Contrasting Disease Progression, Microglia Reactivity, Tolerance, and Resistance to Toxoplasma gondii Infection in Two Mouse Strains.

Our study investigated the innate immune response to Toxoplasma gondii infection by assessing microglial phenotypic changes and sickness behavior as inflammatory response markers post-ocular tachyzoite instillation. Disease progression in Swiss albino mice was compared with the previously documented outcomes in BALB/c mice using an identical ocular route and parasite burden (2 × 105 tachyzoites), with saline as the control. Contrary to expectations, the Swiss albino mice displayed rapid, lethal disease progression, marked by pronounced sickness behaviors and mortality within 11-12 days post-infection, while the survivors exhibited no apparent signs of infection. Comparative analysis revealed the T. gondii-infected BALB/c mice exhibited reduced avoidance of feline odors, while the infected Swiss albino mice showed enhanced avoidance responses. There was an important increase in microglial cells in the dentate gyrus molecular layer of the infected Swiss albino mice compared to the BALB/c mice and their respective controls. Hierarchical cluster and discriminant analyses identified three microglial morphological clusters, differentially affected by T. gondii infection across strains. The BALB/c mice exhibited increased microglial branching and complexity, while the Swiss albino mice showed reduced shrunken microglial arbors, diminishing their morphological complexity. These findings highlight strain-specific differences in disease progression and inflammatory regulation, indicating lineage-specific mechanisms in inflammatory responses, tolerance, and resistance. Understanding these elements is critical in devising control measures for toxoplasmosis.

Genes, inflammatory response, tolerance, and resistance to virus infections in migratory birds, bats, and rodents.

Normally, the host immunological response to viral infection is coordinated to restore homeostasis and protect the individual from possible tissue damage. The two major approaches are adopted by the host to deal with the pathogen: resistance or tolerance. The nature of the responses often differs between species and between individuals of the same species. Resistance includes innate and adaptive immune responses to control virus replication. Disease tolerance relies on the immune response allowing the coexistence of infections in the host with minimal or no clinical signs, while maintaining sufficient viral replication for transmission. Here, we compared the virome of bats, rodents and migratory birds and the molecular mechanisms underlying symptomatic and asymptomatic disease progression. We also explore the influence of the host physiology and environmental influences on RNA virus expression and how it impacts on the whole brain transcriptome of seemingly healthy semipalmated sandpiper (Calidris pusilla) and spotted sandpiper (Actitis macularius). Three time points throughout the year were selected to understand the importance of longitudinal surveys in the characterization of the virome. We finally revisited evidence that upstream and downstream regulation of the inflammatory response is, respectively, associated with resistance and tolerance to viral infections.

Fluoxetine and Curcumin Prevent the Alterations in Locomotor and Exploratory Activities and Social Interaction Elicited by Immunoinflammatory Activation in Zebrafish: Involvement of BDNF and Proinflammatory Cytokines.

The increase in proinflammatory cytokine expression causes behavioral changes consistent with sickness behavior, and this led to the suggestion that depression might be a psychoneuroimmunological phenomenon. Here, we evaluated the effects of the pretreatment with fluoxetine (10 mg/kg, i.p.) and curcumin (0.5 mg/kg, i.p.) on the immune response elicited by the inoculation of an Aeromonas hydrophila bacterin in zebrafish. Non-pretreated but A. hydrophila-inoculated and sham-inoculated groups of fish served as controls. The social preference, locomotor, exploratory activities, and cerebral expression of il1b, il6, tnfa, and bdnf mRNA were compared among the groups. Behavioral changes characteristic of sickness behavior and a significant increase in the expression of il1b and il6 cytokines were found in fish from the immunostimulated group. The behavioral alterations caused by the inflammatory process were different between males and females, which was coincident with the increased expression of cerebral BDNF. Fluoxetine and curcumin prevented the sickness behavior induced by A. hydrophila and the increased expression of proinflammatory cytokines. Our results point to the potential of zebrafish as a translational model in studies related to neuroinflammation and demonstrate for the first time the effects of fluoxetine and curcumin on zebrafish sickness behavior.

Bate palmas mutant mice as a model of Kabuki syndrome: Higher susceptibility to infections and vocalization impairments?

The recessive mutant mouse bate palmas (bapa) arose from N-ethyl-N-nitrosourea mutagenesis. Previous studies of our group revealed some behavioral impairments and a mutation in the lysine (K)-specific methyltransferase 2D (Kmt2d) gene. Because mutations in the KMT2D gene in humans are mainly responsible for Kabuki syndrome, this study was proposed to validate bapa mice as a model of Kabuki syndrome. Besides other symptoms, Kabuki syndrome is characterized by increased susceptibility to infections and speech impairments, usually diagnosed in the early childhood. Thus, juvenile male and female bapa mice were studied in different developmental stages (prepubertal period and puberty). To induce sickness behavior and to study infection susceptibility responses, lipopolysaccharide (LPS) was used. To study oral communication, ultrasonic vocalizations were evaluated. Behavioral (open-field test) and central (astrocytic glial fibrillary acidic protein [GFAP] and tyrosine hydroxylase [TH]) evaluations were also performed. Control and bapa female mice emitted 31-kHz ultrasounds on prepubertal period when exploring a novel environment, a frequency not yet described for mice, being defined as 31-kHz exploratory vocalizations. Males, LPS, and puberty inhibited these vocalizations. Bapa mice presented increased motor/exploratory behaviors on prepubertal period due to increased striatal TH expression, revealing striatal dopaminergic system hyperactivity. Combining open-field behavior and GFAP expression, bapa mice did not develop LPS tolerance, that is, they remained expressing signs of sickness behavior after LPS challenge, being more susceptible to infectious/inflammatory processes. It was concluded that bapa mice is a robust experimental model of Kabuki syndrome.

Cannabidiol prevents lipopolysaccharide-induced sickness behavior and alters cytokine and neurotrophic factor levels in the brain.

BACKGROUND: Major depressive disorder (MDD) affects millions of people worldwide. While the exact pathogenesis is yet to be elucidated, the role of neuro-immune signaling has recently emerged. Despite major advances in pharmacotherapy, antidepressant use is marred by limited efficacy and potential side effects. Cannabidiol (CBD), a phytocannabinoid, exerts antidepressant-like effects in experimental animals. This study investigated the impact of CBD on sickness behavior (SB), a measure of depressive-like response, and neuro-immune changes induced by lipopolysaccharides (LPS) in mice. METHODS: Socially isolated rodents were administered with LPS to trigger SB. and treated with CBD or its vehicle. Animals were submitted to forced swimming test, to evaluate depressive-like behavior, and to open field test, to evaluate locomotory activity. Immediately after behavioral analyses, animals were euthanized and had their hypothalamus, prefrontal cortex and hippocampus dissected, to proceed neurotrophins and cytokines analyses. ELISA was used to detect IL-1ß, BDNF and NGF; and cytometric beads array to measure IL-2, IL-4, IL-6, IFN-γ, TNF-α and IL-10 levels. RESULTS: CBD effectively prevented SB-induced changes in the forced swim test without altering spontaneous locomotion. This phytocannabinoid also partially reversed LPS-evoked IL-6 increase in both the hypothalamus and hippocampus. In addition, CBD prevented endotoxin-induced increase in BDNF and NGF levels in the hippocampus of SB animals. CONCLUSIONS: Apparently, CBD prevents both behavioral and neuro-immunological changes associated with LPS-induced SB, which reinforces its potential use as an antidepressant which modulates neuroinflammation. This opens up potentially new therapeutic avenues in MDD.

Hyperactivation of the amygdala correlates with impaired social play behavior of prepubertal male rats in a maternal immune activation model.

Maternal infection during pregnancy is an environmental risk factor for neurodevelopmental dysfunction, such as autism spectrum disorder (ASD). This study investigated the effect of maternal immune activation (MIA) on the behavior profile of prepubertal offspring and whether MIA alters the neuronal activation pattern of brain areas related to social play behavior. Pregnant Wistar rats received 500 µg/kg of lipopolysaccharide or saline solution on gestational day 16. Their offspring were tested using behavioral tasks to capture some of the core and associated ASD-like symptoms. Neuronal activation, indexed via c-fos expression after social play behavior, was evaluated in several brain areas. MIA had a number of adverse effects on dams and reduced the number of successful births and litter size. MIA induced sex-specific autistic-like features by a reduction in ultrasonic vocalizations in response to separation from the mother and nest, reduction in discrimination between neutral odors and their nest odor, moderate effect in stereotypies in the hole-board test, impaired risk assessment phenotype, and reduction in social play behavior without changes in locomotor activity only in prepubertal male offspring. A decrease in social play behavior may be associated with a decrease in the number of c-fos-positive cells in the prefrontal cortex and striatum, but hyperactivation of the basolateral and basomedial amygdala. Prenatal immune challenge results in ASD-like symptoms such as impaired risk assessment behavior, communication, and social interactions in male prepubertal offspring. Impaired social play behavior is correlated with neuronal hyperactivation in the amygdala.

Role of central endothelin-1 in hyperalgesia, anhedonia, and hypolocomotion induced by endotoxin in male rats.

Sickness syndrome is an adaptive response that can be distinguished by specific signs and symptoms, such as fever and generalized hyperalgesia. Endothelin-1 (ET-1) is produced by inflammatory stimuli, including lipopolysaccharide, and involved in the pathogenesis of inflammation and pain by acting through ETA and ETB receptors. ET-1 also induces fever by acting on the central nervous system. The present study investigated the role of ET-1 in sickness syndrome responses, including hyperalgesia, anhedonia, and hypolocomotion. Intracerebroventricular ET-1 administration induced mechanical and thermal hyperalgesia in rats, which was ameliorated by the ETA receptor antagonist BQ123 and exacerbated by the ETB receptor antagonist BQ788. A cyclooxygenase blocker did not alter hyperalgesia that was induced by ET-1. Lipopolysaccharide administration induced hyperalgesia, and both BQ123 and BQ788 abolished this mechanical hyperalgesia, but the thermal response was only partially blocked. The blockade of ETA receptors in the hypothalamus also abolished lipopolysaccharide-induced mechanical hyperalgesia, and the ETB receptor antagonist did not influence this response. Lipopolysaccharide also induced anhedonia, reflected by lower sucrose preference, and reduced locomotor activity. Both antagonists restored locomotor activity, but only BQ788 reversed the reduction of sucrose preference. These results indicate that ET-1 and both ETA and ETB receptors are involved in various responses that are related to sickness syndrome, including hyperalgesia, anhedonia, and hypolocomotion, that is induced by LPS. Hypothalamic ETA but not ETB receptors are involved in mechanical hyperalgesia that is observed during lipopolysaccharide-induced sickness syndrome.

Bats respond to simulated bacterial infection during the active phase by reducing food intake.

Sickness triggers a series of behavioral and physiological processes collectively known as acute phase response (APR). Bats are known as reservoirs of a broad variety of pathogens and the physiological changes resulting from APR activation have been tested predominantly during the resting phase (daytime) in several species exposed to lipopolysaccharide (LPS). In contrast, behavioral consequences of sickness for bats and other wild mammals have received less attention. We examined the physiological and behavioral consequences of APR activation in a fruit-eating bat (Carollia perspicillata) challenged with LPS during the active phase (nighttime). We measured changes in food intake, body mass, body temperature, total white blood cell counts, and the neutrophil/lymphocyte ratio (N/L). No fever and leukocytosis were observed in bats injected with LPS, but food intake decreased, bats lost body mass and their N/L ratio increased. The effect of LPS on daily energy balance is remarkable and, along with the increase in N/L ratio, it is assumed to be beneficial to fight disease. On the basis of our findings and those with other bats, it is probable that the physiological and behavioral components of the immune response to LPS follow circadian rhythms, but a formal test of this hypothesis is warranted.

Maternal protein malnutrition prolongs sickness behavior in male offspring.

Female rats were fed a normal or hypoproteic diet during the phases of gestation and lactation. The male offspring of these rats were grown to adulthood and used to study the effects of maternal protein malnutrition on progeny. The adult male rats were pretreated with either saline or LPS and subjected to behavioral tests 2 and 6 h after administration. Tumor necrosis factor (TNF-α), corticosterone and body temperature were the parameters used for assessment. Two hours after LPS administration, sickness behavior was developed in all the animals, regardless of maternal protein malnutrition. After 6 h of LPS administration, sickness behavior was more pronounced in the rats that had been subjected to maternal protein malnutrition. Only the rats with maternal protein malnutrition expressed an increase in the plasma levels of TNF-α and corticosterone. Maternal protein malnutrition prolongs sickness behaviors in offspring.

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

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

Lipid dynamics in LPS-induced neuroinflammation by DESI-MS imaging.

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.

Heat Stress Modulates Brain Monoamines and Their Metabolites Production in Broiler Chickens Co-Infected with Clostridium perfringens Type A and Eimeria spp.

Heat stress has been related to the impairment of behavioral and immunological parameters in broiler chickens. However, the literature is not clear on the involvement of neuroimmune interactions in a heat stress situation associated with bacterial and parasitic infections. The present study evaluated the production of monoamines and their metabolites in brain regions (rostral pallium, hypothalamus, brain stem, and midbrain) in broiler chickens submitted to chronic heat stress and/or infection and co-infection with Eimeria spp. and Clostridium perfringens type A. The heat stress and avian necrotic enteritis (NE) modulated the neurochemical profile of monoamines in different areas of the central nervous system, in particular, those related to the activity of the hypothalamus-hypophysis-adrenal (HPA) axis that is responsible for sickness behavior. C. perfringens and/or Eimeria infection, heat stress increased 5-hydroxytryptamine (5-HT), 4,4 dihydroxyphenylacetic acid (DOPAC), and DOPAC/dopamine (DA) in the rostral pallium; 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), homovanillic acid (HVA), HVA/DA, DOPAC/DA, and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT in the hypothalamus; MHPG, 5-HIAA/5-HT, DOPAC/DA, and HVA/DA in the midbrain; and MHPG, DOPAC, HVA, HVA/DA, DOPAC/DA, and 5-HIAA/5-HT in the brainstem. Heat stress decreased noradrenaline + norepinephrine (NOR + AD) in all brain regions analyzed; 5-HT in the hypothalamus, midbrain, and brainstem; and DA in the midbrain. The results also showed the existence and activity of the brain-gut axis in broiler chickens. The brain neurochemical profile and corticosterone production are consistent with those observed in chronic stressed mammals, in animals with sickness behavior, and an overloading of the HPA axis.

Response to lipopolysaccharide in Octodon degus pups produces age-related sickness behavior but does not have effects in juveniles.

During vertebrate development, the immune function is inefficient and is mainly controlled by innate defense. While there have been detailed studies of various aspects of innate immune function, the effects of this function in the growth of vertebrates is still not well known. Similarly, there is little information regarding how early endotoxin exposure would affect juvenile phenotypes, specifically in a non-model mammal like a precocial rodent. We evaluated the response to an antigen and its cost in offspring of the rodent Octodon degus. We inoculated pups at 4 different ages (8, 15, 22 and 30 days after birth) with an antigen to determine the ontogeny and costs of the response to an endotoxin. We assessed changes in body mass, body temperature, sickness behavior and the levels of a key mediator of the inflammatory response, the cytokine interleukin-1ß. We also determined the effects of early endotoxin exposure on the resting metabolic rate of juvenile animals (i.e. 90 days after birth). The cytokine levels, body mass and body temperature were unaffected by time of inoculation and treatment. However, pups subjected to inoculation at 22 days after birth with the antigen showed reduced locomotion. Juvenile resting metabolic rate was not affected by early endotoxin exposure. These results suggest that the magnitude of O. degus responses would not change with age. We discuss whether the lack of effect of the response on body mass or body condition is caused by environmental variables or by the precocial characteristics of O. degus.

The impact of chronic mild stress on long-term depressive behavior in rats which have survived sepsis.

The present study was created to investigate the effects of chronic mild stress (CMS) on the depressive behavior and neurochemical parameters of rats that were subjected to sepsis. Wistar rats were subjected to a CMS protocol, and sepsis was induced by cecal ligation and perforation (CLP). The animals were then divided into 4 separate groups; Control + Sham (n = 20), Control + CLP (n = 30), CMS + Sham (n = 20) and CMS + CLP (n = 30). Body weight, food and water intake and mortality were measured on a daily basis for a period of 10 days after the induction of sepsis. Locomotor activity, splash and forced swimming tests were performed ten days after CLP. At the end of the test period, the animals were euthanized, and the prefrontal cortex and hippocampus were removed to determine the levels of cytokines and oxidative damage. Our results show that there was no significant interaction between CMS and CLP in relation to locomotor activity and the forced swimming test. However, we did observe a significant decrease in total grooming time in the Control + CLP and CMS + Sham groups, with the CMS + CLP group showing behavior similar to that of the control animals. This was found to be related to a decrease in the levels of brain cytokines, and not to oxidative damage parameters. Collectively, our results suggest that a previous stress caused by CMS can protect the brain against the systemic acute and severe stress elicited by sepsis.

Acute Lipopolysaccharide Switches the Selection of Maternal Behavior to Predatory Behavior in Female Rats.

OBJECTIVES: A common problem during the postpartum period and during lactation is being affected by infection due to Gram-negative bacteria. In this situation, a sick mother needs to choose between caring for her pups or the need for survival. This study analyzed the effects of lipopolysaccharide (LPS)-induced sickness behavior on selection between maternal behavior (MB) and predatory behavior (PB) in lactating rats. To assess the LPS-induced sickness behavior, the plasma tumor necrosis factor-α (TNF-α) levels were measured. METHODS: Lactating rats received 100 µg/kg LPS or saline solution on day 5 or 6 of lactation, 2 h before testing. Five pups and 5 cockroaches were introduced to the experimental cage at the same time and maternal and PB were observed for 30 min. The MB was measured by the pup contact, grouping, grooming, and kyphosis and the PB by contacting, eating, and foraging insects. General maternal activity was also observed, including exploration, self-grooming, and immobility. Immediately after the observations, blood was collected to measure the plasma TNF-α levels. RESULTS: LPS administration reduced the time and frequency of pup contact, grouping, grooming, and kyphosis, with an increase in the latency to first pup contact and grouping. With regard to PB, the time of foraging and eating insects increased, and the latencies to first insect contact, eating insects, and foraging decreased. With regard to general maternal activity, immobility time and TNF-α levels increased in the LPS-treated group. CONCLUSIONS: LPS exposure switched MB to PB, prioritizing maternal survival. Thus, in more favorable situations, these rats may have new offspring and therefore her species would survive for long.

Prostaglandins mediate zymosan-induced sickness behavior in mice.

Previous studies have demonstrated that zymosan, a cell wall component of the yeast Saccharomyces cerevisiae, induces inflammation in experimental models. However, few studies have evaluated the potential of zymosan to induce sickness behavior, a central motivational state that allows an organism to cope with infection. To determine whether zymosan administration results in sickness behavior, mice were submitted to the forced swim (FST) and open field (OFT) tests 2, 6, and 24 h after treatment with zymosan (1, 10, or 100 mg/kg). Additionally, to evaluate the possible relationship between zymosan-induced sickness behavior and prostaglandin synthesis, mice were pretreated with the cyclooxygenase inhibitors indomethacin (10 mg/kg) and nimesulide (5 mg/kg) and the glucocorticoid drug dexamethasone (1 mg/kg). Zymosan induced time-dependent decreases in locomotor activity in the OFT, and an increase in immobility in the FST, and increased plasma levels of corticosterone at 2 h. Pretreatment with indomethacin, nimesulide, or dexamethasone blocked zymosan-induced behavioral changes in both the FST and OFT at 2 h post administration. These findings confirm previous observations that zymosan induces sickness behavior. Furthermore, our results provide new evidence that prostaglandin synthesis is necessary for this effect, as anti-inflammatory drugs that inhibit prostaglandin synthesis attenuated zymosan-induced behavioral changes.

Early Life Stress Activates Glial Cells in the Hippocampus but Attenuates Cytokine Secretion in Response to an Immune Challenge in Rat Pups.

OBJECTIVE: Early life stress (ELS) increases the vulnerability to developing psychopathological disorders in adulthood that are accompanied by brain inflammatory processes. However, it is not known how a combined double hit (stress and immune) at an early age affects the response of the neuroimmune system. Here we investigated the effect of periodic maternal separation (MS) followed by administration of lipopolysaccharide (LPS) on glial cells in the CA3 region and hilus of the hippocampus and on cytokine release on postnatal day (PN) 15. METHODS: Male rat pups were subjected to MS (3 h/day, PN1-14). MS and control pups received a single LPS injection (1 mg/kg of body weight) on PN14. They were subjected to an open field test 1 h later. The pups were sacrificed 90 min after LPS injection (PN14) or on PN15 for cytokine or immunohistological analyses, respectively. RESULTS: LPS reduced the locomotion and induced high corticosterone levels in treated pups. MS or LPS reduced microglial density and activated microglial cells in the hippocampal CA3 and hilus regions. Microglial activation was highest in MS-LPS pups. The astrocyte density was mildly reduced by MS or LPS in the CA3 region and hilus, but the reduction was maximal in MS-LPS pups. LPS increased the secretion of plasmatic interleukin (IL)-1ß, tumor necrosis factor-α, and IL-6, and of hippocampal IL-1ß protein, but these were attenuated in MS-LPS pups. CONCLUSION: Although MS and LPS activate neuroimmune cells, stress attenuates the hippocampal and peripheral cytokine response to LPS through an as-yet unidentified adaptive mechanism. These results provide information regarding the neurobiology of stress and inflammation.

Exogenous oxytocin reduces signs of sickness behavior and modifies heart rate fluctuations of endotoxemic rats.

Besides the well-known roles of oxytocin on birth, maternal bonding, and lactation, recent evidence shows that this hypothalamic hormone possesses cardioprotective, anti-inflammatory and parasympathetic neuromodulation properties. In this study, we explore the heart rate fluctuations (HRF) in an endotoxemic rodent model that was accompanied by the administration of exogenous oxytocin. The assessment of HRF has been widely used as an indirect measure of the cardiac autonomic function. In this context, adult male Dark Agouti rats were equipped with a telemetric transmitter to continuously and remotely measure the electrocardiogram, temperature, and locomotion. In a between-subjects experimental design, rats received the following peripheral treatment: saline solution as a vehicle (V); lipopolysaccharide (LPS); oxytocin (Ox); lipopolysaccharide + oxytocin (LPS+Ox). Linear and non-linear parameters of HRF were estimated starting 3h before to 24h after treatments. Our results showed that exogenous oxytocin does not modify by itself the HRF of oxytocin-treated rats in comparison to vehicle-treated rats. However, in animals undergoing endotoxemia it: a) provokes a less anticorrelated pattern in HRF, b) decreased mean heart rate, c) moderated the magnitude and duration of the LPS-induced hyperthermia, and d) increased locomotion, up to 6h after the LPS injection. The less anticorrelated pattern in the HRF and decreased mean heart rate may reflect a cardiac pacemaker coupling with cholinergic influences mediated by oxytocin during LPS-induced endotoxemia. Finally, the anti-lethargic and long-term temperature moderating effects of the administration of oxytocin during endotoxemia could be a consequence of the systemic anti-inflammatory properties of oxytocin.

Sickness Behavior in Honey Bees.

During an infection, animals suffer several changes in their normal physiology and behavior which may include lethargy, appetite loss, and reduction in grooming and general movements. This set of alterations is known as sickness behavior and although it has been extensively believed to be orchestrated primarily by the immune system, a relevant role for the central nervous system has also been established. The aim of the present work is to develop a simple animal model to allow studying how the immune and the nervous systems interact coordinately during an infection. We administered a bacterial lipopolysaccharide (LPS) into the thorax of honey bees to mimic a bacterial infection, and then we evaluated a set of stereotyped behaviors of the animals that might be indicative of sickness behavior. First, we show that this immune challenge reduces the locomotor activity of the animals in a narrow time window after LPS injection. Furthermore, bees exhibit a loss of appetite 60 and 90 min after injection, but not 15 h later. We also demonstrate that LPS injection reduces spontaneous antennal movements in harnessed animals, which suggests a reduction in the motivational state of the bees. Finally, we show that the LPS injection diminishes the interaction between animals, a crucial behavior in social insects. To our knowledge these results represent the first systematic description of sickness behavior in honey bees and provide important groundwork for the study of the interaction between the immune and the neural systems in an insect model.

Absence of gut microbiota influences lipopolysaccharide-induced behavioral changes in mice.

Changes in the microbiota composition of gastrointestinal tract are emerging as potential players in the physiopathology of neuropsychiatric disorders. In the present work we evaluated the relationship between the absence of gut microbiota and neuroinflammatory mechanisms in a murine model of LPS-induced behavioral alterations. Germ-free (GF) or conventional male mice received a single i.p. injection of lipopolysaccharide (LPS i.p.; 0.83mg/Kg) or PBS, and after 24h they were tested for depressive-like behaviors (forced swimming test, tail suspension test - TST, or sucrose preference test - SPT). After behavioral evaluation, animals were analyzed for possible changes in neuroplasticity by means of BDNF, NGF and cytokines levels in prefrontal cortex and hippocampus, and the expression of Iba-1 (microglial activation marker) in the hippocampus, and the cellular activity marker, ΔFosB, in the dorsal raphe nucleus. In conventional mice, LPS induced depressive-like behaviors. LPS-induced changes were followed by up-regulation of the expression of TNF and Iba-1 in the hippocampus. The same effects were not observed in GF mice. Behavioral effects of LPS were not observed in GF mice submitted to TST. GF mice present a lower response to the anhedonia-like effect induced by LPS when compared to conventional animals (SPT). There was up-regulation of ΔFosB in the dorsal raphe nucleus in the absence of gut microbiota, events not influenced by LPS treatment. Our results suggest that gut-microbiota interactions influence depressive-like behaviors, raphe nucleus activation and activation of pro-inflammatory mechanisms within the hippocampus.