High-fat diet alters stress behavior, inflammatory parameters and gut microbiota in Tg APP mice in a sex-specific manner

Long-term high-fat diet (HFD) consumption commonly leads to obesity, a major health concern of western societies and a risk factor for Alzheimer's disease (AD). Both conditions present glial activation and inflammation and show sex differences in their incidence, clinical manifestation, and disease course. HFD intake has an important impact on gut microbiota, the bacteria present in the gut, and microbiota dysbiosis is associated with inflammation and certain mental disorders such as anxiety. In this study, we have analyzed the effects of a prolonged (18 weeks, starting at 7 months of age) HFD on male and female mice, both wild type (WT) and TgAPP mice, a model for AD, investigating the behavioral profile, gut microbiota composition and inflammatory/phagocytosis-related gene expression in hippocampus. In the open-field test, no overt differences in motor activity were observed between male and female or WT and TgAPP mice on a low-fat diet (LFD). However, HFD induced anxiety, as judged by decreased motor activity and increased time in the margins in the open-field, and a trend towards increased immobility time in the tail suspension test, with increased defecation. Intriguingly, female TgAPP mice on HFD showed less immobility and defecation compared to female WT mice on HFD. HFD induced dysbiosis of gut microbiota, resulting in reduced microbiota diversity and abundance compared with LFD fed mice, with some significant differences due to sex and little effect of genotype. Gene expression of pro-inflammatory/phagocytic markers in the hippocampus were not different between male and female WT mice, and in TgAPP mice of both sexes, some cytokines (IL-6 and IFN¿) were higher than in WT mice on LFD, more so in female TgAPP (IL-6). HFD induced few alterations in mRNA expression of inflammatory/phagocytosis-related genes in male mice, whether WT (IL-1ß, MHCII), or TgAPP (IL-6). However, in female TgAPP, altered gene expression returned towards control levels following prolonged HFD (IL-6, IL-12ß, TNF¿, CD36, IRAK4, PYRY6). In summary, we demonstrate that HFD induces anxiogenic symptoms, marked alterations in gut microbiota, and increased expression of inflammatory genes, except for female TgAPP that appear to be resistant to the diet effects. Lifestyle interventions should be introduced to prevent AD onset or exacerbation by reducing inflammation and its associated symptoms; however, our results suggest that the eventual goal of developing prevention and treatment strategies should take sex into consideration.This work was supported by Ministerio de Economía, Industria y Competitividad (MINECO), Grant Numbers BFU2014-51836-C2-1-R to LMGS and MAA, BFU2014-51836-C2-2-R and BFU2017-82565-C21-R2 to JAC; Madrid Council S2010/BMD-2349 to MLC; Centre for Biomedical Network Research for Physiopathology of Obesity and Nutrition (CIBEROBN) to JAC, Centre for Biomedical Network Research for Frailty and Healthy Ageing (CIBERFES) to LMGS and MAA, and Centre for Biomedical Network Research for Neurodegenerative Diseases (CIBERNED) to MLC. AC-C was granted with a FPI fellowship by the MINECO (BES-2015-072980)

Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice

While gap junctions mediate intercellular communication and support liver homeostasis, connexin hemichannels are preferentially opened by pathological stimuli, including inflammation and oxidative stress. The latter are essential features of non-alcoholic steatohepatitis. In this study, it was investigated whether connexin32 and connexin43 hemichannels play a role in non-alcoholic steatohepatitis. Mice were fed a choline-deficient high-fat diet or normal diet for 8 weeks. Thereafter, TAT-Gap24 or TAT-Gap19, specific inhibitors of hemichannels composed of connexin32 and connexin43, respectively, were administered for 2 weeks. Subsequently, histopathological examination was carried out and various indicators of inflammation, liver damage and oxidative stress were tested. In addition, whole transcriptome microarray analysis of liver tissue was performed. Channel specificity of TAT-Gap24 and TAT-Gap19 was examined in vitro by fluorescence recovery after photobleaching analysis and measurement of extracellular release of adenosine triphosphate. TAT-Gap24 and TAT-Gap19 were shown to be hemichannel-specific in cultured primary hepatocytes. Diet-fed animals treated with TAT-Gap24 or TAT-Gap19 displayed decreased amounts of liver lipids and inflammatory markers, and augmented levels of superoxide dismutase, which was supported by the microarray results. These findings show the involvement of connexin32 and connexin43 hemichannels in non-alcoholic steatohepatitis and, simultaneously, suggest a role as potential drug targets in non-alcoholic steatohepatitis

Seguimiento de las recomendaciones sobre psicofarmacología y su repercusión conductual en la discapacidad intelectual

En la población con discapacidad intelectual -DI- hay una elevada morbilidad psiquiátricaconductual. Se estima que por este motivo entre un tercio y tres cuartos de estas personas reciben antipsicóticos. Existe un consenso de expertos para guiar la toma de decisiones farmacoterapéuticas en estos casos. Su aplicación conseguiría una mayor eficacia del tratamiento, reduciendo los problemas conductuales, mejorando las habilidades adaptativas. El ICAP Inventory for client and agency planning es un instrumento para valoración y evaluación de servicios para personas con DI, que incluye escalas para puntuación de problemas conductuales y de conductas adaptativas. Para determinar la asociación entre el seguimiento de las recomendaciones farmacoterapeuticas de los expertos y las puntuaciones de los problemas conductuales y las habilidades adaptativas en un grupo de sujetos con DI, se realizó un estudio observación transversal. El tratamiento farmacológico recibido por cada sujeto de un colectivo de sujetos diagnosticados de DI -CIE-10- se clasificó como conforme o no con las recomendaciones de la guía en lo referente a los criterios de indicación, dosis, duración y polifarmacia. Se compararon las puntuaciones de conducta adaptativa y de problemas de conducta del ICAP en función de la conformidad del tratamiento con los criterios. El cumplimiento del criterio de dosis se asoció con mejor conducta adaptativa -p menor que 0,05-, el cumplimiento de los criterios de duración y polifarmacia se asociaron con menores problemas de conducta -p menor que 0,05-. No hubo asociación entre cumplimiento del criterio de indicación con la puntuación de problemas de conducta, ni de las habilidades adaptativas

Concepts, Capabilities, and Limitations of Global Models : A Review

International audienceFor researchers wishing to generate an understanding of complex plasma systems, global models often present an attractive first step, mainly due to their ease of development and use. These volume averaged models are able to give descriptions of plasmas with complex chemical kinetics, and without the computationally intensive numerical methods required for spatially resolved models. This paper gives a tutorial on global modeling, including development and techniques, and provides a discussion on the issues and pitfalls that researchers should be aware of. Further discussion is provided in the form of two reviews on methods of extending global modeling techniques to encompass variations in either time or space

Aging and sex: Impact on microglia phagocytosis

Microglia dysfunction and activation are important hallmarks of the aging brain and are concomitant with age-related neurodegeneration and cognitive decline. Age-associated changes in microglia migration and phagocytic capacity result in maladaptive responses, chronic neuroinflammation, and worsened outcomes in neurodegenerative disorders. Given the sex bias in the incidence, prevalence, and therapy response of most neurological disorders, we have here examined whether the phagocytic activity of aged microglia is different in males and females. With this aim, the phagocytosis activity of male and female cells was compared in an in vitro aged microglia model and in microglia isolated from adult (5-month-old) or aged (18-month-old) mice. In both models, the phagocytosis of neural debris increased with aging in male and female cells and was higher in aged female microglia than in aged male cells. However, female aged microglia lost its ability to adapt its phagocytic activity to inflammatory conditions. These findings suggest that microglia phagocytosis of neural debris may represent a previously unexplored neuroprotective characteristic of aged microglia that may contribute to the generation of sex differences in the manifestation of neurodegenerative diseases.The study was supported by a grant from Agencia Estatal de Investigación (AEI), co-funded by Fondo Europeo de Desarrollo Regional (FEDER): BFU2017-82754-R and by CIBERFES

Estrogenic Regulation of Glia and Neuroinflammation

Estrogens are rapid and potent facilitators of synaptic plasticity in the adult brain; however, the steps that link estrogens to factors that regulate synaptic strength remain unclear. The present chapter will first review the acute effects of 17β‎-estradiol on synaptic transmission and long-term potentiation (LTP). It will then describe a synaptic model used to study the substrates of LTP and provide evidence for the ability of estradiol to rapidly engage a selective actin signaling cascade associated with the consolidation of LTP. Finally, it will be shown that chronic reductions in estradiol levels disrupt LTP and actin dynamics but can be reversed by acute infusions of the hormone. It is concluded here that estradiol can promote learning-related plasticity by modifying the synaptic cytoskeleton.Authors acknowledge economic support from Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Spain

Curso CSIC: Una visión actualizada de la neurociencia desde el Instituto Cajal

El impresionante avance de la investigación en Neurociencia del último siglo ha arrojado luz acerca de la estructura y funcionamiento del sistema nervioso central. La Neurociencia ha experimentado increíbles avances que han permitido no sólo ampliar nuestro conocimiento acerca de cómo funcionan procesos mentales como la memoria o el aprendizaje, sino también diseñar terapias específicas para enfermedades neurodegenerativas o desarrollar tecnologías de elevado impacto social como es el caso de la inteligencia artificial. En este curso, se hará un recorrido general sobre la historia de la Neurociencia, incidiendo en la estructura macroscópica y microscópica del cerebro y médula espinal, así como patologías asociadas al desarrollo y en el adulto. También se comentarán los últimos datos acerca de disciplinas asociadas como la inteligencia artificial y los trastornos de la conducta alimentaria, así como campos emergentes como la Neuroeducación. Finalmente, se plantearán las técnicas y modelos disponibles para el estudio de la Neurociencia, y se propondrán fuentes para la búsqueda de noticias y recursos científicos fiables

Connexin and pannexin (hemi)channels : emerging targets in the treatment of liver disease

Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin-like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin-based and pannexin-based channels in noncancerous liver disease