Association between Circulating Levels of C-reactive Protein and Positive and Negative Symptoms of Psychosis in Adolescents in a General Population Birth Cohort

Background Schizophrenia is associated with elevated levels of circulating C-reactive protein (CRP) and other inflammatory markers, but it is unclear whether these associations extend to psychotic symptoms occurring in adolescence in the general population. A symptom-based approach may provide important clues for apparent trans-diagnostic effect of inflammation, which is also associated with depression and other psychiatric disorders. Methods Based on data from 2421 participants from the Avon Longitudinal Study of Parents and Children birth cohort, we examined associations of serum CRP levels assessed around age 16 with ten positive and ten negative symptoms of psychosis assessed using questionnaires around age 17, using both individual symptoms and symptom dimension scores as outcomes. Regression models were adjusted for sex, body mass index, depressive symptoms, substance use, and other potential confounders. Results Most prevalent positive symptoms were paranoid ideation (4.8%), visual (4.3%) and auditory (3.5%) hallucinations. Negative symptoms were more strongly correlated with concurrent depressive symptoms (r=0.51; P < 0.001) than positive symptoms (rpb=0.19; P < 0.001). The associations of CRP with positive and negative symptom dimension scores were similar. At individual symptom level, after adjusting for potential confounders including depressive symptoms, CRP was associated with auditory hallucinations (adjusted OR = 2.22; 95% CI, 1.04–4.76) and anhedonia (adjusted OR = 1.13; 95% CI, 1.02–1.26). Conclusions Inflammation is associated with sub-clinical psychotic symptoms in young people in general population. Association of CRP with symptoms commonly shared between mood and psychotic disorders, such as auditory hallucinations and anhedonia, could be one explanation for the apparent trans-diagnostic effect of inflammation

Social effects of territorial neighbours on the timing of spring breeding in North American red squirrels

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordOrganisms can affect one another’s phenotypes when they socially interact. Indirect genetic effects occur when an individual’s phenotype is affected by genes expressed in another individual. These heritable effects can enhance or reduce adaptive potential, thereby accelerating or reversing evolutionary change. Quantifying these social effects is therefore crucial for our understanding of evolution, yet estimates of indirect genetic effects in wild animals are limited to dyadic interactions. We estimated indirect phenotypic and genetic effects, and their covariance with direct effects, for the date of spring breeding in North American red squirrels (Tamiasciurus hudsonicus) living in an array of territories of varying spatial proximity. Additionally, we estimated indirect effects and the strength of selection at low and high population densities. Social effects of neighbours on the date of spring breeding were different from zero at high population densities but not at low population densities. Indirect phenotypic effects accounted for a larger amount of variation in the date of breeding than differences attributable to the among-individual variance, suggesting social interactions are important for determining breeding dates. The genetic component to these indirect effects was however not statistically significant. We therefore showcase a powerful and flexible method that will allow researchers working in organisms with a range of social systems to estimate indirect phenotypic and genetic effects, and demonstrate the degree to which social interactions can influence phenotypes, even in a solitary species

Physiological stress and spatio-temporal fluctuations of food abundance and population density in Eurasian red squirrels

In continuously changing environments, variation of different ecological factors could affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis in wild mammals, increasing the secretion of glucocorticoids (GCs). In different animal species, GC concentrations are often used as a measure of the physiological stress response to environmental pressures, such as fluctuations in food abundance, population density, intra-and interspecific competition, and predation risk. However, previous studies reported contrasting results or did not find clear associations between physiological stress and environmental variables. Here, we used concentrations of faecal glucocorticoid metabolites (FGMs) as an integrated measure of physiological stress in wild Eurasian red squirrels (Sciurus vulgaris) from three study areas in the Italian Alps, to investigate whether variations in conifer-seed crop size and/or population density affected HPA axis activity. Squirrel density was estimated in each trapping session using the minimum number of animals alive, and annual counts of fresh cones from different conifer species were used to estimate annual food abundance (MJ/ha). We expected higher FGMs in response to increasing population density and/or decreasing food abundance, since these two variables could act as environmental stressors. Our results showed a lack of association between population density and FGMs and a significant effect of food abundance on FGMs. When conifer seed-crops were poor to moderate, FGMs increased with food abundance, while in the range of high seed-crops, FGMs remained first constant and then slightly decreased with a further increase in seed abundance. We also found differences in FGMs among seasons, as previously observed in this species. Our study adds further evidence that physiological stress can be influenced in different ways by environmental pressures and that long-term studies using individually marked animals are needed to disentangle the potential adaptive outcome of the physiological stress response in pulsed resource systems

Serum kynurenic acid is reduced in affective psychosis

A subgroup of individuals with mood and psychotic disorders shows evidence of inflammation that leads to activation of the kynurenine pathway and the increased production of neuroactive kynurenine metabolites. Depression is hypothesized to be causally associated with an imbalance in the kynurenine pathway, with an increased metabolism down the 3-hydroxykynurenine (3HK) branch of the pathway leading to increased levels of the neurotoxic metabolite, quinolinic acid (QA), which is a putative Nmethyl- D-aspartate (NMDA) receptor agonist. In contrast, schizophrenia and psychosis are hypothesized to arise from increased metabolism of the NMDA receptor antagonist, kynurenic acid (KynA), leading to hypofunction of GABAergic interneurons, the disinhibition of pyramidal neurons and striatal hyperdopaminergia. Here we present results that challenge the model of excess KynA production in affective psychosis. After rigorous control of potential confounders and multiple testing we find significant reductions in serum KynA and/or KynA/QA in acutely ill inpatients with major depressive disorder (N = 35), bipolar disorder (N = 53) and schizoaffective disorder (N = 40) versus healthy controls (N = 92). No significant difference was found between acutely ill inpatients with schizophrenia (n = 21) and healthy controls. Further, a post hoc comparison of patients divided into the categories of non-psychotic affective disorder, affective psychosis and psychotic disorder (non-affective) showed that the greatest decrease in KynA was in the affective psychosis group relative to the other diagnostic groups. Our results are consistent with reports of elevations in proinflammatory cytokines in psychosis, and preclinical work showing that inflammation upregulates the enzyme, kynurenine mono-oxygenase (KMO), which converts kynurenine into 3-hydroxykynurenine and quinolinic acid

Optimisation of energetic and reproductive gains explains behavioural responses to environmental variation across seasons and years

Animals switch between inactive and active states, simultaneously impacting their energy intake, energy expenditure and predation risk, and collectively defining how they engage with environmental variation and trophic interactions. We assess daily activity responses to long‐term variation in temperature, resources and mating opportunities to examine whether individuals choose to be active or inactive according to an optimisation of the relative energetic and reproductive gains each state offers. We show that this simplified behavioural decision approach predicts most activity variation (R2 = 0.83) expressed by free‐ranging red squirrels over 4 years, as quantified through accelerometer recordings (489 deployments; 5066 squirrel‐days). Recognising activity as a determinant of energetic status, the predictability of activity variation aggregated at a daily scale, and the clear signal that behaviour is environmentally forced through optimisation of gain, provides an integrated approach to examine behavioural variation as an intermediary between environmental variation and energetic, life‐history and ecological outcomes.By assessing daily activity responses to long‐term variation in temperature, resources, and mating opportunities, we examine whether individuals choose to be active or inactive according to an optimization of energetic and reproductive gains. This simplified behavioural decision approach predicts most daily activity variation (R2 = 0.83) expressed by free‐ranging red squirrels over four years, as quantified through accelerometer recordings. Here we provide an integrated approach to examine behavioural variation as an intermediary between environmental variation and energetic, life‐history, and ecological outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154889/1/ele13494_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154889/2/ele13494.pd

Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation.

INTRODUCTION: Observational studies indicate a potentially causal role for interleukin 6 (IL-6), a proinflammatory cytokine, in pathogenesis of depression, but interventional studies based on patients with depression have not been conducted. Tocilizumab, anti-inflammatory drug, is a humanised monoclonal antibody that inhibits IL-6 signalling and is licensed in the UK for treatment of rheumatoid arthritis. The main objectives of this study are to test whether IL-6 contributes to the pathogenesis of depression and to examine potential mechanisms by which IL-6 affects mood and cognition. A secondary objective is to compare depressed participants with and without evidence of low-grade systemic inflammation. METHODS AND ANALYSIS: This is a proof-of-concept, randomised, parallel-group, double-blind, placebo-controlled clinical trial. Approximately 50 participants with International Classification of Diseases 10th revision (ICD-10) diagnosis of depression who have evidence of low-grade inflammation, defined as serum high-sensitivity C reactive protein (hs-CRP) level ≥3 mg/L, will receive either a single intravenous infusion of tocilizumab or normal saline. Blood samples, behavioural and cognitive measures will be collected at baseline and after infusion around day 7, 14 and 28. The primary outcome is somatic symptoms score around day 14 postinfusion. In addition, approximately, 50 depressed participants without low-grade inflammation (serum hs-CRP level <3 mg/L) will complete the same baseline assessments as the randomised cohort. ETHICS AND DISSEMINATION: The study has been approved by the South Central-Oxford B Research Ethics Committee (REC) (Reference: 18/SC/0118). Study findings will be published in peer-review journals. Findings will be also disseminated by conference/departmental presentations and by social and traditional media. TRIAL REGISTRATION NUMBER: ISRCTN16942542; Pre-results

Validation of a fecal glucocorticoid assay to assess adrenocortical activity in meerkats using physiological and biological stimuli

In mammals, glucocorticoid (i.e. GC) levels have been associated with specific life-history stages and transitions, reproductive strategies, and a plethora of behaviors. Assessment of adrenocortical activity via measurement of glucocorticoid metabolites in feces (FGCM) has greatly facilitated data collection from wild animals, due to its non-invasive nature, and thus has become an established tool in behavioral ecology and conservation biology. The aim of our study was to validate a fecal glucocorticoid assay for assessing adrenocortical activity in meerkats (Suricata suricatta), by comparing the suitability of three GC enzyme immunoassays (corticosterone, 11β-hydroxyetiocholanolone and 11oxo-etiocholanolone) in detecting FGCM increases in adult males and females following a pharmacological challenge with adrenocorticotropic hormone (ACTH) and biological stimuli. In addition, we investigated the time course characterizing FGCM excretion, the effect of age, sex and time of day on FGCM levels and assessed the potential effects of soil contamination (sand) on FGCM patterns. Our results show that the group specific 11β-hydroxyetiocholanolone assay was most sensitive to FGCM alterations, detecting significant and most distinctive elevations in FGCM levels around 25 h after ACTH administration. We found no age and sex differences in basal FGCM or on peak response levels to ACTH, but a marked diurnal pattern, with FGCM levels being substantially higher in the morning than later during the day. Soil contamination did not significantly affect FGCM patterns. Our results emphasize the importance of conducting assay validations to characterize species-specific endocrine excretion patterns, a crucial step to all animal endocrinology studies using a non-invasive approach.SUPPORTING INFORMATION : S1 FILE. Group FGCM response (median ± SE, μg/g) to a natural attack on a group member (ZIM005) that resulted in its permanent eviction. The victim showed the greatest FGCM response to the event. Group FGCM levels returned to baseline levels after the male was removed from the colony. “Within 48 h” represent FGCM levels measured within 2 days after the attack on M5 took place. = p < 0.01 (Fig A). Average (median ± SE) baseline FGCM levels (μg/g) in fecal samples deposited in the morning (AM), at midday (MD) and late afternoon (PM), as measured with the 11β-hydroxyetiocholanolone assay. N = 128 fecal samples from 13 individuals. = p < 0.05 (Fig B). Remove selectedThe Swiss National Science Foundation (grant no. 31003A_13676) to Marta B. Manser, the University of Zurich, and by an ERC grant (no. 294494, THCB2011) to Tim H. Clutton-Brock at the University of Cambridge.http://www.plosone.orgam2016Anatomy and Physiolog

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Serum cytokine and glucose levels as predictors of poststroke fatigue in acute ischemic stroke patients

Fatigue is a common but often overlooked symptom after stroke. This study investigated whether stroke type, infarct volume, and laterality, as well as the levels of various cytokines and other blood components in the acute phase of acute ischemic stroke (AIS), can predict the level of fatigue at 6, 12, and 18 months after its onset. In 45 patients with acute stroke, serum levels of C-reactive protein, hemoglobin, glucose, and 13 cytokines were measured within 72 h of stroke onset. The cytokine measurements were performed using BioPlex XMap technology (Luminex). The acute serum levels of interleukin (IL)-1β and glucose were positively correlated with the score on the Fatigue Severity Scale (FSS) at 6 months after the stroke (r = 0.37, p = 0.015, and r = 0.37, p = 0.017, respectively). The acute serum levels of IL-ra and IL-9 were negatively correlated with FSS score at 12 months after the stroke (r = −0.38, p = 0.013, and r = −0.36, p = 0.019, respectively). The FSS score at 12 months after stroke was significantly lower in patients with radiologically confirmed infarction than in those without such confirmation (p = 0.048). The FSS score at 18 months was not correlated with any of the measured variables. High acute serum levels of glucose and IL-1β, and low IL1-ra and IL-9 may predict fatigue after AIS, indicating that the development of poststroke fatigue can be accounted for by the proinflammatory response associated with AIS. These novel findings support a new cytokine theory of fatigue after stroke. However, more research is needed to validate the results of this study

Increased food availability raises eviction rate in a cooperative breeding mammal

In group-living mammals, the eviction of subordinate females from breeding groups by dominants may serve to reduce feeding competition or to reduce breeding competition. Here, we combined both correlational and experimental approaches to investigate whether increases in food intake by dominant females reduces their tendency to evict subordinate females in wild meerkats ($\textit{Suricata suricatta}$). We used 20 years of long-term data to examine the association between foraging success and eviction rate, and provisioned dominant females during the second half of their pregnancy, when they most commonly evict subordinates. We show that rather than reducing the tendency for dominants to evict subordinates, foraging success of dominant females is positively associated with the probability that pregnant dominant females will evict subordinate females and that experimental feeding increased their rates of eviction. Our results suggest that it is unlikely that the eviction of subordinate females serves to reduce feeding competition and that its principal function may be to reduce reproductive competition. The increase in eviction rates following experimental feeding also suggests that rather than feeding competition, energetic constraints may normally constrain eviction rates.The KMP is supported by the Universities of Cambridge, Zurich and Pretoria. Components of this research were supported by the Natural Environment Research Council (grant no. NE/G006822/1) and the European Research Council (grant no. 294494)