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Background Symptomatic peripheral artery disease (PAD) is challenging to diagnose in the presence of media sclerosis with incompressible arteries since standard ankle-brachial index (ABI) cannot be applied. Shear wave elastography (SWE) provides a novel ultrasound technique to measure muscle stiffness and to visualize muscle deficits at rest and during contraction. Furthermore, reduced muscle stiffness correlates with a possible hypoperfusion in the affected area. It is fast, non-invasive and associated with peripheral muscle weakness in chronic heart failure patients. Purpose SWE presents an important diagnostic tool for patients with PAD and concomitant media sclerosis. In this prospective observation study we evaluated the alterations of muscle stiffness (measured in kPa) at rest and during controlled activity. Methods Fifteen patients with peripheral artery disease and media sclerosis were included in this pilot study. Thirteen patients were symptomatic in different stages of PAD as a result of significant arterial stenosis/occlusions of the lower legs as assessed by oscillography and duplex sonography. ABI was invalid due to media sclerosis in all 15 patients. The examination was performed at rest and during contraction depicted by active dorsal flexion of the foot on both sides. The medial gastrocnemius muscle was used as a region of interest. Results Mean SWE measurements of medial gastrocnemius muscles showed significant muscle weakness at maximum exercise (103.4±25.9 kPa on the asymptomatic vs. 62.5±21.9 kPa in the symptomatic lower leg (p Conclusion SWE is suitable to detect muscle weakness during exercise in the symptomatic leg of mediasclerotic PAD patients. Since ABI measurements are usually invalid these patients with media sclerosis, shear wave elastography of lower limb muscles may contribute for a non-invasive diagnosis of symptomatic PAD. Larger randomized clinical trials are necessary to confirm our results. Funding Acknowledgement Type of funding sources: None.

Human adipose stem cells (ASCs) hold great potential for regenerative medicine approaches, including osteogenic regeneration of bone defects, that fail to heal autonomously. Osteogenic differentiation of stem cells is dependent on the stimulation of biophysical factors. In the present study, the effects of hypergravity, hypoxia, and hyperbaric treatment were investigated on adipose stem cell (ASC) metabolic activity, quantified by PrestoBlue conversion, and cell numbers, evaluated by crystal violet staining. Osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity and cresolphthalein staining of calcium deposition. Differentiation was performed for 12 days, which was accompanied by periodical stimulation. Increasing gravity forces up to 50x g did not affect ASC viability, but it enhanced osteogenic markers with a strongest effect between 20 and 30x g. Hyperbaric stimulation at 3 bar decreased ASC cell numbers but increased ALP activity and calcium deposition. Hypoxia at 8 % atmospheric oxygen did not affect ASC proliferation, while cell numbers were reduced at 3 % oxygen. Furthermore, hypoxic conditions produced opposing results on osteogenic markers, as ALP activity increased whereas cresolphthalein staining decreased upon stimulation. These data demonstrated that intermittent short duration of basal physical or chemical impulses interfere with the osteogenic differentiation of ASCs. Our findings could be of specific relevance in ASC based therapies for regenerative medicine and bone tissue engineering approaches.

OBJECTIVE Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. METHODS C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. RESULTS Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice. SIGNIFICANCE Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.

Discordant immune response to antiretroviral therapy (ART) in HIV infection is characterized by insufficient reconstitution of peripheral CD4+ T lymphocyte numbers despite suppression of virus replication. The causes of inefficient regeneration of CD4+ T cells on ART remain elusive. The paper reports the study involving two groups of HIV-positive patients: patients with discordant response to ART (n = 20) and patients with standard response to therapy (n = 21). The numbers of cycling (Ki-67+), senescent (CD57+), and exhausted (PD-1+) CD4+ T lymphocytes of varying degree of maturity have been determined in peripheral blood and lymph nodes of HIV-positive individuals. CD4+ T cell division asymmetry index after in vitro stimulation has been analyzed. Histological study of the lymph nodes of HIV-infected patients was carried out. It has been demonstrated that in the individuals with discordant immune response to ART, intensive CD4+ T cell cycling does not result in the increase in their count neither in peripheral blood, nor in the secondary lymphoid organs. At the same time, in the patients with impaired immune system recovery, increased cell proliferation is followed by the accumulation of exhausted CD4+ T lymphocytes. Moreover, patients with discordant immune response to ART revealed an asymmetric division of in vitro stimulated CD4+ T cells. The observed defects may be the cause of inefficient immune system recovery in HIV-infected patients on ART.

While the fire service has long been a male-dominated occupation, women’s participation in this strenuous, high risk, high performance activity has increased in recent years. Firefighting induces significant cardiovascular strain, including hemostatic disruption; however, the effect of sex on hemostatic responses has not been investigated despite evidence that there are sex-related differences in hemostatic variables at rest and following exercise. Thus, we investigated hemostatic responses in age- and BMI-matched male and female firefighters who performed 3–4 evolutions of firefighting drills over a 3 h period. Venous blood samples were collected before and after the firefighting training drills and hemostatic variables were assessed. Firefighting significantly increased platelet count and factor VIII, tissue plasminogen activator (t-PA) antigen, and t-PA activity, and decreased activated partial thromboplastin time and plasminogen activator inhibitor (PAI-1) activity. Females had lower values for epinephrine-induced platelet closure time, antithrombin III, PAI-1 activity, and PAI-1 antigen. There were no interactions between sex and time for any variables assessed. In conclusion, multiple bouts of firefighting activity resulted in a procoagulatory state. Although there were sex differences for several hemostatic variables, male and female firefighters did not differ in their hemostatic response to multiple bouts of firefighting.

Zusammenfassung. In Ergänzung zum klassischen Vorlesen von Kinderbüchern hat sich in den letzten Jahren ein wachsendes Angebot an digitalen Lesemedien für Kinder im Vorschulalter etabliert. Besonders prominente Vertreter sind dabei digitale Lese- und Lernstifte sowie elektronische Kinderbücher mit Vorlesefunktion. Im Rahmen unserer Studie wurden 102 Eltern aus der Region Oberfranken zur Verfügbarkeit, dem Nutzungsverhalten sowie der Bewertung des pädagogischen Nutzens digitaler Lesemedien befragt. Die Ergebnisse zeigen, dass viele Vorschulkinder Zugang zu digitalen Lese- und Lernstiften haben und diese auch überwiegend selbstständig, d.h. ohne elterliche Hilfe nutzen. Elektronische Kinderbücher mit Vorlesefunktion werden dagegen deutlich seltener und auch weniger selbständig von Kindern genutzt. Die Befunde werden mit Ergebnissen zum klassischen Vorlesen von Kinderbüchern sowie dem Fernsehverhalten in Relation gesetzt.

Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2). Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent. Thus, C57BL/6J mice were used to characterize DO expression in brain-regions, astrocytes and microglia to characterize restraint-stress-induced DO expression. Stress increased kynurenine in brain and plasma, demonstrating increased DO activity. Of three Ido1 transcripts, only Ido1-v1 expression was increased by stress and within astrocytes, not microglia, indicating transcript- and glial-specificity. Stress increased Ido1-v1 only in frontal cortex and hypothalamus, indicating brain-region specificity. Of eight Ido2 transcripts, Ido2-v3 expression was increased by stress, again only within astrocytes. Likewise, stress increased Tdo2-FL expression in astrocytes, not microglia. Interestingly, Ido2 and Tdo2 transcripts were not correspondingly induced in Ido1-knockout (Ido1KO) mice, suggesting that Ido1 is necessary for the central DO response to acute stress. Unlike acute inflammatory models resulting in DO induction within microglia, only astrocyte DO expression was increased by acute restraint-stress, defining their unique role during stress-dependent activation of the Kynurenine Pathway. Keywords: Stress, Ido, Tdo, Kynurenine, Astrocyte, Liver

Warnerin pretreatment of catheter segments subcutaneously implanted to mice under conditions of immunosuppression led to a significant increase in the number of neutrophils in the surrounding tissues on day 1; the number of fibroblasts tended to decrease by day 3. Immunohistochemical study showed the presence of T and B lymphocytes on day 3, but no positive reactions to vimentin and CD34 were observed during the first 2 days. These changes suggest that warnerin reduced the intensity of regeneration processes in tissues around the implant, which can be used for suppression of fibrosis.

Acute stressors can induce fear and physiologic responses that prepare the body to protect from danger. A key component of this response is immune system readiness. In particular, inflammasome activation appears critical to linking stress to the immune system. Here, we show that a novel combination of handling procedures used regularly in mouse research impairs novel object recognition (NOR) and activates caspase-1 in the amygdala. In male mice, this handling-stress paradigm combined weighing, scruffing and sham abdominal injection once per hr. While one round of weigh/scruff/needle-stick had no impact on NOR, two rounds compromised NOR without impacting location memory or anxiety-like behaviors. Caspase-1 knockout (KO), IL-1 receptor 1 (IL-1R1) KO and IL-1 receptor antagonist (IL-RA)-administered mice were resistant to handling stress-induced loss of NOR. In addition, examination of the brain showed that handling stress increased caspase-1 activity 85% in the amygdala without impacting hippocampal caspase-1 activity. To delineate danger signals relevant to handling stress, caffeine-administered and adenosine 2A receptor (A2AR) KO mice were tested and found resistant to impaired learning and caspase-1 activation. Finally, mice treated with the β-adrenergic receptor antagonist, propranolol, were resistant to handling stress-induced loss of NOR and caspase-1 activation. Taken together, these results indicate that handling stress-induced impairment of object learning is reliant on a pathway requiring A2AR-dependent activation of caspase-1 in the amygdala that appears contingent on β-adrenergic receptor functionality.

Decomposition of allochthonous organic matter that enters shaded headwater streams during a short autumn leaf fall period provides much of the energy the streams receive throughout the year. As such, alterations of riparian communities, including those resulting from invasive species, should have a significant impact on these energy inputs and potentially alter microbial communities and the behavior of shredders that process leaf litter. We compared consumption of leaves of an abundant native species (green ash Fraxinus pennsylvanica) and nonnative species (common buckthorn Rhamnus cathartica) by the northern spring amphipod Gammarus pseudolimnaeus, with and without periods of stream conditioning. Amphipods consumed a very small proportion of the unconditioned leaves of common buckthorn and green ash and demonstrated no significant preference for the unconditioned leaves of either species. When leaves were stream-conditioned, there was a significant interaction between the effects of leaf species...

Psychoneuroimmunology (PNI) aims to elucidate mechanisms by which the immune system can influence behavior. Given the complexity of the brain, studies using inbred rodents have shed critical insight into the presumed vagaries of the human condition. This is particularly true for stress modeling where adverse stimuli, conditions and/or interactions elicit patterned behavioral reactions that can translate across species. As example, sickness behaviors are as easily recognized in mice as they are in humans, and a family pet. Recently, nutrition has gained prominence as a regulator of brain function. Once perceived as mostly a peripheral player, except when manifest at extremes like starvation or gluttony, nutritional and/or metabolic stress is now recognized as a worrisome contributor to poor mental health especially in those who suffer from food insecurity or overnutrition. In this review, we will explore emerging areas of rodent research that demonstrate the impact of nutritional status on the stressed brain. Our overall goal is to implicate inflammasome activation as a critical convergence point for stress and nutritional dysregulation. In doing so, we will present results from studies focused on macronutrient, micronutrient and dietary bioactives so as to encourage innovative investigation into the emerging field of nutritional PNI.

The field of psychoneuroimmunology (PNI) aims to uncover the processes and consequences of nervous, immune, and endocrine system relationships. Behavior is a consequence of such interactions and manifests from a complex interweave of factors including immune-to-neural and neural-to-immune communication. Often the signaling molecules involved during a particular episode of neuroimmune activation are not known but behavioral response provides evidence that bioactives such as neurotransmitters and cytokines are perturbed. Immunobehavioral phenotyping is a first-line approach when examining the neuroimmune system and its reaction to immune stimulation or suppression. Behavioral response is significantly more sensitive than direct measurement of a single specific bioactive and can quickly and efficiently rule in or out relevance of a particular immune challenge or therapeutic to neuroimmunity. Classically, immunobehavioral research was focused on sickness symptoms related to bacterial infection but neuroimmune activation is now a recognized complication of diseases and disorders ranging from cancer to diabesity to Alzheimer's. Immunobehaviors include lethargy, loss of appetite, and disinterest in social activity/surrounding environment. In addition, neuroimmune activation can diminish physical activity, precipitate feelings of depression and anxiety, and impair cognitive and executive function. Provided is a detailed overview of behavioral tests frequently used to examine neuroimmune activation in mice with a special emphasis on pre-experimental conditions that can confound or prevent successful immunobehavioral experimentation.

Mechanisms by which parasites induce phenotypic alterations are poorly understood in many host–parasite systems. Amphipods are an intermediate host for a range of acanthocephalan parasites, and there is substantial evidence that parasites manipulate the physiology and behavior of amphipods in a variety of ways, including significant reproductive impacts. Evidence suggests such manipulations may result from disruption of serotonergic and dopaminergic pathways. However, correlations with other hormones have not been widely investigated, in part because we lack understanding of the production and action of hormones such as estrogen and testosterone in amphipods. We investigated how estrogen (17β-estradiol) and testosterone concentrations vary between unparasitized male and female amphipods Gammarus pseudolimnaeus that were and were not in precopulatory pairs. We also investigated whether infection with the acanthocephalan Corynosoma sp. is correlated with differences in estrogen or testosterone concentrations when compared to unparasitized conspecifics. Our results indicate that estrogen and testosterone differ significantly between male and female amphipods, whether paired or unpaired, suggesting they may have sex-specific functions. The biological relevance of these hormones merits increased attention in light of the prevalence of endocrine-disrupting compounds in aquatic systems. Further, we found that encysted acanthocephalan parasites are correlated with elevated concentrations of estrogen and depressed concentrations of testosterone in male, but not female amphipods. This correlation suggests the need for a broader investigation of the mechanisms underlying phenotypic alterations of amphipod behavior and physiology by acanthocephalan parasites.

The presence and biological significance of vertebrate-related steroid sex hormones in aquatic invertebrates are poorly understood. We compared the concentrations of estrogen (17β-estradiol) and testosterone between amplexing male and female freshwater amphipods of three species from two continents: Gammarus duebeni celticus Liljeborg, 1852 and G. pulex (L., 1758) from Europe, and G. pseudolimnaeus Bousfield, 1958 from North America. All three species were found to have measureable concentrations of both hormones in whole body lysate samples but the concentrations differed between species, with testosterone differing significantly between species only for male amphipods and estradiol differing significantly between species only for female amphipods. Concentrations of both testosterone and estrogen differed between males and females in two of the three species ( G. duebeni celticus and G. pseudolimnaeus ). Females had the highest concentration of both hormones in G. duebeni celticus and the lowest concentration of both hormones in G. pseudolimnaeus . These results contribute to a growing body of evidence that these hormones are endogenously produced and biologically relevant in amphipods. Such evidence is particularly important in light of increasing prevalence of endocrine-disrupting compounds in the environment and the central role played by amphipods in aquatic ecosystems.

Leseprobe ----- Abstract Interactive audio pens – pens that contain a built-in speaker and that can be used in combination with books that are made for this purpose – are new, commercially available technological developments that have found widespread dissemination. In the current paper, we studied the availability and use of these interactive audio pens and their associations with home literacy activities and children’s emergent literacy skills in a sample of 103 German preschool children. We found that the availability of interactive audio pens at home showed small positive relations to children’s verbal short-term memory. Home literacy activities were not correlated to the availability of interactive audio pens. Results are discussed against the background of current research in multimedia storybook reading. Keywords: interactive audio pens, emergent literacy skills, multimedia storybooks, home literacy environment, verbal short-term memory ----- Zusammenhange zwischen der Nutzung digitaler Lese- und Lernstifte mit der hauslichen Lernumwelt und schriftsprachlichen Vorlauferfahigkeiten Zusammenfassung In den letzten Jahren hat sich ein breites Angebot elektronisch gestutzter Lesemedien etabliert. Besonders bekannt sind die digitalen Lese- und Lernstifte, das heist elektronische Lesegerate mit Lautsprecher in Stiftform, die beispielsweise zugehorige Kinderbucher nach Beruhrung des Buchtextes vorlesen. In der vorliegenden Studie (N = 103 Vorschulkinder) wurde kein statistisch bedeutsamer Zusammenhang zwischen der Verfugbarkeit digitaler Lese- und Lernstifte und der hauslichen Lernumwelt gefunden. Fur die schriftsprachlichen Vorlauferfahigkeiten (Buchstabenkenntnis, phonologische Bewusstheit, verbales Kurzzeitgedachtnis) zeigt sich ein gering positiver korrelativer Zusammenhang der hauslichen Verfugbarkeit digitaler Lese- und Lernstifte mit dem verbalen Kurzzeitgedachtnis. Schlagworter: Digitale Lese- und Lernstifte, schriftsprachliche Vorlauferfahigkeiten, elektronische Kinderbucher, hausliche Lernumwelt, verbales Kurzzeitgedachtnis ----- Bibliographie: Pfost, Maximilian/Freund, Jana G.: Interactive Audio Pens, Home Literacy Activities and Emergent Literacy Skills, Diskurs Kindheits- und Jugendforschung / Discourse. Journal of Childhood and Adolescence Research, 3-2018, S. 337-349. https://doi.org/10.3224/diskurs.v13i3.06

Firefighting activities appear to increase the risk of acute and chronic lung disease, including malignancy. While self-contained breathing apparatuses (SCBA) mitigate exposures to inhalable asphyxiates and carcinogens, firefighters frequently remove SCBA during overhaul when the firegrounds appear clear of visible smoke. Using a mouse model of overhaul without airway protection, the impact of fireground environment exposure on lung gene expression was assessed to identify transcripts potentially critical to firefighter-related chronic pulmonary illnesses. Lung tissue was collected 2 hrs post-overhaul and evaluated via whole genome transcriptomics by RNA-seq. Although gas metering showed that the fireground overhaul levels of carbon monoxide (CO), carbon dioxide (CO2), hydrogen cyanine (HCN), hydrogen sulfide (H2S) and oxygen (O2) were within NIOSH ceiling recommendations, 3852 lung genes were differentially expressed when mice exposed to overhaul were compared to mice on the fireground but outside the overhaul environment. Importantly, overhaul exposure was associated with an up/down-regulation of 86 genes with a fold change of 1.5 or greater (p

The field of psychoneuroimmunology (PNI) aims to uncover the processes and consequences of nervous, immune, and endocrine system relationships. Behavior is a consequence of such interactions and manifests from a complex interweave of factors including immune-to-neural and neural-to-immune communication. Often the signaling molecules involved during a particular episode of neuroimmune activation are not known but behavioral response provides evidence that bioactives such as neurotransmitters and cytokines are perturbed. Immunobehavioral phenotyping is a first-line approach when examining the neuroimmune system and its reaction to immune stimulation or suppression. Behavioral response is significantly more sensitive than direct measurement of a single specific bioactive and can quickly and efficiently rule in or out relevance of a particular immune challenge or therapeutic to neuroimmunity. Classically, immunobehavioral research was focused on sickness symptoms related to bacterial infection but neuroimmune activation is now a recognized complication of diseases and disorders ranging from cancer to diabesity to Alzheimer's. Immunobehaviors include lethargy, loss of appetite, and disinterest in social activity/surrounding environment. In addition, neuroimmune activation can diminish physical activity, precipitate feelings of depression and anxiety, and impair cognitive and executive function. Provided is a detailed overview of behavioral tests frequently used to examine neuroimmune activation in mice with a special emphasis on pre-experimental conditions that can confound or prevent successful immunobehavioral experimentation.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.

Background Inflammation within the central nervous system (CNS) is frequently comorbid with anxiety. Importantly, the pro-inflammatory cytokine most commonly associated with anxiety is IL-1β. The bioavailability and activity of IL-1β are regulated by caspase-1-dependent proteolysis vis-a-vis the inflammasome. Thus, interventions regulating the activation or activity of caspase-1 should reduce anxiety especially in states that foster IL-1β maturation. Methods Male C57BL/6j, C57BL/6j mice treated with the capase-1 inhibitor biotin-YVAD-cmk, caspase-1 knockout (KO) mice and IL-1R1 KO mice were fasted for 24 h or allowed ad libitum access to food. Immediately after fasting, caspase-1 activity was measured in brain region homogenates while activated caspase-1 was localized in the brain by immunohistochemistry. Mouse anxiety-like behavior and cognition were tested using the elevated zero maze and novel object/object location tasks, respectively. Results A 24 h fast in mice reduced the activity of caspase-1 in whole brain and in the prefrontal cortex, amygdala, hippocampus, and hypothalamus by 35%, 25%, 40%, 40%, and 40% respectively. A 24 h fast also reduced anxiety-like behavior by 40% and increased novel object and object location recognition by 21% and 31%, respectively. IL-1β protein, however, was not reduced in the brain by fasting. ICV administration of YVAD decreased caspase-1 activity in the prefrontal cortex and amygdala by 55%, respectively leading to a 64% reduction in anxiety like behavior. Importantly, when caspase-1 KO or IL1-R1 KO mice are fasted, no fasting-dependent reduction in anxiety-like behavior was observed. Conclusions Results indicate that fasting decrease anxiety-like behavior and improves memory by a mechanism tied to reducing caspase-1 activity throughout the brain.

Background Diets that include some aspect of fasting have dramatically increased in popularity. In addition, fasting reduces inflammasome activity in the brain while improving learning. Here, we examine the impact of refeeding a low-fat diet (LFD) or high-fat diet (HFD) after fasting. Methods Male wildtype (WT), caspase-1 knockout (KO) and/or IL-1 receptor 1 (IL-1R1) KO mice were fasted for 24 h or allowed ad libitum access to food (chow). Immediately after fasting, mice were allowed to refeed for 2 h in the presence of LFD, HFD or chow. Mouse learning was examined using novel object recognition (NOR) and novel location recognition (NLR). Caspase-1 activity was quantified in the brain using histochemistry (HC) and image analysis. Results Refeeding with a HFD but not a LFD or chow fully impaired both NOR and NLR. Likewise, HFD when compared to LFD refeeding increased caspase-1 activity in the whole amygdala and, particularly, in the posterior basolateral nuclei (BLp) by 2.5-fold and 4.6-fold, respectively. When caspase-1 KO or IL-1R1 KO mice were examined, learning impairment secondary to HFD refeeding did not occur. Equally, administration of n-acetylcysteine to fasted WT mice prevented HFD-dependent learning impairment and caspase-1 activation in the BLp. Finally, the free-fatty acid receptor 1 (FFAR1) antagonist, DC260126, mitigated learning impairment associated with HFD refeeding while blocking caspase-1 activation in the BLp. Conclusions Consumption of a HFD after fasting impairs learning by a mechanism that is dependent on caspase-1 and the IL-1R1 receptor. These consequences of a HFD refeeding on the BLP of the amygdala appear linked to oxidative stress and FFAR1.

The objective of this study was to evaluate the impact of obesity and firefighting activities on coagulation and fibrinolytic activity in relatively young, apparently healthy firefighters. Firefighters performed simulated firefighting activities for 18 minutes in a live-fire training structure. Blood samples were obtained at baseline, before firefighting, and within a few minutes of completing the activity. Nearly all markers of coagulation and fibrinolytic activity increased immediately after firefighting with an overall shift toward a procoagulatory profile. Obese firefighters exhibited lower levels of tissue plasminogen activator activity (0.98 vs 0.63 IU/ml) and higher levels of plasminogen activator inhibitor-1 activity (2.2 vs 4.5 ng/ml) at baseline compared with normal-weight firefighters, suggesting that fibrinolytic activity was lower in obese firefighters. There were few interactions between body mass index and firefighting activity, thus our findings suggest that obese firefighters did not exhibit a greater procoagulatory response to live firefighting compared with normal-weight firefighters. Acute live firefighting produced increases in both fibrinolytic and coagulatory responses; although obesity was associated with a reduced fibrinolytic profile at baseline, the changes produced by acute firefighting were similar in obese and nonobese firefighters.

Anxiety is one of the most commonly reported psychiatric conditions, but its pathogenesis is poorly understood. Ailments associated with activation of the innate immune system, however, are increasingly linked to anxiety disorders. In adult male mice, we found that adenosine doubled caspase-1 activity in brain by a pathway reliant on ATP-sensitive potassium (KATP) channels, protein kinase A (PKA) and the A2A adenosine receptor (AR). In addition, adenosine-dependent activation of caspase-1 increased interleukin (IL)-1β in the brain by two-fold. Peripheral administration of adenosine in wild-type (WT) mice led to a 2.3-fold increase in caspase-1 activity in the amygdala and to a 33% and 42% reduction in spontaneous locomotor activity and food intake, respectively, that were not observed in caspase-1 knockout (KO), IL-1 receptor type 1 (IL-1R1) KO and A2A AR KO mice or in mice administered a caspase-1 inhibitor centrally. Finally, adenosine administration increased anxiety-like behaviors in WT mice by 28% in the open field test and by 55% in the elevated zero-maze. Caspase-1 KO mice, IL-1R1 KO mice, A2A AR KO mice and WT mice treated with the KATP channel blocker, glyburide, were resistant to adenosine-induced anxiety-like behaviors. Thus, our results indicate that adenosine can act as an anxiogenic by activating caspase-1 and increasing IL-1β in the brain.

Headwater streams derive a majority of their energy from allochthonous inputs; alteration of these inputs may lead to changes in stream communities and ecological function. Common buckthorn (Rhamnus cathartica) is invasive over much of the northern United States and southern Canada, and has the potential to become an ecosystem dominant and alter stream communities. However, while much is known of the effects of buckthorn on terrestrial ecosystems, little is known of its effects on aquatic ecosystems. Using leaf collection nets, we estimated that leaf fall to the stream consisted predominantly of green ash (69.0%) and common buckthorn (24.2%). Green ash leaves fell from September through mid-October, reaching its peak in early October, whereas common buckthorn contributed leaves for an additional month until mid-November. We placed leaf packs of common buckthorn and two native species, American elm and green ash, in a headwater stream to determine differences in leaf decomposition rates. Common buckthorn l...

The cytokine IL-1 is critical to the pathogenesis of a variety of human conditions and diseases. Unlike most other cytokines, IL-1 is counterbalanced by two endogenous inhibitors. The functional significance of IL-1 receptor antagonist (IL-1RA) is well documented due to the clinical utilization of the recombinant human IL-1RA analog, anakinra. In contrast, much less is known about the type 2 IL-1 receptor (IL-1R2), which acts as a decoy receptor for IL-1. While IL-1R2 is structurally similar to the type 1 IL-1 receptor (IL-1R1) responsible for IL-1 signal transduction, its truncated cytoplasmic domain and lack of Toll-IL-1 receptor (TIR) region renders IL-1R2 incapable of transmembrane signaling. IL-1R2 competes with IL-1R1 for ligands and for the IL-1R1 co-receptor, IL-1 receptor accessory protein (IL-1RAP). Additionally, IL-1R2 exists in both a membrane bound and soluble form (sIL-1R2) that has biological properties similar to both a decoy receptor and a binding protein. Thus far, IL-1R2 has been implicated in arthritis, endometriosis, organ transplantation, sepsis/sickness behavior, diabetes, atherosclerosis, autoimmune inner ear disease (AIED), Alzheimer’s disease and ulcerative colitis. In this review, we will detail the functional properties of IL-1R2 and examine its role in human disease.

Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2). Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent. Thus, C57BL/6J mice were used to characterize DO expression in brain-regions, astrocytes and microglia to characterize restraint-stress-induced DO expression. Stress increased kynurenine in brain and plasma, demonstrating increased DO activity. Of three Ido1 transcripts, only Ido1-v1 expression was increased by stress and within astrocytes, not microglia, indicating transcript- and glial-specificity. Stress increased Ido1-v1 only in frontal cortex and hypothalamus, indicating brain-region specificity. Of eight Ido2 transcripts, Ido2-v3 expression was increased by stress, again only within astrocytes. Likewise, stress increased Tdo2-FL expression in astrocytes, not microglia. Interestingly, Ido2 and Tdo2 transcripts were not correspondingly induced in Ido1-knockout (Ido1KO) mice, suggesting that Ido1 is necessary for the central DO response to acute stress. Unlike acute inflammatory models resulting in DO induction within microglia, only astrocyte DO expression was increased by acute restraint-stress, defining their unique role during stress-dependent activation of the Kynurenine Pathway., Highlights • Acute stress increased tryptophan metabolism to kynurenine. • Stress increased Ido1, Ido2 and Tdo2 expression by astrocytes. • Stress did not increase Ido2 in astrocytes from Ido1KO mice. • Stress did not increase Tdo2 in brains fromIdo1KO mice. • Brain and hepatic Ido1, Ido2 and Tdo2 are differentially regulated by stress.

Reactive oxygen species (ROS) generate a type of DNA damage called tandem lesions, two adjacent nucleotides both modified. A subcategory of tandem lesions consists of adjacent nucleotides linked by a covalent bond. Covalently linked tandem lesions generate highly characteristic liquid chromotography-tandem mass spectrometry (LC-MS/MS) elution profiles. We have used this property to comprehensively survey X-irradiated DNA for covalently linked tandem lesions. A total of 15 tandem lesions were detected in DNA irradiated in deoxygenated aqueous solution, five tandem lesions were detected in DNA that was irradiated in oxygenated solution.

Terminal restriction fragment length polymorphism (T-RFLP) analysis has been widely used for studying microbial communities. However, most T-RFLP assays use 16S rDNA as the target and are unable to accurately characterize a microbial subpopulation. In this study, we developed a novel T-RFLP protocol based on Lactobacillus hsp60 to rapidly characterize and compare lactobacilli composition. The theoretical terminal restriction fragment (TRF) profiles were calculated from 769 Lactobacillus hsp60 sequences from online databases. In silico digestion with restriction endonucleases AluI and TacI on hsp60 amplicons generated 83 distinct TRF patterns, of which, 70 were species specific. To validate the assay, five previously sequenced lactobacilli were cultured independently, mixed at known concentrations and subjected to analysis by T-RFLP. All five strains generated the predicted TRFs and a qualitative consistent relationship was revealed. We performed the T-RFLP protocol on fecal samples from mice fed 6 different diets (n=4). Principal component analysis and agglomerative hierarchical clustering revealed that the lactobacilli community was strongly connected to dietary supplementation. Our study demonstrates the potential for using Lactobacillus specific T-RFLP to characterize lactobacilli communities in complex samples.

Reports in humans advocate a link between hypoglycemia and altered mood. Such observations, however, have not been mechanistically explored. Here we examined depressive-like behaviors in mice resulting from acute hypoglycemia. Mice were fasted for 12 hours and then administered intraperitoneal insulin to induce a blood glucose nadir of 50 mg/dL at 0.75 hour after injection that by 2 hours postinjection had returned to normal. The behaviors of locomotion, forced swim, saccharin preference, and novel object recognition were subsequently examined. Mice made hypoglycemic showed depressive-like behaviors 24 hours after resolution of hypoglycemia as evidenced by increased immobility in the forced swim test (FST) and reduced saccharin preference. Movement and memory were not impacted by hypoglycemia 24 hours after its resolution. By 48 hours posthypoglycemia, depressive-like behaviors resolved. In contrast, neither peripheral insulin administration without resultant hypoglycemia nor intracerebroventricular insulin administration altered performance in the FST. The antidepressants fluoxetine and desipramine prevented hypoglycemia-induced immobility in the FST, as did the antiadrenergic agents phentolamine, metoprolol, and butoxamine. Epinephrine and norepinephrine administration caused increased immobility in the FST at 24 hours postadministration that subsequently resolved by 48 hours. These data indicate that, in mice, acute hypoglycemia through adrenergic pathways caused depressive-like behaviors that exist well beyond the resolution of hypoglycemia.

The macrophage (MΦ) is an essential cellular first responder in the innate immune system, sensing, alerting, removing and destroying intrinsic and extrinsic pathogens. While congenital aplasia of granulocytes, T or B lymphocytes leads to serious disease, lack of MΦs is incompatible with life. The MΦ, however, is not a monomorphic entity. These constructers, repairers and defenders of the body are diverse in form and function. What controls MΦ phenotype is beginning to be understood and involves a complex interplay of origination, location and microenvironment. Common to all MΦ developmental pathways are pro-inflammatory and anti-inflammatory cytokines. MΦs respond to these bioactives in distinct ways developing recently recognized activation phenotypes that canonically support bacterial clearance (classical activation), parasite defense/tissue repair (alternative activation) and anti-inflammation (deactivation). Critically, the same cytokines which orchestrate immune defense and homeostasis dramatically impact sense of well being and cognition by eliciting sickness symptoms. Such behaviors are the manifestation of pro/anti-inflammatory cytokine action in the brain and are a direct consequence of MΦ function. This review describes the “new” archetypal MΦ activation states, delineates microglia phenotypic plasticity and explores the importance of these macrophage activation states to sickness behavior.

The neuroimmunological and behavioral consequences of a high-fat diet (HFD) are not well delineated. This is especially true when short term (24 h) fasting is used as a physiologic stressor. In this study, we examined the impact of a HFD on learning and memory and depressive-like behaviors to understand how fasting impacts neuroimmunity and whether obesity modulates the response. Mice were fed diets containing either 10% (low-fat diet (LFD) mice) or 60% (HFD mice) calories from fat for 10-12 weeks. Gene transcripts for 26 pro-/anti-inflammatory cytokines and markers of macrophage activation were examined in adipose tissue and whole brain. Mouse learning and memory (spontaneous alternation, novel object) and depressive-like behaviors (saccharin preference, burrowing, forced swim) were studied in the fed and fasted state as were gene transcripts for F4/80, CD11b, interleukin-1α (IL-1α), IL-1β, IL-1R1, IL-1R2, IL-1RA, IL-6 and tumor necrosis factor-α in cortex, hippocampus and hypothalamus. In the fed state, HFD mice compared to LFD mice had reduced locomotor activity, and were adverse to saccharin and burrowed less. After fasting, LFD mice vs. HFD mice lost 18 vs. 5% of their body weight, respectively. In addition, HFD mice failed to downregulate gene transcripts for the myeloid-cell associated proteins F4/80, CD11b and IL-1α in the brain, failed to appropriately explore a novel object, failed to reduce locomotor activity and had increased saccharin consumption and burrowing. These data indicate that fasting induces an anti-inflammatory effect on the neuroimmune system which a HFD prevents. This breakdown appears linked to the IL-1 system because of the association of this cytokine with memory and learning.

The leading cause of line-of-duty death among firefighters is sudden cardiac events. Platelets play a critical role in the formation of an occlusive thrombus during an ischemic event.The purpose of this study was to examine the acute effect of firefighting on platelet number and aggregability.Apparently healthy male firefighters (N = 114; age 29.4 ± 7.8 years) participated in 18 minutes of simulated firefighting activity in a training structure that contained live fires. Blood samples were obtained before and after simulated firefighting activity and analyzed for complete blood cell count (CBC), chemistry, and platelet number and function. Platelet function was measured using a PFA-100 analyzer to assess platelet aggregability.As expected, performing firefighting activity resulted in significant increases in heart rate (75 b·min(-1)) and core temperature (0.7 °C), and significant changes in blood chemistry values. The most important finding in this study is that 18 minutes of simulated firefighting caused a 24% increase in platelet number and a significant increase in platelet aggregability.Firefighting resulted in a significant increase in platelet number and aggregability, indicating that even short bouts of firefighting can increase thrombotic potential in apparently healthy firefighters.

As obesity prevalence increases year-over-year the neurological comorbidities that present with it are increasing as well. Over consumption of calories is a significant causal factor in the development of obesity, and induces a pro-inflammatory state in the brain. Importantly, brain-based IL-1 β appears to be crucial to obesity-related cognitive dysfunction, and several fasting paradigms have been shown to be effective at ameliorating both obesity and IL-1 β -induced cognitive dysfunction. However, these fasting programs can induce binge eating following fasting and it remains unknown whether this type of acute overconsumption can result in negative inflammatory and cognitive sequela. Here, we show that 2hr of high-fat diet (HFD) refeeding reduces novel object recognition (NOR) and novel location recognition (NLR) memory by 13% and 14%, respectively. Additionally, HFD refeeding increases the IL-1 β activating enzyme caspase-1 in the amygdala by ∼ 100%. Calorie intake was significantly correlated with both cognitive performance and caspase-1 activity. Additionally, knockout of either caspase-1 or IL-1 receptor 1 (IL1R1) eliminated recognition memory impairments due to HFD. The antioxidant n-acetylcysteine (NAC; 50 mg/kg) improved NOR and NLR performance by 18% and 14% respectively, and reduced caspase-1 in HFD fed animals by 169%, suggesting a causal role for oxidative stress. Taken together, these data suggest that acute overconsumption during refeeding activates caspase-1 in the amygdala which leads to cognitive impairment via a mechanism mediated by oxidative stress.

Motivated by recent experiments, we study a rich variation of the familiar Rayleigh–Bénard convection (RBC), where the temperature at the lower boundary varies sinusoidally about a mean value. As usual the Rayleigh number R measures the average temperature gradient, while the additional spatial modulation is characterized by a (small) amplitude δm and a wavevector qm. Our analysis relies on precise numerical solutions of suitably adapted Oberbeck–Boussinesq equations (OBE). In the absence of forcing (δm = 0), convection rolls with wavenumber qc bifurcate only for R above the critical Rayleigh number Rc. In contrast, for δm≠0, convection is unavoidable for any finite R; in the most simple case in the form of ‘forced rolls’ with wavevector qm. According to our first comprehensive stability diagram of these forced rolls in the qm – R plane, they develop instabilities against resonant oblique modes at R ≲ Rc in a wide range of qm/qc. Only for qm in the vicinity of qc, the forced rolls remain stable up to fairly large R > Rc. Direct numerical simulations of the OBE support and extend the findings of the stability analysis. Moreover, we are in line with the experimental results and also with some earlier theoretical results on this problem, based on asymptotic expansions in the limit δm → 0 and R → Rc. It is satisfying that in many cases the numerical results can be directly interpreted in terms of suitably constructed amplitude and generalized Swift–Hohenberg equations.

The 1-carbamoyl-2-oxo-4,5-dihydroxyimidazolidine modification of cytosine is a known base modification produced in vitro by oxidative stress. However, the presence of this modification in vivo has not been established. In this study the introduction of this base modification into dinucleoside monophosphates was accomplished using the Fenton reaction. Subsequently, the modification was produced in short isotopically labeled oligomers. Labeled tetramers bearing the lesion were used as internal standards for LC-MS/MS determinations of the base modification in the DNA of white blood cells from healthy donors. The background level of the 1-carbamoyl-2-oxo-4,5-dihydroxyimidazolidine modification of cytosine was found to be larger than the levels of the formamide and thymine glycol base modifications.

Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber became less sick and recovered faster from endotoxin-induced sickness behaviors than mice fed insoluble fiber. In response to intraperitoneal endotoxin, mice fed soluble fiber had up-regulated IL-1RA and reduced IL-1beta and TNF-alpha in the brain as compared to mice fed insoluble fiber. Importantly, mice fed soluble fiber had a basal increase in IL-4 in the ileum and spleen which was absent in MyD88 knockout mice. Con-A stimulated splenocytes from mice fed soluble fiber showed increased IL-4 and IL-5 and decreased IL-2, IL-12 and IFN-gamma when compared to mice fed insoluble fiber. Likewise, endotoxin-stimulated macrophages from mice fed soluble fiber demonstrated decreased IL-1beta, TNF-alpha, IFN-gamma, IL-12 and nitrate and increased IL-1RA, arginase 1 and Ym1 when compared to mice fed insoluble fiber. Finally, the behavioral protection afforded by feeding mice soluble fiber was reduced in IL-4 knockout mice, as was the impact of soluble fiber on Con-A stimulated splenocytes and endotoxin activated macrophages. These data show that a diet rich in soluble fiber protects against endotoxin-induced sickness behavior by polarizing mice Th2 and promoting alternative activation of macrophages.

Background: A long-standing hypothesis is that oxidative stress is a risk factor for cancer. Support for this hypothesis comes from observations of higher levels of oxidative damage in the DNA of WBC of cancer patients compared with healthy controls. Methods: Two generally overlooked types of DNA damage, the formamide modification and the thymine glycol modification, both derived from pyrimidine bases, were assayed as markers of oxidative stress. Damage levels were measured in the DNA of WBC of ovarian cancer patients and of healthy controls. Results: The levels of both modifications were higher in ovarian cancer patients than in healthy controls although in the case of the formamide modification age could not be ruled out as a factor. Conclusion: Our results in combination with other published measurements of oxidative DNA damage support the hypothesis that oxidative damage, on average, is higher in WBC of cancer patients than in healthy controls.

The idea that type 2 diabetes is associated with augmented innate immune function characterized by increased circulating levels of acute phase reactants and altered macrophage biology is fairly well established, even though the mechanisms involved in this complex interaction still are not entirely clear. To date, the majority of studies investigating innate immune function in type 2 diabetes are limited to the context of wound healing, atherosclerosis, stroke, and other commonly identified comorbidities. Several important recurring themes come out of these data. First, type 2 diabetes is associated with a state of chronic, subclinical inflammation. Second, in macrophages, type 2 diabetic conditions enhance proinflammatory reactions and impair anti-inflammatory responses. Third, after acute activation of the innate immune system in type 2 diabetes, recovery or resolution of inflammation is impaired. The consequences of type 2 diabetes-associated inflammatory alterations on PNI processes have been recognized only recently. Given the impact of diminished emotional well-being on the quality of life in patients who have type 2 diabetes, diabetes-induced exacerbation of PNI responses should be considered a serious complication of type 2 diabetes that warrants further clinical attention.

Individuals affected by hypoxia experience a variety of immune-associated sickness symptoms including malaise, fatigue, lethargy and loss of interest in the physical and social environment. Recently, we demonstrated that the interleukin (IL)-1β arm of the neuroimmune system was critical to the sickness symptoms caused by hypoxia, and that IL-1 receptor antagonist (IL-1RA), IL-1β’s endogenous inhibitor, was critical to promoting sickness recovery. Here, we report that leptin is key to recovery from hypoxia because it dramatically augmented IL-1RA production in mice. We found that hypoxia increased leptin in white adipose tissue (WAT) which in turn, caused a marked rise in serum IL-1RA. Interestingly, in-vitro, leptin was a more potent inducer of IL-RA, in macrophages, than hypoxia. In leptin receptor defective (db/db) and leptin deficient (ob/ob) mice, sickness recovery from hypoxia was delayed 3-fold. Importantly, in ob/ob mice, leptin administration completely reversed this delayed recovery and induced a marked increase in serum IL-1RA. Finally, leptin administration to normal mice reduced hypoxia recovery time by 1/3 and dramatically increased WAT and serum IL-1RA. Leptin did not alter recovery from hypoxia in IL-1RA knock out mice. These results show that by enhancing IL-1RA production leptin promoted sickness recovery from hypoxia.

Summary Objective Hypoglycemia is associated with a variety of adverse behaviors including fatigue, confusion and social withdrawal. While these clinical symptoms are well characterized, the mechanism of their cause is not understood. Here we investigated how insulin-induced hypoglycemia causes social withdrawal. Research design and methods Male 8–12-week-old C57BL/6J mice were injected intraperitoneally (IP) with or without and/or insulin, norepinephrine (NE) and epinephrine (Epi), terbutaline and butoxamine with subsequent measurement of blood glucose, social withdrawal and plasma catecholamines. Results Insulin generated (0.75 h post-injection) significant hypoglycemia with blood glucose nadirs of 64 ± 4 and 48 ± 5 mg/dl for 0.8 and 1.2 units/kg of insulin, respectively. Insulin (0.8 or 1.2 units/kg) caused near total social withdrawal at 0.75 h with full recovery not occurring until 4 h (0.8 units/kg) or 8 h (1.2 units/kg) post-insulin injection. Insulin also caused a marked elevation in plasma catecholamines. Basal 12 h fasting NE and Epi were 287 ± 38 and 350 ± 47 pg/ml, respectively. Insulin at 0.8 units/kg increased plasma NE and Epi to 994 ± 73 and 1842 ± 473 pg/ml, respectively. Administration of exogenous NE or Epi caused social withdrawal similar in magnitude to insulin. Importantly, administration of the beta-2 adrenergic receptor agonist terbutaline also caused social withdrawal while administration of the beta-2 adrenergic receptor antagonist butoxamine blocked NE-induced social withdrawal. Finally, butoxamine blocked insulin-induced social withdrawal. Conclusions These data demonstrate that hypoglycemia-associated social withdrawal is dependent on catecholamines via a beta-2 receptor-mediated pathway.

Acute cognitive disorders are common in elderly patients with peripheral infections but it is not clear why. Here, we injected old and young mice with Escherichia coli lipopolysaccharide (LPS) to mimic an acute peripheral infection and separated the hippocampal neuronal cell layers from the surrounding hippocampal tissue by laser capture microdissection and measured mRNA for several inflammatory cytokines (IL-1 beta, IL-6, and TNFalpha) that are known to disrupt cognition. The results showed that old mice had an increased inflammatory response in the hippocampus after LPS compared to younger cohorts. Immunohistochemistry further showed more microglial cells in the hippocampus of old mice compared to young adults, and that more IL-1 beta-positive cells were present in the dentate gyrus and in the CA1, CA2, and CA3 regions of LPS-treated old mice compared to young adults. In a test of cognition that required animals to effectively integrate new information with a preexisting schema to complete a spatial task, we found that hippocampal processing is more easily disrupted in old animals than in younger ones when the peripheral innate immune system is stimulated. Collectively, the results suggest that aging can facilitate neurobehavioral complications associated with peripheral infections probably by allowing the over expression of inflammatory cytokines in brain areas that mediate cognitive processing.