune activation is associated with lethargy and social withdrawal, irritability and aggression; changes in social motivation could, in theory, lead to less functional interactions. This might also be the case for animals housed in close confinement. Tail biting in pigs is an example of damaging social behavior, and sickness is thought to be a risk factor for tail biting outbreaks. One possible mechanism whereby sickness may influence behavior is through cytokines. To identify possible mediators between immune activation and behavioral change, we injected 16 gilts with lipopolysaccharide (LPS; O111:B4; 1.5 μg kg -1 IV through a permanent catheter). In LPS-treated pigs, a significant increase in cortisol, TNF-α, IL-1 receptor antagonist, IL-6, and IL-8 was observed alongside decreased activity within the first 6 h after the injection. CRP was elevated at 12 and 24 h after injection, and food intake was reduced for the first 24 h after injection. Three days post-injection, LPS pigs had lower levels of noradrenaline in their hypothalamus, hippocampus and frontal cortex compared to saline-injected pigs. Pigs injected with LPS also had higher levels of the pro-inflammatory cytokine IFN-γ in their frontal cortex compared to saline-injected pigs. Thus, a low dose of LPS can induce changes in brain cytokine levels and neurotransmitter levels that persist after inflammatory and stress markers in the periphery have returned to baseline levels., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Previous work in our lab has shown that early-life infection affects female reproductive physiology and function (i.e., smaller ovaries, abnormal estrous cycles) and alters investigation and aggression towards male conspecifics in a reproductive context. Although many studies have investigated the effects of postnatal immune challenge on physiological and behavioral development, fewer studies have examined whether these changes have ultimate effects on reproduction. In the current study, we paired Siberian hamsters (Phodopus sungorus) and simulated a bacterial infection in early life by administering lipopolysaccharide (LPS) to male and female pups on pnd3 and pnd5. In adulthood, hamsters were paired with novel individuals of the same sex, and we scored an array of social behaviors (e.g., investigation, aggression). We then paired animals with individuals of the opposite sex for 5 consecutive nights, providing them with the opportunity to mate. We found that females exhibited impaired reproductive physiology and function in adulthood (i.e., smaller ovaries and abnormal estrous cycles), similar to our previous work. However, both LPS-treated males and females exhibited similar same-sex social behavior when compared with saline-treated controls, they successfully mated, and there were no significant changes in fecundity. These data suggest that the physiological changes in response to neonatal immune challenge may not have long-term effects on reproductive success in a controlled environment. Collectively, the results of this study are particularly important when investigating the relationships between physiology and behavior within an ultimate context. Animals exposed to early-life stress may in fact be capable of compensating for changes in physiology in order to survive and reproduce in some contexts., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Yawning has been proposed to serve both physiological and social functions, the latter likely to have developed later in its evolution. A central hypothesis is that yawning cools the brain but whether yawning is a thermoregulatory mechanism that is activated during hyperthermia (i.e., thermoregulatory failure) or is activated in any instance of brain temperature increase (e.g., also during fever) is unclear and experimental assessments of yawning during fever are lacking. In this study, we determined the effect of experimentally induced fever on yawning frequency. We also explored alternative predictors of yawning during sickness (sleepiness, autonomic nervous system indexes and sickness symptoms). Twenty-two healthy human subjects participated in a randomized, placebo-controlled, cross-over study, where the subjects received an injection of the bacterial endotoxin lipopolysaccharide (LPS) at a dose of 2ng/kg body weight in one condition and placebo in the other. Yawning was scored from video recordings from 30min before to 4h after the injection. Body temperature was measured frequently, alongside with heart rate, blood pressure, nausea and overall sickness symptoms. Yawning frequency was found to significantly increase over time during experimentally induced sickness, but not in the placebo condition. In particular, yawning frequency was increased during the rising phase of body temperature induced by LPS administration, although no significant correlation was found between body temperature increase and yawning frequency. In addition, exploratory analyses showed that a higher yawning frequency was associated with less increase in sickness symptoms and nausea intensity. While the current study adds to previous research showing significant increase in yawning frequency during hyperthermia, further studies are needed if we are to properly characterize the brain cooling role of yawning in humans. The investigation of other functions, such as being a vasovagal inhibitory, may shed stronger light on the functions of yawning., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Tail biting is detrimental to animal welfare and has negative consequences for producer economy. Poor health is one of the risk factors for tail biting. The first aim of this study was therefore to test for links between health status and behavior related to tail biting at the individual level. The second aim of this study was to test whether variation in cytokines was related to variation in social behavior. These small molecules produced upon immune activation are known to influence behavior both in the direction of withdrawal and increased aggression. This could potentially increase non-functional social behavior and thereby the risk of a tail biting outbreak. To investigate this, we collected behavioral data, health data, feeding data and blood samples from undocked boars at a test station farm in Norway. We compared groups with three different diagnoses: osteochondrosis diagnosed by computer tomography scanning (OCSAN), osteochondrosis diagnosed by clinical examination (OCCLIN) and respiratory tract disease (RESP), with healthy controls (CTR). We tested whether the diagnoses were associated with feeding and growth, social behavior and cytokine levels. We then tested whether there were correlations between cytokine levels and social behavior. We also provide raw data on cytokine levels in the extended sample (N=305) as there are few publications on cytokine levels measured in pigs living under commercial conditions. OCCLIN pigs visited the feeder less, and fed longer compared to CTR pigs. Pigs diagnosed with RESP showed a large drop in growth the first week after filming, which corresponds to the week they were likely to have been diagnosed with illness, and a tendency to compensatory increase in the week after that. Social behavior differed between experimental groups with OCSCAN pigs receiving more social behavior (both aggressive and non-aggressive) compared to CTR, and RESP pigs tending to perform more ear- and tail-biting than controls. There were no differences in absolute levels of cytokines between categories. However IL1-ra and IL-12 showed correlations with several behaviors that have been shown by others to be associated with current or future tail biting activity. To our knowledge, this is the first published study indicating a role for illness in non-functional social behavior in pigs and the first showing a correlation between cytokine levels and social behavior., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague-Dawley rats. We chose lipopolysaccharide (LPS 100 μg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Sickness behavior is a series of behavioral and psychological changes that develop in inflammatory disease, including infections and cancers. Administration of the bacterial endotoxin lipopolysaccharide (LPS) induces sickness behavior in rodents. Genipin, an aglycon derived from an iridoid glycoside geniposide extracted from the fruit of Gardenia jasminoides, has anti-inflammatory and antidepressant activities. However, the effects of genipin on inflammation-induced changes in emotional behaviors are unknown. In this study, we examined the effects of genipin on LPS-induced inflammation in BV-2 cells and sickness behavior in mice. Pretreatment with genipin inhibited LPS-induced increases in NO production and reduced the mRNA levels of inflammation-related genes (iNOS, COX-2, IL-1β and IL-6) in BV-2 cells. Oral administration of genipin ameliorated LPS-induced depressive-like behavior in the forced swim test and social behavior deficits 24h after LPS administration in mice. LPS-induced expression of mRNAs for inflammation-related genes and the number of c-fos immunopositive cells decreased in the paraventricular nucleus (PVN) of the hypothalamus and the central nucleus of the amygdala (CeA), suggesting that genipin attenuates LPS-induced changes of emotional behaviors through inhibition of neural activation and inflammatory responses in the PVN and CeA. These novel pharmacological effects of genipin may be useful for treatment of patients with sickness behavior., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Re-homing centres present a range of potential stressors to kennelled dogs which are likely to impact negatively on their welfare. Despite the presence of visitors to the kennel often being considered a potential stressor, empirical investigation into their impact on the behaviour and welfare of kennelled dogs in re-homing centres is lacking. This study investigated the influence of changing visitor access policy from open access to prohibited viewing at kennels (with organised single meetings for viewing dogs outside of the kennel environment) on the welfare of 15 dogs housed in a dog-only re-homing facility. Data were collected across a number of domains comprising kennel noise levels, behavioural measures (activity, repetitive behaviour, response to human approach); physiological measures (urinary cortisol:creatinine ratios); sickness events and faecal scoring. The general kennel noise levels were significantly lower when visitor access to the kennel area was restricted. Furthermore, dogs were found to display behaviour indicative of improved welfare during this time period; dogs spent significantly more time sedentary, less time moving and exhibited significantly fewer episodes of repetitive behaviours. No significant change was seen in the urinary cortisol:creatinine ratio, nor in sickness behaviour, faecal scoring or response to a human approach test. Overall, the results from this study suggest that restricting visitors from viewing the dogs while in their kennels may be better for the dogs' short term welfare., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Poly I:C, a viral mimetic, is a synthetic double-stranded RNA that is known to cause activation of the innate immune system, resulting in the emergence of sickness behaviors in otherwise healthy adult mice. However, the way in which such effects of poly I:C manifest themselves in aged mice are not currently known. We hypothesized that poly I:C administration would lead to burrowing deficits, but that these deficits would be exaggerated in aged subjects (19-months old) compared to young subjects (4-months old) that received the same dose. In order to associate these behavioral decrements with inflammatory factors, we measured mRNA expression of IL-1β and IL-6 in the hippocampus and parietal cortex and peripheral protein expression of IL-6, TNF-α, MCP-1, MIP-1α, and IL-1β in the serum. After exposure to poly I:C, aged subjects demonstrated significant impairments in their burrowing behavior, compared to younger subjects administered the same dose. These behavioral decrements coincided with increased expression of IL-6 among animals exposed to poly I:C and increased expression of IL-1β among aged animals in the hippocampus and cortex. Furthermore, we observed an increase in peripheral poly I:C-induced IL-6, TNF-α, MCP-1, and MIP-1α, but not IL-1β. These results indicate that virus-mediated immune activation in the aging body can lead to increased sickness behavior. Furthermore, these data indicated a possible dissociation between the effects of poly I:C on sickness behaviors in aged mice, with central expression of IL-1β potentially playing a role in age-related impairments., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In spite of their prevalence and importance, recurrent acute infections seldom have been investigated in the laboratory. We set out to measure fever and sickness behaviour in simulated recurrent Mycoplasma infection; Mycoplasma is a common clinical cause of recurrent acute infection. Male Sprague-Dawley rats had radiotransponders implanted to measure abdominal temperature and cage activity. After recovery, rats received three intraperitoneal (I.P.) injections, 10 days apart, of either fibroblast-stimulating lipopeptide-1 (FLS-1), a pyrogenic moiety of Mycoplasma salivarium, at a dose of 500 μg.kg(-1) in 1 ml.kg(-1) phosphate-buffered saline (PBS), or vehicle (PBS, 1 ml.kg(-1)). Body mass and food intake were measured daily. For measurement of learning and memory, training in a Morris Water Maze commenced 10 days after the last of the three successive injections and continued daily for 4 days. Spatial memory was assessed on the following day. Hippocampal tissue of rats was collected on the day of the last exposure to the maze. Recurrent FSL-1 administration induced recurrent fevers (~1°C) for about 9h, recurrent lethargy (~40-60%) for 1 day, recurrent anorexia (~16-30%) for 1 day, and recurrent reductions in the rate of mass gain (~112%) for 1 day, but did not induce persistent stunting. Recurrent FSL-1 administration did not result in tolerance to fever, lethargy or anorexia. There was no residual histological damage to the hippocampus and no residual detrimental effect in learning or memory in rats. Though we cannot extrapolate our results directly to humans, clinical recurrent acute Mycoplasma infection may not impose a high risk of stunting or impaired spatial learning and memory., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Previous evidence has shown that prostaglandins play a key role in the development of sickness behavior observed during inflammatory states. In particular, prostaglandin E2 (PGE2) is produced in the brain by a variety of inflammatory signals such as endotoxins or cytokines. Its injection has been also shown to induce symptoms of sickness behavior. The role of cyclooxygenase enzymes (COX), the rate-limiting enzymes converting arachidonic acid into prostaglandins, in sickness behavior has been extensively studied, and it has been demonstrated that strategies aiming at inhibiting these enzymes limit anorexia, body weight loss and fever in animals with inflammatory diseases. However, inhibiting COX activity may lead to negative gastric or cardiovascular effects, since COX enzymes play a role in the synthesis of others prostanoids with various and sometimes contrasting properties. Recently, prostaglandin E synthases (PGES), which specifically catalyze the final step of PGE2 biosynthesis, were characterized. Among these enzymes, the microsomal prostaglandin E synthase-1 (mPGES-1) was of a particular interest since it was shown to be up-regulated by inflammatory signals in a variety of cell types. Moreover, mPGES-1 was shown to be crucial for correct immune-to-brain communication and induction of fever and anorexia by pro-inflammatory agents. This review takes stock of previous knowledge and recent advances in understanding the role of prostaglandins and of their specific synthesizing enzymes in the molecular mechanisms underlying sickness behavior. The review concludes with a short summary of key questions that remain to be addressed and points out therapeutic developments in this research field.

Although fever and sickness behavior are common responses to infection, it has been proposed that the sickness behaviors associated with infection, in particular lethargy and fatigue, may be more valuable clinical markers of illness and recovery in patients, than is body temperature alone. Measuring abdominal temperature, food intake and wheel running we therefore determined the dose thresholds and sensitivities of these responses to lipopolysaccharide (LPS). Male Sprague-Dawley rats were randomly assigned to receive one of three LPS doses (10, 50, 250 microg/kg), or saline, subcutaneously. Administration of LPS induced a dose-dependent increase in abdominal temperature and decrease in wheel running, food intake and body mass. Regression analysis revealed that decreased running was the most-sensitive of the sickness responses to LPS administration, with a regression slope of -41%/log microg, compared to the slopes for food intake (-30%/log microg, F(1,2)=244, P=0.004) and body mass (-2.2%/log microg, F(1,5)=7491, P<0.0001). To determine the likelihood that exercise training influenced the sickness responses we measured in our dose-response study we performed a second experiment in which we investigated whether fever and anorexia induced by LPS administration would present differently depending on whether rats had been exercising or sedentary. Six weeks of wheel running had no effect on the magnitude of fever and anorexia induced by LPS administration. Avoidance of physical activity therefore appears to be a more-sensitive indicator of a host's reaction to LPS than is anorexia and fever.

We have all at some time experienced the non-specific symptoms that arise from being ill following a systemic infection. These symptoms, such as fever, malaise, lethargy and loss of appetite are often referred to as "sickness behavior" and are a consequence of systemically produced pro-inflammatory mediators. These inflammatory mediators signal to the brain, leading to activation of microglial cells, which in turn, signal to neurons to induce adaptive metabolic and behavioral changes. In normal healthy persons this response is a normal part of our defense, to protect us from infection, to maintain homeostasis and causes no damage to neurons. However, in animals and patients with chronic neurodegenerative disease, multiple sclerosis, stroke and even during normal aging, systemic inflammation leads to inflammatory responses in the brain, an exaggeration of clinical symptoms and increased neuronal death. These observations imply that, as the population ages and the number of individuals with CNS disorders increases, relatively common systemic infections and inflammation will become significant risk factors for disease onset or progression. In this review we discuss the underlying mechanisms responsible for sickness behavior induced by systemic inflammation in the healthy brain and how they might be different in individuals with CNS pathology.