Susceptibility to acute cognitive dysfunction in aged mice is underpinned by reduced white matter integrity and microgliosis.

Age is a significant but heterogeneous risk factor for acute neuropsychiatric disturbances such as delirium. Neuroinflammation increases with aging but the determinants of underlying risk for acute dysfunction upon systemic inflammation are not clear. We hypothesised that, with advancing age, mice would become progressively more vulnerable to acute cognitive dysfunction and that neuroinflammation and neuronal integrity might predict heterogeneity in such vulnerability. Here we show region-dependent differential expression of microglial transcripts, but a ubiquitously observed primed signature: chronic Clec7a expression and exaggerated Il1b responses to systemic bacterial LPS. Cognitive frailty (vulnerability to acute disruption under acute stressors LPS and double stranded RNA; poly I:C) was increased in aged animals but showed heterogeneity and was significantly correlated with reduced myelin density, synaptic loss and severity of white matter microgliosis. The data indicate that white matter disruption and neuroinflammation may be key substrates of the progressive but heterogeneous risk for delirium in aged individuals.

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder.

BACKGROUND: Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD. METHODS: We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 µg/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal-Wallis or Mann-Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p < 0.05. For correlation analyses, data were adjusted by a linear regression model. RESULTS: Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5-48 h. LIMITATIONS: We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements. CONCLUSIONS: The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits.

Metaanálisis de generalización de la fiabilidad de los mitos de violación / Meta-analysis of reliability generalization of the rape myths

Resumen Los mitos de violación son actitudes y creencias generalmente falsas, amplias y persistentes, acerca de la violación, la víctima y el agresor, que son utilizadas para negar o justificar la agresión sexual hacia las mujeres. En las últimas dos décadas, los instrumentos más utilizados para medir este constructo corresponden a la escala de aceptación de mitos de violación de Illinois (IRMAS), que utiliza expresiones directas y explícitas mediante un lenguaje clásico, y la escala de aceptación de mitos modernos de agresión sexual (AMMSA) que usa un lenguaje sutil, indirecto y moderno. Se realizó un metaanálisis de generalización de la fiabilidad de 69 estudios empíricos que utilizaron alguna de las dos escalas de mitos de violación. El objetivo fue estimar la fiabilidad media de las puntuaciones combinadas de las escalas IRMAS y AMMSA para obtener un valor aproximado de su fiabilidad general y evaluar el posible efecto moderador de algunas variables de interés. El promedio de la fiabilidad por consistencia interna de las puntuaciones de las escalas para las 98 muestras estudiadas fue de .85, IC95 % [.84, .86]. Se observó una alta heterogeneidad (I. = 96 %), y el número de ítems es la única variable moderadora que explica significativamente la variabilidad de la fiabilidad observada. Estos resultados muestran que ambas escalas presentan índices de consistencia interna aceptables en sus diversas aplicaciones. Por lo tanto, las medidas de aceptación de mitos de violación cumplen con los criterios de fiabilidad adecuados para ser utilizadas en investigaciones empíricas en distintos contextos.

Abstract Rape myths are widespread and persistent attitudes, beliefs, and stereotypes, usually false, about rape, the victim, and the perpetrator. Their function is to deny and justify sexual assaults against women, affecting the victim's attributions of responsibility and the perpetrator's attributions of guilt in rape cases. These myths exert a bias in the processing of information, directing attention and perception toward stimuli that justify the victim's responsibility for sexual aggression. These beliefs can be grouped into several types of myths: Myths that hold the victim responsible by arguing that women should be careful and not expose themselves to avoid sexual aggression, myths that justify and reduce the responsibility of the aggressor by stating that the man could not contain his sexual desire and those myths that deny or normalize sexual aggression, which propose that rape occurs only in very specific contexts. In the last two decades, the instruments most commonly used to measure these beliefs are The Illinois Rape Myth Acceptance Scale (IRMAS), which uses direct and explicit expressions through classic language, and the Modern Sexual Assault Myth Acceptance Scale (AMMSA), where its expressions are modern, subtle and indirect. Considering the wide use of these instruments, it is justified to provide empirical evidence showing information on the psychometric properties of these scales. One of the procedures for synthesizing empirical results is meta-analyses (MA). This methodology can synthesize studies of specific variables and analyze the psychometric properties of the measurement instruments, providing relevant information on the quality of a given scale. Within this last type of RM are reliability generalizations (RG), those that study the reliability coefficients obtained in different applications of a scale, providing evidence on the properties of the measures used in measuring a construct. A meta-analysis of the RGs of 69 empirical studies that used any of the rape myth scales was performed. The objective was to estimate the mean reliability of the combined scores of the IRMAS and AMMSA scales to obtain an approximate value of their overall reliability and to assess the possible moderating effect of some variables of interest (e.g., research design, culture, sample type, etc.). The mean internal consistency reliability of the scale scores for the 98 samples studied was .85, 95 % C.I. [.84, .86] and the mean coefficient for each of the IRMAS and AMMSA scales was .84 and .85 respectively. All these values are above .80, a value established as satisfactory reliability of the instrument for general research. The Cronbach's alpha coefficients reported by the studies ranged from .71 to .98, with values considered moderate to excellent. These results show that both scales present acceptable internal consistency indices in various applications. There is high heterogeneity (I. = 96 %), with the number of items being the only moderating variable significantly explaining the observed reliability variability. This result was to be expected, given that the effect of test length on the estimation of reliability indices has a long tradition and is widely known in the psychometric literature.

Modern Rape Myths: Justifying Victim and Perpetrator Blame in Sexual Violence.

Rape myths are beliefs, stereotypes, and attitudes usually false, widespread, and persistent about rape, victims, and perpetrators. They aim to deny and justify men's sexual assault against women. This study evaluates the mediating effect of modern rape myths on the relationship between gender system justification and attribution of blame to both victim and perpetrator in a fictional case of sexual violence. A total of 375 individuals residing in Chile, 255 women and 120 men, 19-81 years (M = 37.6 SD = 13.06) participated in the study. Results from a Structural Equation Model show that gender system justification is directly related to the attribution of blame to the victim, showing an indirect relationship throughout the modern rape myth. However, gender system justification and attribution of blame to the aggressor are indirectly related, being mediated by modern rape myths. The study of the relationship between the acceptance of modern rape myths, gender-specific system justification, and victim and aggressor blame for rape is a contribution to understanding beliefs justifying sexual violence against women.

Mitos de violación, creencias que justifican la violencia sexual: una revisión sistemática / Rape myths, beliefs that justify sexual violence: a systematic review / Mitos do estupro, crenças que justificam a violência sexual: uma revisão sistemática

Resumen En investigación social existe una importante línea de estudios que intentan comprender el fenómeno de la violencia sexual. Un constructo que ha centrado el interés de no pocos investigadores corresponde al de "mitos de violación". Este concepto agrupa creencias erróneas respecto a la atribución de culpabilidad del agresor y la responsabilidad de la víctima en caso de violación sexual. El objetivo del presente artículo fue realizar una revisión sistemática de los estudios empíricos que reportan evidencia acerca de la relación entre la aceptación de mitos de violación y variables psicosociales. Las bases de datos consultadas fueron, ProQuest, Web of Science, Scopus, PsycINFO, EBSCOhost y JSTOR. Se seleccionaron estudios empíricos en español e inglés publicados entre los años 2009 y 2019. Se encontraron 96 artículos que cumplían con los criterios de selección. Dentro de los resultados el 63,4 % de las investigaciones se desarrollaron en Estados Unidos, 24,7 % en países de Europa y solo 1 % en América Latina. Los hallazgos muestran que los hombres son los que mantienen mayores niveles de aceptación de los mitos de violación en la mayoría de los estudios. Además, se encontraron relaciones con variables como violencia interpersonal y violencia sexual, rasgos de personalidad, variables ideológicas, psicosociales, sexuales y de género. Finalmente se discute sus implicancias y limitaciones.

Abstract In social research, there is an important line of studies that try to understand the phenomenon of sexual violence. A construct that has focused the interest of not a few researchers corresponds to that of "rape myths". This concept brings together a set of erroneous beliefs regarding the attribution of guilt of the aggressor and the responsibility of the victim in case of rape. The objective of this study was to conduct a systematic review of empirical studies that have reported evidence about the relationship between the acceptance of rape myths and psychosocial variables. The databases consulted were, ProQuest, Web of Science, Scopus, PsycINFO, EBSCOhost, JSTOR. We selected empirical studies in Spanish and English that have been published between 2009 and 2019. We found 96 articles that met the selection criteria. Within the results, 63.4% of the studies have been developed in the United States, 24.7% in European countries and only one in Latin America (1.0%). The findings show that men maintain the highest levels of acceptance of rape myths in most studies. In addition, relationships have been found with variables such as interpersonal violence and sexual violence, personality traits, ideological, psychosocial, sexual and gender variables. Finally, its implications and limitations are discussed.

Resumo Na pesquisa social, há uma importante linha de estudos que tentam entender o fenômeno da violência sexual. Uma construção que tem focado o interesse de poucos pesquisadores corresponde à de "mitos do estupro". Esse conceito reúne um conjunto de crenças errôneas sobre a atribuição de culpa do agressor e a responsabilidade da vítima em caso de estupro. O objetivo deste estudo foi realizar uma revisão sistemática de estudos empíricos que relataram evidências sobre a relação entre a aceitação de mitos de estupro e variáveis psicossociais. As bases de dados consultadas foram: ProQuest, Web of Science, Scopus, PsycINFO, EBSCOhost, JSTOR. Selecionamos estudos empíricos em espanhol e inglês que foram publicados entre 2009 e 2019. Encontramos 96 artigos que atenderam aos critérios de seleção. Dentro dos resultados, 63,4% dos estudos foram desenvolvidos nos Estados Unidos, 24,7% em países europeus e apenas um na América Latina (1,0%). Os achados mostram que os homens mantêm os mais altos níveis de aceitação dos mitos do estupro na maioria dos estudos. Além disso, têm sido encontradas relações com variáveis como violência interpessoal e violência sexual, traços de personalidade, variáveis ideológicas, psicossociais, sexuais e de gênero. Finalmente, suas implicações e limitações são discutidas.

Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1ß drives amplified responses in primed astrocytes and neuronal network dysfunction.

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin-1ß (IL-1ß) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL-1ß. Systemic LPS triggered microglial IL-1ß, astrocytic chemokines, IL-6, and acute cognitive dysfunction, whereas IL-1ß disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL-1ß and IL-6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans.

Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analogue poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disorders including schizophrenia, autism, Parkinson's disease and Alzheimer's disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1-6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF-α responses than poly I:C of < 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFNß nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFNß binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1ß and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length-, IFNAR1- and age-dependent effects on anti-viral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

Double stranded RNA drives innate immune responses, sickness behavior and cognitive impairment dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analog poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disease including autism, schizophrenia, Parkinsons disease and Alzheimers disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1 to 6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF alpha responses than poly I:C of less than 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFN beta nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFN beta binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1beta and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length, IFNAR1 and age-dependent effects on antiviral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice.

Locus coeruleus (LC)-derived noradrenaline is important in cognition and decreases with age, but the impact of prior noradrenaline deficiency on vulnerability to inflammation-induced acute cognitive dysfunction is unclear. Here we assessed whether noradrenergic depletion, in female mice, impacted upon inflammation, locomotor activity and working memory directly after acute systemic immune challenge with bacterial lipopolysaccharide (LPS), a paradigm we have previously used to capture delirium-like acute cognitive deficits. Mice received 2 doses of the LC-selective noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg i.p.) and were challenged, 2 weeks later, with LPS (100 µg/kg i.p.). DSP-4 dramatically reduced noradrenaline concentrations and tyrosine hydroxylase-positive afferents in the frontal cortex and hippocampus. This did not significantly alter numbers of Pu.1-positive microglia, Iba1-positive microglial morphology or mRNA expression of microglia-associated gene transcripts (Tyrobp, Sall1, Cd68, Sra2, Clec7a) in the hippocampus or frontal cortex and produced modest reductions in Cx3cr1 and P2ry12. LPS induced blood and brain cytokine levels, cFOS activation and locomotor responses that were highly similar in DSP-4- and vehicle-treated mice, although LPS-induced plasma TNF-α was significantly reduced in those treated with DSP-4. Importantly, prior noradrenergic depletion did not predispose to LPS-induced T-maze working memory deficits. The data demonstrate that significant depletion of noradrenaline in the hippocampus and frontal cortex does not prompt acutely exaggerated neuroinflammation or leave the brain vulnerable to acute, transient working memory deficits upon low dose LPS challenge. These findings have implications for our understanding of the impact of systemic inflammation on the aging and vulnerable brain during septic encephalopathy and delirium.

Evidence for a Bifactor Structure of the Caregiving Questionnaire with Individuals Involved in Different and Same-Sex Couple Relationships.

Despite the Caregiving Questionnaire (CQ) being a widely used measure for the study of caregiving behavior in the context of romantic relationships, to date, few studies have focused on empirically evaluating its underlying theoretical structure. The aim of this study was to examine the factorial structure and equivalence across sex and sexual orientation of this instrument. A sample of 912 Chilean individuals currently involved in a couple relationship completed the Caregiving Questionnaire and the Experiences in Close Relationship Scale. After comparing various traditional Confirmatory Factor Analysis (CFA)models, the results provide support for a multidimensional and hierarchical nature of a brief 16-items version of the CQ. More specifically, the analyses supported a bifactor-CFA solution composed of two global factors and four specific factors, suggesting that they add information to the caregiving construct in the context of couple relationships. Additionally, the scale showed measurement invariance across sex and sexual orientation. Finally, significant associations were found between CQ scores with measures of romantic attachment in the expected directions. Theoretical implications about the nature of the caregiving system are discussed.

Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium.

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1ß (25 µg/kg) but not prevented in IL-1RI-/- mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1ß synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1ß trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus "bioenergetic stress" drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium.

Correction: Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

Following publication of this article, the authors noticed an error in the abstract, where they incorrectly stated that: "Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-/--dependent fashion". This has now been corrected to: "Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion". The authors would like to apologise for this error. This has been corrected in both the PDF and HTML versions of the article.

Chronic neurodegeneration induces type I interferon synthesis via STING, shaping microglial phenotype and accelerating disease progression.

Type I interferons (IFN-I) are the principal antiviral molecules of the innate immune system and can be made by most cell types, including central nervous system cells. IFN-I has been implicated in neuroinflammation during neurodegeneration, but its mechanism of induction and its consequences remain unclear. In the current study, we assessed expression of IFN-I in murine prion disease (ME7) and examined the contribution of the IFN-I receptor IFNAR1 to disease progression. The data indicate a robust IFNß response, specifically in microglia, with evidence of IFN-dependent genes in both microglia and astrocytes. This IFN-I response was absent in stimulator of interferon genes (STING-/- ) mice. Microglia showed increased numbers and activated morphology independent of genotype, but transcriptional signatures indicated an IFNAR1-dependent neuroinflammatory phenotype. Isolation of microglia and astrocytes demonstrated disease-associated microglial induction of Tnfα, Tgfb1, and of phagolysosomal system transcripts including those for cathepsins, Cd68, C1qa, C3, and Trem2, which were diminished in IFNAR1 and STING deficient mice. Microglial increases in activated cathepsin D, and CD68 were significantly reduced in IFNAR1-/- mice, particularly in white matter, and increases in COX-1 expression, and prostaglandin synthesis were significantly mitigated. Disease progressed more slowly in IFNAR1-/- mice, with diminished synaptic and neuronal loss and delayed onset of neurological signs and death but without effect on proteinase K-resistant PrP levels. Therefore, STING-dependent IFN-I influences microglial phenotype and influences neurodegenerative progression despite occurring secondary to initial degenerative changes. These data expand our mechanistic understanding of IFN-I induction and its impact on microglial function during chronic neurodegeneration.

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1ß replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1ß synthesis. Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1ß but direct hippocampal action of IL-1ß causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

Application of a Framework to Implement Trauma-Informed Care Throughout a Pediatric Health Care Network.

INTRODUCTION: To evaluate the initial application of a recently published three-step framework for implementing trauma-informed care (TIC) in a pediatric health care network by applying Framework for Spread. METHODS: In steps 1 and 2 of the framework, we established commitment from the health care network leadership and initial interest in TIC among clinical providers (step 1), set evidence-based training goals and created the associated TIC training content (step 2). In step 3, 440 health care professionals (from 27 health care teams) participated in single-session, 1-hour training that covered the psychological impact of injury- and illness-related trauma, identification of traumatic stress symptoms, and how to respond to children exposed to potentially traumatic events. A concomitant quality improvement project allowed us to assess potential changes in training participants' favorable attitudes toward the integration of TIC and confidence in delivering TIC. RESULTS: Compared with pretraining, participants demonstrated increases in attitude toward TIC, t(293) = 5.8, P < .001, Cohen's d = 0.32, and confidence in delivering TIC, t(293) = 20.9, P < .001, Cohen's d = 1.09. DISCUSSION: Trainings were effective in achieving proximal goals targeting attitudes and confidence, thereby demonstrating the feasibility and clinical relevance of TIC training when implemented according to the three-step framework. Future research should examine methods of training to reach wide audiences to promote systematic change and evaluate changes in patient outcomes associated with providers' implementation of TIC.

Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration.

Inflammation influences chronic neurodegeneration but its precise roles are not yet clear. Systemic inflammation caused by infection, trauma or co-morbidity can alter the brain's inflammatory status, produce acute cognitive impairments, such as delirium, and drive new pathology and accelerated decline. Consistent with this, elevated systemic TNF-α is associated with more rapid cognitive decline over 6months in Alzheimer's disease patients. In the current study we challenged normal animals and those with existing progressive neurodegeneration (ME7 prion disease) with TNF-α (i.p.) to test the hypothesis that this cytokine has differential effects on cognitive function, sickness behavior and features of underlying pathology contingent on the animals' baseline condition. TNF-α (50µg/kg) had no impact on performance of normal animals (normal brain homogenate; NBH) on working memory (T-maze) but produced acute impairments in ME7 animals similarly challenged. Plasma TNF-α and CCL2 levels were equivalent in NBH and ME7 TNF-challenged animals but hippocampal and hypothalamic transcription of IL-1ß, TNF-α and CCL2 and translation of IL-1ß were higher in ME7+TNF-α than NBH+TNF-α animals. TNF-α produced an exaggerated sickness behavior response (hypothermia, weight loss, inactivity) in ME7 animals compared to that in NBH animals. However a single challenge with this dose was not sufficient to produce de novo neuronal death, synaptic loss or tau hyperphosphorylation that was distinguishable from that arising from ME7 alone. The data indicate that acutely elevated TNF-α has robust acute effects on brain function, selectively in the degenerating brain, but more sustained levels may be required to significantly impact on underlying neurodegeneration.

Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C.

Type I interferons (IFN-I) are expressed in the brain during many inflammatory and neurodegenerative conditions and have multiple effects on CNS function. IFN-I is readily induced in the brain by systemic administration of the viral mimetic, poly I:C (synthetic double-stranded RNA). We hypothesised that IFN-I contributes to systemically administered poly I:C-induced sickness behaviour, metabolic and neuroinflammatory changes. IFN-I receptor 1 deficient mice (IFNAR1(-/-)) displayed significantly attenuated poly I:C-induced hypothermia, hypoactivity and weight loss compared to WT C57BL/6 mice. This amelioration of sickness was associated with equivalent IL-1ß and TNF-α responses but much reduced IL-6 responses in plasma, hypothalamus and hippocampus of IFNAR1(-/-) mice. IFN-ß injection induced trivial IL-6 production and limited behavioural change and the poly I:C-induced IFN-ß response did not preceed, and would not appear to mediate, IL-6 induction. Rather, IFNAR1(-/-) mice lack basal IFN-I activity, have lower STAT1 levels and show significantly lower levels of several inflammatory transcripts, including stat1. Basal IFN-I activity appears to play a facilitatory role in the full expression of the IL-6 response and activation of the tryptophan-kynurenine metabolism pathway. The deficient IL-6 response in IFNAR1(-/-) mice partially explains the observed incomplete sickness behaviour response. Reconstitution of circulating IL-6 revealed that the role of IFNAR in burrowing activity is mediated via IL-6, while IFN-I and IL-6 have additive effects on hypoactivity, but the role of IFN-I in anorexia is independent of IL-6. Hence, we have demonstrated both interdependent and independent roles for IFN-I and IL-6 in systemic inflammation-induced changes in brain function.

Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium.

BACKGROUND: Delirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e., cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk. METHODS: Humans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by Mini-Mental State Exam (MMSE) (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 weeks, and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100 µg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry. RESULTS: In the Vantaa cohort, 465 persons (88.4 ± 2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p = 0.02). LPS precipitated severe and fluctuating cognitive deficits in 16-week ME7 mice but lower incidence or no deficits in 12-week ME7 and controls, respectively. This was associated with progressive thalamic synaptic loss and axonal pathology. CONCLUSION: A human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology.

Endogenous IL-1 in cognitive function and anxiety: a study in IL-1RI-/- mice.

Interleukin-1 (IL-1) is a key pro-inflammatory cytokine, produced predominantly by peripheral immune cells but also by glia and some neuronal populations within the brain. Its signalling is mediated via the binding of IL-1α or IL-1ß to the interleukin-1 type one receptor (IL-1RI). IL-1 plays a key role in inflammation-induced sickness behaviour, resulting in depressed locomotor activity, decreased exploration, reduced food and water intake and acute cognitive deficits. Conversely, IL-1 has also been suggested to facilitate hippocampal-dependent learning and memory: IL-1RI(-/-) mice have been reported to show deficits on tasks of visuospatial learning and memory. We sought to investigate whether there is a generalised hippocampal deficit in IL-1RI(-/-) animals. Therefore, in the current study we compared wildtype (WT) mice to IL-1RI(-/-) mice using a variety of hippocampal-dependent learning and memory tasks, as well as tests of anxiety and locomotor activity. We found no difference in performance of the IL-1RI(-/-) mice compared to WT mice in a T-maze working memory task. In addition, the IL-1RI(-/-) mice showed normal learning in various spatial reference memory tasks including the Y-maze and Morris mater maze, although there was a subtle deficit in choice behaviour in a spatial discrimination, beacon watermaze task. IL-1RI(-/-) mice also showed normal memory for visuospatial context in the contextual fear conditioning paradigm. In the open field, IL-1RI(-/-) mice showed a significant increase in distance travelled and rearing behaviour compared to the WT mice and in the elevated plus-maze spent more time in the open arms than did the WT animals. The data suggest that, contrary to prior studies, IL-1RI(-/-) mice are not robustly impaired on hippocampal-dependent memory and learning but do display open field hyperactivity and decreased anxiety compared to WT mice. The results argue for a careful evaluation of the roles of endogenous IL-1 in hippocampal and limbic system function.

Cyclooxygenase-1-dependent prostaglandins mediate susceptibility to systemic inflammation-induced acute cognitive dysfunction.

Systemic inflammatory events often precipitate acute cognitive dysfunction in elderly and demented populations. Delirium is a highly prevalent neuropsychiatric syndrome that is characterized by acute inattention and cognitive dysfunction, for which prior dementia is the major predisposing factor and systemic inflammation is a frequent trigger. Inflammatory mechanisms of delirium remain unclear. We have modeled aspects of delirium during dementia by exploiting progressive neurodegeneration in the ME7 mouse model of prion disease and by superimposing systemic inflammation induced by the bacterial endotoxin lipopolysaccharide (LPS). Here, we have used this model to demonstrate that the progression of underlying disease increases the incidence, severity, and duration of acute cognitive dysfunction. This increasing susceptibility is associated with increased CNS expression of cyclooxygenase (COX)-1 in microglia and perivascular macrophages. The COX-1-specific inhibitor SC-560 provided significant protection against LPS-induced cognitive deficits, and attenuated the disease-induced increase in hippocampal and thalamic prostaglandin E2, while the COX-2-specific inhibitor NS-398 was ineffective. SC-560 treatment did not alter levels of the proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, or C-X-C chemokine ligand 1 in blood or brain, but systemic IL-1RA blocked LPS-induced cognitive deficits, and systemic IL-1ß was sufficient to induce similar deficits in the absence of LPS. Furthermore, the well tolerated COX inhibitor ibuprofen was protective against IL-1ß-induced deficits. These data demonstrate that progressive microglial COX-1 expression and prostaglandin synthesis can underpin susceptibility to cognitive deficits, which can be triggered by systemic LPS-induced IL-1ß. These data contribute to our understanding of how systemic inflammation and ongoing neurodegeneration interact to induce cognitive dysfunction and episodes of delirium.