Impact of immunological state on eco-physiological variables in one of the southernmost lizards in the world.

The immune state is an essential component of survival as it directly influences physiological performance and health status. Variation in the leukocyte profile, a significantly increase in body temperature, and a detriment of the eco-physiological performance are among the possible consequences of an unhealthy state. In this study we analyse and discuss how field body temperature, preferred body temperature, the speed for sprint and long runs, locomotor stamina, and body condition can be affected by the immunological state (i.e. leukocyte profile) in a wild population of Liolaemus sarmentoi. Juveniles and adult males with a high percentage of eosinophils, basophils, and a low percentage of monocytes preferred higher body temperatures in a thermal gradient, while pregnant females maintained thermal preferences independently of leukocyte profile. Although juveniles with a high percentage of heterophils showed less locomotor stamina, adult males and pregnant females showed no differences in locomotor performance in relation to leukocyte profile. This study represents a starting point in eco-immunology of a wild lizard population of Liolaemus in cold and temperate environments of Patagonia where the southward shift in the geographic ranges of pathogen populations due to global warming represents a threat to resident host populations.

Maternal immune activation in mid-late gestation alters amphetamine sensitivity and object recognition, but not other schizophrenia-related behaviours in adult rats.

Maternal immune activation induced by Poly(I:C) administration is one of the most commonly used animal models of schizophrenia at present. Previous work from our team has demonstrated that some, but not all of the features often reported for maternal immune activation exposure in rodents can be observed in rats exposed to maternal immune activation at mid or late gestation. To determine whether previous findings in our laboratory were due to these time points simply being less sensitive neurodevelopmental periods for rats with regard to maternal immune activation effects, we aimed to investigate whether maternal immune activation at an often-reported sensitive period (mid-late gestation, day 14) resulted in more behavioural features reflective of face validity for schizophrenia. We examined the behavioural outcomes of mid-late maternal immune activation on a battery of behavioural tests aimed at assessing validity for positive, negative and cognitive symptoms of schizophrenia. We found that rats exposed to maternal immune activation, compared to controls, exhibited enhanced sensitivity to the locomotor-stimulating effects of amphetamine and reduced exploration of novel objects. These findings present a unique profile of effects, different to what has already been established for the same time point in rats, and different to what we had found at earlier and later time points. This work, among others in the literature, highlights the varying nature of models of maternal immune activation and we submit that it is essential for laboratories to characterise their models of maternal immune activation on behaviour rather than assuming that the effects from one laboratory apply in their own.

Simulated viral infection in early-life alters brain morphology, activity and behavior in zebra finches (Taeniopygia guttata).

Early-life immune challenges (ELIC) have long-term effects on adult behavior and brain development. ELIC studies on birds are still few, but they are epidemiologically crucial since birds are important hosts of many mosquito-borne viruses. In this study, we administered a viral infection mimicking agent, Polyinosinic: polycytidylic acid (Poly I:C), to nestling zebra finches on post-hatch day 14. When birds became sexually mature, their general activity (i.e., hopping, feeding behavior) and mosquito defense behaviors (i.e., hops, head movements, pecks, wing movements, foot movements, and scratches) were measured. Following behavioral trials, brains of male birds were collected for anatomical and histochemical analyses. Poly I:C challenge had sex-dependent effects on general activity and mosquito defense behaviors. When compared to control females, Poly I:C challenged females hopped and fed less often in their general activities, but hopped more often in the presence of mosquitoes. Poly I:C challenged males did not differ from control males in any behaviors. Brain analysis revealed that the nucleus taeniae of the amygdala (TnA) of Poly I:C challenged males were smaller in volume yet had more neurons expressing immediate-early gene proteins compared with controls, suggesting a more active TnA. These results suggest that immune challenges early in the life could have long-term effects on behaviors and brains of zebra finches, which may influence disease spread and fitness of individual birds.

Early life exposure of zebrafish (Danio rerio) to synthetic pyrethroids and their metabolites: a comparison of phenotypic and behavioral indicators and gene expression involved in the HPT axis and innate immune system.

Ecotoxicological studies have revealed the association between synthetic pyrethroid (SP) exposure and aquatic toxicity in fish; however, research on the toxic effects of SP metabolites is still limited. In this study, the toxicity of two SPs (permethrin (PM) and ß-cypermethrin (ß-CP)) and their three metabolites (3-phenoxybenzoic alcohol (PBCOH), 3-phenoxybenzaldehyde (PBCHO), and 3-phenoxybenzoic acid (PBCOOH)) towards zebrafish embryos and larvae was evaluated. Both SPs and their metabolites exhibited significant developmental toxicities, caused abnormal vascular development, and changed locomotor activities in larvae. The alteration of gene expression involved in the thyroid system and the innate immune system indicated that SPs and their three metabolites have the potency to induce thyroid disruption and trigger an immune response. The results from the present study suggest that SP metabolites could induce multiple toxic responses similar to parent compounds, and their toxicity should be considered for improving the understanding of environmental risks of SPs.

Perinatal Immune Activation Produces Persistent Sleep Alterations and Epileptiform Activity in Male Mice.

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions, including autism spectrum disorder (ASD). Previous work in rodents has established that immune activation during critical developmental periods can cause phenotypes that reproduce core features of ASD, including decreased social interaction, aberrant communication, and increased repetitive behavior. In humans, ASD is frequently associated with comorbid medical conditions including sleep disorders, motor hyperactivity, and seizures. Here we use a 'two-hit' immune-activation paradigm to determine whether perinatal immune activation can also produce these comorbid features in mice. In this paradigm, we treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, on gestational day 12.5 according to an established maternal immune activation regimen. A subset of the offspring also received a second 'hit' of lipopolysaccharide (LPS), which simulates a bacterial infection, on postnatal day 9. At 6 weeks of age, mice were implanted with wireless telemetry transmitters that enabled continuous measurements of electroencephalography (EEG), electromyography (EMG), locomotor activity, and subcutaneous temperature. Effects at 7 and 12 weeks of age were compared. Both prenatal Poly I:C and postnatal LPS produced changes in locomotor activity and temperature patterns, increases in slow-wave sleep, and shifts in EEG spectral power, several of which persisted at 12 weeks of age. Postnatal LPS also produced persistent increases in spontaneous bursts of epileptiform activity (spike-wave discharges) that occurred predominantly during sleep. Our findings demonstrate that early-life immune activation can lead to long-lasting physiologic perturbations that resemble medical comorbidities often seen in ASD and other neuropsychiatric conditions.

The innate immune cell response to bacterial infection in larval zebrafish is light-regulated.

The circadian clock, which evolved to help organisms harmonize physiological responses to external conditions (such as the light/dark cycle, LD), is emerging as an important regulator of the immune response to infection. Gaining a complete understanding of how the circadian clock influences the immune cell response requires animal models that permit direct observation of these processes within an intact host. Here, we investigated the use of larval zebrafish, a powerful live imaging system, as a new model to study the impact of a fundamental zeitgeber, light, on the innate immune cell response to infection. Larvae infected during the light phase of the LD cycle and in constant light condition (LL) demonstrated enhanced survival and bacterial clearance when compared with larvae infected during the dark phase of the LD cycle and in constant dark condition (DD). This increased survival was associated with elevated expression of the zebrafish orthologues of the mammalian pro-inflammatory cytokine genes, Tumour necrosis factor-α, Interleukin-8 and Interferon-γ, and increased neutrophil and macrophage recruitment. This study demonstrates for the first time that the larval zebrafish innate immune response to infection is enhanced during light exposure, suggesting that, similar to mammalian systems, the larval zebrafish response to infection is light-regulated.

Maternal inflammation induces immune activation of fetal microglia and leads to disrupted microglia immune responses, behavior, and learning performance in adulthood.

Maternal inflammation during pregnancy can have detrimental effects on embryonic development that persist during adulthood. However, the underlying mechanisms and insights in the responsible cell types are still largely unknown. Here we report the effect of maternal inflammation on fetal microglia, the innate immune cells of the central nervous system (CNS). In mice, a challenge with LPS during late gestation stages (days 15-16-17) induced a pro-inflammatory response in fetal microglia. Adult whole brain microglia of mice that were exposed to LPS during embryonic development displayed a persistent reduction in pro-inflammatory activation in response to a re-challenge with LPS. In contrast, hippocampal microglia of these mice displayed an increased inflammatory response to an LPS re-challenge. In addition, a reduced expression of brain-derived neurotrophic factor (BDNF) was observed in hippocampal microglia of LPS-offspring. Microglia-derived BDNF has been shown to be important for learning and memory processes. In line with these observations, behavioral- and learning tasks with mice that were exposed to maternal inflammation revealed reduced home cage activity, reduced anxiety and reduced learning performance in a T-maze. These data show that exposure to maternal inflammation during late gestation results in long term changes in microglia responsiveness during adulthood, which is different in nature in hippocampus compared to total brain microglia.

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue.

Sepsis is a systemic inflammatory response to infection, with no preventative strategies. In this study, we identify a role for habitual physical activity in the prevention of adipose tissue inflammation induced by a model of sepsis, lipopolysaccharide (LPS). Male C57BL/6J mice (8 weeks old) were housed with access to voluntary wheel running (VWR) or sedentary (SED) for 10 weeks. Mice were then injected with LPS (2 mg/kg) or saline (SAL), and tissues were removed 6 hours post-injection. VWR attenuated body, epididymal adipose tissue (eWAT), and subcutaneous inguinal adipose tissue (iWAT) mass gain, improved glucose tolerance, increased markers of mitochondrial biogenesis in iWAT and eWAT, and increased UCP-1 protein content in iWAT. In iWAT, VWR attenuated the LPS induced increase in mRNA expression of TNF-α, MCP-1, and follistatin, along with phosphorylation of STAT3. In addition, VWR had a main effect for reducing iWAT mRNA expression of IL-1ß, IL-6, and SOCS3. In eWAT, VWR had a main effect for reducing mRNA expression of IL-1ß, MCP-1, IL-6, and follistatin. Further, VWR increased SOCS3 mRNA expression and phosphorylation of STAT3 in SAL mice, thus the relative change in response to LPS for these markers was attenuated. The protective effect of prior physical activity occurred in conjunction with increases in the protein content of a component of the LPS binding complex, MyD88. Overall, the results from this study demonstrate that habitual physical activity can attenuate the LPS induced inflammatory response in adipose tissue and this occurs to a greater extent in iWAT compare with eWAT.

The effects of voluntary wheel running on neuroinflammatory status: Role of monocyte chemoattractant protein-1.

The health benefits of exercise and physical activity (PA) have been well researched and it is widely accepted that PA is crucial for maintaining health. One of the mechanisms by which exercise and PA exert their beneficial effects is through peripheral immune system adaptations. To date, very few studies have looked at the regulation of neuroimmune reactions in response to PA. We studied the effect of voluntary wheel running (VWR) on pro- and anti-inflammatory cytokine levels, patterns of glial cell activation and expression of immune receptors in the brains of female C57BL/6 mice. By using homozygous monocyte chemoattractant protein (MCP)-1 null mice, we investigated the role of this key immunoregulatory cytokine in mediating VWR-induced neuroinflammatory responses. We demonstrated that, compared to their sedentary counterparts, C57BL/6 mice exposed for seven weeks to VWR had increased levels of pro- and anti-inflammatory cytokines, markers of glial cell activation and a trend towards increased expression of toll-like receptor (TLR) 4 in the brain. Measurements of serum cytokines revealed that the alterations in brain cytokine levels could not be explained by the effects of PA on peripheral cytokine levels. We propose that the modified neuroimmune status observed in the VWR group represents an activated immune system, as opposed to a less activated immune system in the sedentary group. Since MCP-1 knockout mice displayed differing patterns of pro- and anti-inflammatory brain cytokine expression and glial activation when compared to their wild-type counterparts, we concluded that the effects of VWR on neuroimmune reactions may be modulated by MCP-1. These identified immunomodulatory effects of PA in the brain could contribute to the observed positive relationship between physically active lifestyles and a reduced risk for a number of neurodegenerative diseases that possess a significant neuroinflammatory component.

Distinct alterations in motor & reward seeking behavior are dependent on the gestational age of exposure to LPS-induced maternal immune activation.

The dopaminergic system is involved in motivation, reward and the associated motor activities. Mesodiencephalic dopaminergic neurons in the ventral tegmental area (VTA) regulate motivation and reward, whereas those in the substantia nigra (SN) are essential for motor control. Defective VTA dopaminergic transmission has been implicated in schizophrenia, drug addiction and depression whereas dopaminergic neurons in the SN are lost in Parkinson's disease. Maternal immune activation (MIA) leading to in utero inflammation has been proposed to be a risk factor for these disorders, yet it is unclear how this stimulus can lead to the diverse disturbances in dopaminergic-driven behaviors that emerge at different stages of life in affected offspring. Here we report that gestational age is a critical determinant of the subsequent alterations in dopaminergic-driven behavior in rat offspring exposed to lipopolysaccharide (LPS)-induced MIA. Behavioral analysis revealed that MIA on gestational day 16 but not gestational day 12 resulted in biphasic impairments in motor behavior. Specifically, motor impairments were evident in early life, which were resolved by adolescence, but subsequently re-emerged in adulthood. In contrast, reward seeking behaviors were altered in offspring exposed MIA on gestational day 12. These changes were not due to a loss of dopaminergic neurons per se in the postnatal period, suggesting that they reflect functional changes in dopaminergic systems. This highlights that gestational age may be a key determinant of how MIA leads to distinct alterations in dopaminergic-driven behavior across the lifespan of affected offspring.

A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses.

Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson's disease and Huntington's disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson's disease, Huntington's disease, Alzheimer's disease, and other amyloidoses.

Motor plasticity after extra-intracranial bypass surgery in occlusive cerebrovascular disease.

OBJECTIVE: To explore plasticity in patients scheduled for extra-intracranial bypass surgery due to unilateral symptomatic occlusive cerebrovascular disease via navigated transcranial magnetic stimulation. METHODS: In this observational study, patients were allocated to different substudies and examined before and 3 months after operation. (1) Corticospinal excitability was determined via identification of the resting motor threshold. (2) Intracortical inhibition and facilitation were tested by paired pulse transcranial magnetic stimulation. (3) Area of cortical representation of the first dorsal interosseous muscle was identified. RESULTS: (1) Resting motor thresholds were higher in the affected hemispheres with impaired cerebrovascular reserve capacity compared to the unaffected hemispheres (45.7% ± 2.2% compared to 39.2% ± 1.4%, n = 39, p < 0.05). Reduced excitability normalized 3 months after revascularization (51% ± 2.6% → 45% ± 1.9%, n = 21, p < 0.05). (2) In paired pulse paradigms, there was a motor disinhibition in the operated hemispheres. (3) There was a reduction of the cortical representation areas of the first dorsal interosseous muscle (2.3 ± 0.5 cm(2) → 0.9 ± 0.6 cm(2), n = 9, p < 0.05) after operation. CONCLUSIONS: Our data demonstrate a reversibly impaired motor cortical function in the chronically ischemic brain. In carefully selected patients, cerebral revascularization leads to improved motor output indicated by a lower resting motor threshold, intracortical disinhibition, and more focused motor cortical representation.

Implicit Spoken Words and Motor Sequences Learning Are Impaired in Children with Specific Language Impairment.

OBJECTIVES: This study aims to compare verbal and motor implicit sequence learning abilities in children with and without specific language impairment (SLI). METHODS: Forty-eight children (24 control and 24 SLI) were administered the Serial Search Task (SST), which enables the simultaneous assessment of implicit spoken words and visuomotor sequences learning. RESULTS: Results showed that control children implicitly learned both the spoken words as well as the motor sequences. In contrast, children with SLI showed deficits in both types of learning. Moreover, correlational analyses revealed that SST performance was linked with grammatical abilities in control children but with lexical abilities in children with SLI. CONCLUSIONS: Overall, this pattern of results supports the procedural deficit hypothesis and suggests that domain general implicit sequence learning is impaired in SLI.

Neonatal BCG vaccination of mice improves neurogenesis and behavior in early life.

Bacillus Calmette-Guérin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain. Newborn C57BL/6 mice were injected subcutaneously with BCG or phosphate-buffered saline (PBS) and their mood status and spatial cognition were observed at four and eight weeks (w) old. The mice were also subjected to tests at 2 and 6 w to examine BCG's effects on neurogenesis, the hippocampal microglia phenotype and number, and the expression of hippocampal neuroimmune molecules and peripheral cytokines. The BCG-injected mice showed better behavioral performances at 4 w. We observed elevated neurogenesis, M2 microglial activation and a neurotrophic profile of neuroimmune molecules [more interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor (TGF)-ß, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1 and less tumor necrosis factor (TNF)-α and IL-1ß] in the hippocampus of the 2-w-old BCG-mice. In the periphery, BCG induced a T helper (Th)-1 serum response. At the individual level, there were positive correlations between the serum IFN-γ/IL-4 ratio and the levels of neurotrophins and neurogenesis in the hippocampus. These findings suggest that neonatal BCG vaccination improved neurogenesis and mouse behavior in early life by affecting the neuroimmune milieu in the brain, which may be associated with a systemic Th1 bias.

Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring.

Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100 µg/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-α and IL-6 in dam blood withdrawn 2h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.

Influencia de las características urbanísticas ambientales en el nivel de actividad física de la población de 18 a 65 años del área metropolitana de Pamplona / Influence of urbanistic characteristics in the level of physical activity in people aged 18 to 65 of the metropolitan area Pamplona, Spain

Fundamentos: Un entorno adecuado puede favorecer la práctica de la actividad física, siendo una opción fácil para la población. El objetivo fue determinar la influencia de la percepción de los factores urbanísticos ambientales en el nivel de actividad física de las personas adultas. Métodos: Estudio transversal basado en el International Physical Activity and the Environment Network. Las personas participantes fueron seleccionadas de forma aleatoria y estratificada de la población de las zonas básicas de salud del Área Metropolitana de Pamplona entre las que tenían edad de 18 a 65 años. Se utilizó un cuestionario autoadministrado que incluyó la versión completa de la escala Neighborhood Environment Walkability Scale para valorar la percepción de los factores urbanísticos ambientales y la versión larga del International Physical Activity Questionnaire para recoger datos de actividad física. Se calculó la chi2 y se realizó un análisis multivariable mediante regresión logística no condicional. Resultados: Participaron 905 sujetos (54,70% mujeres). Tener sendas de paseo próximas al domicilio o lugar de trabajo se relacionó con practicar actividad física moderada OR: 3,86 (IC 95% 1,70-8,74)] y actividad física total (suma de actividad física vigorosa, moderada y caminar) OR: 2,61 (IC 95% 1,24-5,45)]. La presencia en el barrio de lugares a los que podían ir caminando se asoció con dedicar más tiempo a caminar [OR: 1,26 (IC 95% 1,01-1,58)] y disponer cerca del domicilio o lugar de trabajo de espacios deportivos se asoció con practicar más actividad física vigorosa [OR: 1,46 (IC 95% 1,01 - 2,12). Conclusiones: Existe asociación directa entre la práctica de la actividad física y las características urbanísticas ambientales, como la existencia de sendas de paseo o instalaciones deportivas (AU)

Background: A suitable environment can encourage the practice of physical activity, being an easy option for the population, for this reason the main objective was to determine the influence of the urban environmental characteristics relate with the physical activity on adult people living on the Pamplona Area. Methods: Cross-sectional study based on the International Physical Activity and the Environment Network (IPEN Adult). Participants were selected in random and stratified from the basic areas of health attached to resident’s population in the Pamplona area, aged ranged between 18-65years old. A self-administered questionnaire was used, including a complete version of the Neighborhood Environment Walkability Scale scale, to evaluate the perception of the urban environmental factors. In addition, the extended version of International Physical Activity Questionnaire for the physical activity data collection was employed. Chi2 test was calculated and a multi variable analysis using non-conditional logistic regression. Results: The representative sample was composed of 905 subjects, [54,70% female]. The perception of having footpaths near to their place of resident or workplace was greater in the group that practice moderated physical activity OR: 3,86 [CI95% 1.70-8.74] and greater total physical activity (the summary of vigorous, moderated physical activity and walking) (OR: 2,61 [CI95% 1.24-5.45]). The people perception of having many places for walk in the neighborhood was associated with major habit of taking a walk (OR: 1,26 [IC95% 1.01-1.58]. Having sport spaces close to the workplace or place of resident was associated with major practice of vigorous physical s activity, OR: 1,46 [CI95% 1.01-2.12]. Conclusions: There is a direct association between the practice of physical activity and environmental urban characteristics, such as the existence of paths of walk or sports facilities (AU)

Effect of Diet and Exercise on the Peripheral Immune System in Young Balb/c Mice.

Although diet and exercise clearly have an influence on immune function, studies are scarce on the effect caused by exercise and the consumption of a carbohydrate-rich or fat-rich diet on the peripheral immune system. The aim of the present study was to evaluate the effect of exercise and the two aforementioned unbalanced diets on young Balb/c mice, especially in relation to BMI, the level of glucose, and the percentage of lymphocyte subpopulations in peripheral blood. The changes found were then related to the synthesis of leptin and adiponectin as well as the production of oxidative stress. The increase in BMI found with the carbohydrate-rich and fat-rich diets showed correlation with the levels of leptin and adiponectin. An increase in leptin and a decrease in adiponectin directly correlated with an increase in total lymphocytes and CD4+ cells and with a decrease in B cells. The increase in leptin also correlated with an increase in CD8+ cells. Glycemia and oxidative stress increased with the two unbalanced diets, negatively affecting the proliferation of total lymphocytes and the percentage of B cells, apparently by causing alterations in proteins through carbonylation. These alterations caused by an unbalanced diet were not modified by moderate exercise.

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway.

The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects.

Hippocampal structure and function are maintained despite severe innate peripheral inflammation.

Chronic peripheral inflammation mediated by cytokines such as TNFα, IL-1ß, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-α transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1ß and IL-6 expression in tarsal joints with highly elevated human TNF-α levels in the serum. Intriguingly, IL-1ß and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation.

Lithium modulates the production of peripheral and cerebral cytokines in an animal model of mania induced by dextroamphetamine.

OBJECTIVES: Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d-AMPH). METHODS: Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1ß, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. RESULTS: The present study showed that d-AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d-AMPH increased the levels of IL-4, IL-6, IL-10, and TNF-α in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). CONCLUSIONS: Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d-AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy.