Reglament de l'Institut de Neurociències

Acord del Consell de Govern de 14 de desembre de 200

Memòria científica

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Toll-like receptors as modulators of intestinal barrier function /

BibliografiaPremi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2016-2017Las patologías funcionales (síndrome del intestino irritable, IBS) e inflamatorias gastrointestinales (enfermedad inflamatoria intestinal, IBD) se caracterizan por alteraciones de la función barrera epitelial, con un aumento de la permeabilidad, y cambios en la microbiota intestinal. Los receptores de tipo Toll (TLRs) participan en el reconocimiento bacteriano en el intestino y en el control neuroinmune local, estando, por tanto, implicados en la regulación de la función barrera del epitelio intestinal. El objetivo de este trabajo ha sido caracterizar la implicación de los receptores TLR5 y TLR7 en la regulación de la función barrera epitelial del colon. Para ello se ha caracterizado la función barrera epitelial, tanto en condiciones in vitro (electrofisiología y permeabilidad a macromoléculas en un sistema de cámaras de Ussing), como in vivo (permeabilidad a macromoléculas), tras la sobre-estimulación local de los receptores TLR5 y TLR7 con agonistas selectivos, flagelina e imiquimod, respectivamente, en rata y ratón. Los efectos en la función barrera se han caracterizado en condiciones normales, en estados de permeabilización del epitelio con DMSO, y en condiciones de inflamación (colitis inducida por dextrano sulfato de sodio -DSS-). Con la finalidad de definir el mecanismo de acción, se ha valorado la dinámica de las uniones estrechas epiteliales (expresión génica de proteínas -RT-qPCR- y distribución celular -inmunohistoquímica-) y la activación inmune local (expresión de citoquinas pro-inflamatorias). Los resultados obtenidos muestran que la sobre-estimulación del TLR7 del colon in vivo mejora la función barrera epitelial en la rata en condiciones fisiológicas, observando una reducción dosis-dependiente de la permeabilidad epitelial a macromoléculas evaluada en las cámaras de Ussing. No obstante, en condiciones de permeabilización del epitelio con DMSO, la sobre-estimulación del TLR7 causa un empeoramiento de la función barrera valorada in vivo. En ratones, la sobre-estimulación del TLR7 cólico in vitro no tiene efecto. Sin embargo, en un modelo de colitis inducida por DSS, reduce el aumento de la permeabilidad epitelial causado por la inflamación. Por tanto, parecen existir diferencias especie-específicas en los efectos de la sobre-estimulación del TLR7 cólico, pudiéndose observar tanto acciones promotoras como lesivas de la función barrera epitelial. La sobre-estimulación del TLR5 cólico agrava la disfunción de la barrera asociada a la inflamación (colitis inducida por DSS) en el ratón, incrementando la permeabilidad a macromoléculas. Sin embargo, la adición del agonista del TLR5, flagelina, en las cámaras de Ussing no afecta a la función barrera epitelial, ni en condiciones fisiológicas, ni durante la inflamación. En ningún caso, estos efectos moduladores de la función barrera se asociaron a cambios en la expresión génica de las principales proteínas de las uniones estrechas (claudina-2, claudina-3, ocludina, tricelulina, molécula de adhesión de la unión de tipo 1 y Zonula Occludens 1) ni a su distribución celular (claudina-2, claudina-3 y ZO-1). De la misma forma, los factores moduladores de la barrera, quinasa de la cadena ligera de la miosina y pro-glucagón (precursor del péptido similar al glucagón de tipo 2), tampoco presentaron cambios en su expresión asociados a la sobre-estimulación del TLR5 o del TLR7. Finalmente, se observó un efecto inmunomodulador receptor-específico. La sobre-estimulación del TLR7 reveló efectos potencialmente protectores al reducir la expresión de la citoquina pro-inflamatoria IL12-p40. Por el contrario, la sobre-estimulación del TLR5 tendió a aumentar la expresión de marcadores pro-inflamatorios, sugiriendo, por tanto, efectos pro-lesivos. En conclusión, estos resultados muestran la importancia de las interacciones microbiota-hospedador mediadas por TLRs en el control de la función barrera epitelial intestinal. Tanto el TLR7 como el TLR5 cólicos pueden considerarse potenciales dianas terapéuticas para el control de la función barrera y las respuestas inmunes locales en desórdenes funcionales e inflamatorios gastrointestinales como el IBD y el IBS.Functional (irritable bowel syndrome, IBS) and inflammatory (inflammatory bowel disease, IBD) gastrointestinal disorders are characterized by an altered epithelial barrier function, with an increased permeability, and changes in the intestinal microbiota. Toll-Like Receptors (TLRs) participates in bacterial recognition within the intestine and in local neuro-immune control, thus participating in the regulation of intestinal epithelial barrier function. The objective of this work has been to characterize the implication of TLR5 and TLR7 in the regulation of colonic epithelial barrier function. For this, colonic epithelial barrier function has been studied in vitro (electrophysiology and permeability to macromolecules in a Ussing chamber system), as well as in in vivo conditions (permeability to macromolecules), after the local over-stimulation of TLR5 and TLR7 with selective agonists, flagellin and imiquimod, respectively, in rats and mice. The effects on barrier function have been studied in normal conditions, under states epithelial permeabilization with DMSO, and in conditions of inflammation -dextran sulfate sodium (DSS)-induced colitis-. In order to characterize the mechanisms of action, dynamics of tight junction (gene expression -RT-qPCR- and cellular distribution -immunohistochemistry- of tight junction proteins) and the presence of a local immune activation (gene expression of pro-inflammatory cytokines) were assessed. The results obtained indicate that the in vivo over-stimulation of colonic TLR7 improves epithelial barrier function in rats in physiological conditions, with a dose-dependent reduction in epithelial permeability to macromolecules, as assessed in Ussing chambers. However, under conditions of epithelial permeabilization with DMSO, the over-stimulation of TLR7 deteriorates barrier function, as assessed in vivo. In mice, the in vitro over-stimulation of colonic TLR7 was without effects. However, in a model of DSS-induced colitis, imiquimod reduces inflammation-induced increased epithelial permeability. Therefore, specie-specific differences seemed to exist for the barrier effects associated to the over-stimulation of colonic TLR7, leading to either protective or damaging actions on epithelial barrier function, depending upon the experimental conditions. The over-stimulation of colonic TLR5 aggravates the barrier dysfunction associated to inflammation (DSS-induced colitis) in mice, increasing the permeability to macromolecules. However, the direct addition of flagellin to the Ussing chambers did not affect epithelial barrier function, neither in physiologic conditions nor during inflammation. Regardless the conditions considered, TLR5/7-mediated modulatory actions on barrier function were not associated to changes in gene expression of the main tight junction-related proteins (claudin-2, claudin-3, occludin, tricellulin, junctional adhesion molecule 1 and Zonula Occludens 1). Moreover, no changes in the cellular distribution of tight junction proteins (claudin-2, claudin-3 y ZO-1) was observed. Likewise, TLR5/7 over-stimulation was not associated to changes in the expression of the barrier-modulating factors myosin light chain kinase and proglucagon (precursor of glucagon-like peptide 2). Finally, TLR-specific immunomodulatory effects were also observed. Over-stimulation of TLR7 revealed potential protective effects, reducing the expression of the pro-inflammatory cytokine IL12-p40. In contrast, over-stimulation of TLR5 tended to increase the expression of pro-inflammatory markers, thus suggesting pro-damaging effects. In conclusion, these results provide evidence of the importance of TLRs-dependent host-microbial interactions in the control of intestinal epithelial barrier function. Colonic TLR5 and TLR7 should be considered potential therapeutic targets for the control of barrier function and local immune responses in functional and gastrointestinal disorders, such as IBD and IBS

Millorar la memòria amb adrenalina

Aquesta recerca ha estudiat la influència positiva de l'adrenalina sobre la memòria de reconeixement, en concret per a la identitat i la localització d'un objecte determinat. Aquesta hormona afecta la manera en què el cervell guarda els records. Usant models animals de laboratori, s'ha pogut observar que l'administració d'adrenalina, després de l'entrenament de memòria, allarga la durada del record, en tasques de memòria de reconeixement, fins a deu vegades més que en els animals control.Esta investigación ha estudiado la influencia positiva de la adrenalina sobre la memoria de reconocimiento, en concreto para la identidad y la localización de un objeto determinado. Esta hormona afecta la manera en la que el cerebro guarda los recuerdos. Usando modelos animales de laboratorio, se ha podido observar que la administración de adrenalina, después del entrenamiento de memoria, alarga la duración del recuerdo, en tareas de memoria de reconocimiento, hasta diez veces más que en los animales control

Crosstalk of Alzheimer's disease-phenotype, HPA axis, splenic oxidative stress and frailty in late-stages of dementia, with special concerns on the effects of social isolation : A translational neuroscience approach

Altres ajuts: Envellir bé-Saber envejecer-Healthy Aging.org Memorial Mercedes Llort Sender 2022/81/24091941/02Coping with emotional stressors strongly impacts older people due to their age-related impaired neuroendocrine and immune systems. Elevated cortisol levels seem to be associated with an increased risk of cognitive decline and dementia. In Alzheimer's disease (AD), alterations in the innate immune system result in crosstalk between immune mediators and neuronal and endocrine functions. Besides, neuropsychiatric symptoms such as depression, anxiety, or agitation are observed in most patients. Here, we studied the psychophysiological response to intrinsic (AD-phenotype) and extrinsic (anxiogenic tests) stress factors and their relation to liver, kidneys, heart, and spleen oxidative status in 18-months-old female gold-standard C57BL/6 mice and 3xTg-AD mice model for AD. The emotional, cognitive, and motor phenotypes were assessed under three different anxiogenic conditions. Survival, frailty index, and immunoendocrine status (corticosterone levels and oxidative stress of peripheral organs) were evaluated. Genotype differences in neuropsychiatric-like profiles and cognitive disfunction in 3xTg-AD females that survived beyond advanced stages of the disease persisted despite losing other behavioral and hypothalamic-pituitary-adrenal (HPA) physiological differences. A secondary analysis studied the impact of social isolation, naturally occurring in 3xTg-AD mice due to the death of cage mates. One month of isolation modified hyperactivity and neophobia patterns and disrupt the obsessive-compulsive disorder-like digging ethogram. Frailty index correlated with spleen organometrics in all groups, whereas two AD-specific salient functional correlations were identified: (1) Levels of corticosterone with worse performance in the T-maze, (2) and with a lower splenic GPx antioxidant enzymatic activity, which may suppose a potent risk of morbidity and mortality in AD

Exercici físic i dieta en models animals : efectes emocionals, fisiològics i cognitius

El sedentarisme es podria considerar una de les grans epidèmies del segle XXI. En els darrers 100 anys, els avenços tecnològics i el desenvolupament socioeconòmic han modelat la societat, eliminant gran part del treball físic i alterant els hàbits alimentaris. Les conseqüències d'aquests canvis es fan evidents en un augment de les malalties cardiovasculars, l'obesitat, la diabetis, l'estrès i l'ansietat. Aquesta tesi pretén analitzar les recomanacions sobre activitat física que fan els organismes mundials experts en salut en un model de recerca bàsica. Són adequades les recomanacions d'estil de vida saludable?El sedentarismo se podría considerar una de las grandes epidemias del siglo XXI. En los últimos 100 años, los avances tecnológicos y el desarrollo socioeconómico han modelado la sociedad, eliminando gran parte del trabajo físico y alterando los hábitos alimentarios. Las consecuencias de estos cambios se hacen evidentes en un aumento de las enfermedades cardiovasculares, la obesidad, la diabetes, el estrés y la ansiedad. Esta tesis pretende analizar las recomendaciones sobre actividad física que hacen los organismos mundiales expertos en salud en un modelo de investigación básica. ¿Son adecuadas las recomendaciones sobre un estilo de vida saludable?A sedentary lifestyle could be considered one of the great epidemics of the century. In the past 100 years, technological advances and socioeconomic development have shaped society, eliminating much of the physical work and altering eating habits. The consequences of these changes are evident in increased cardiovascular disease, obesity, diabetes, stress and anxiety. This thesis aims to analyze the physical activity recommendations made by global health organizations in a basic research model. Are recommendations for a healthy lifestyle adequate

Impact of Behavioral Assessment and Re-Test as Functional Trainings That Modify Survival, Anxiety and Functional Profile (Physical Endurance and Motor Learning) of Old Male and Female 3xTg-AD Mice and NTg Mice with Normal Aging

Altres ajuts: UAB-GE-260408; Memorial Mercedes Llort Sender 2021/80/09241941.8Longitudinal approaches for disease-monitoring in old animals face survival and frailty limitations, but also assessment and re-test bias on genotype and sex effects. The present work investigated these effects on 56 variables for behavior, functional profile, and biological status of male and female 3xTg-AD mice and NTg counterparts using two designs: (1) a longitudinal design: naïve 12-month-old mice re-tested four months later; and (2) a cross-sectional design: naïve 16-month-old mice compared to those re-tested. The results confirmed the impact as (1) improvement of survival (NTg rested females), variability of gait (3xTg-AD 16-month-old re-tested and naïve females), physical endurance (3xTg-AD re-tested females), motor learning (3xTg-AD and NTg 16-month-old re-tested females), and geotaxis (3xTg-AD naïve 16-month-old males); but (2) worse anxiety (3xTg-AD 16-month-old re-tested males), HPA axis (3xTg-AD 16-month-old re-tested and naïve females) and sarcopenia (3xTg-AD 16-month-old naïve females). Males showed more functional correlations than females. The functional profile, biological status, and their correlation are discussed as relevant elements for AD-pathology. Therefore, repetition of behavioral batteries could be considered training by itself, with some variables sensitive to genotype, sex, and re-test. In the AD-genotype, females achieved the best performance in physical endurance and motor learning, while males showed a deterioration in most studied variables

Nova descoberta sobre la formació de neurones

Investigadors del Institut de Neurociències i del Departament de Bioquímica i Biologia Molecular de la UAB han definit una via de senyalització intracel·lular clau per a la correcta formació de les neurones. La recerca, liderada pel doctor Jose R. Bayascas, ha estat publicada a Molecular and Cellular Biology, i pot permetre en el futur desenvolupar fàrmacs d'interès terapèutic, especialment en el camp de la psiquiatria.Investigadores del Instituto de Neurociencias y del Departamento de Bioquímica y Biología Molecular de la UAB han definido una vía de señalización intracelular clave para la correcta formación de las neuronas. La investigación, liderada por el doctor Jose R. Bayascas, ha sido publicada en Molecular and Cellular Biology y puede permitir desarrollar fármacos de interés terapéutico en el futuro, especialmente en el campo de la psiquiatría

Social Media Use, Fake News and Mental Health during the Uncertain Times of the COVID-19 Pandemic in Ukraine

Publisher Copyright: © 2023 by the authors.A sample of 351 adults (women/men 4:1) aged 18 to 60 participated in an online survey administered during the first two waves (15 March-25 April and 10 October-25 November 2020) of the COVID-19 pandemic in Ukraine. The user ethnography profile was Generation Z (born in the 1990s), female (81.2%), Instagrammer (60.3%), unmarried (56.9%) and student (42.9%). An increased time spent on social media (3.18 h/day), searching for COVID-19-related information (1.01 h/day) after the first COVID-19 case and the observation of fake news that went viral (58.8%) decreased in the second wave. Alterations (increase or reduction) in sleep patterns (46.7%) and changes (increase or loss) in appetite (32.7%) affected participants' well-being, but only sleep ameliorated in the second wave. Mental health reports unveiled moderate perceived stress (PSS-10: 20.61 ± 1.13) and mild anxiety (GAD-7: 14.17 ± 0.22), which improved in the second wave. A higher prevalence of severe anxiety (8.5%) was found among individuals in the first survey (8.5%) than those in the second (3.3%). Social media counteracted physical distance policies and played as an immediate source of (mis)information for users, but also anticipated the impact of the most uncertain times of this COVID-19 physical health crisis on well-being and mental health

Preferential regeneration and collateral dynamics of motor and sensory neurons after nerve injury in mice

Altres ajuts: acords transformatius de la UABSpecificity in regeneration after peripheral nerve injuries is a major determinant of functional recovery. Unfortunately, regenerating motor and sensory axons rarely find their original pathways to reinnervate appropriate target organs. Although a preference of motor axons to regenerate towards the muscle has been described, little is known about the specificity of the heterogeneous sensory populations. Here, we propose the comparative study of regeneration in different neuron subtypes. Using female and male reporter mice, we assessed the regenerative preference of motoneurons (ChAT-Cre/Ai9), proprioceptors (PV-Cre/Ai9), and cutaneous mechanoreceptors (Npy2r-Cre/Ai9). The femoral nerve of these animals was transected above the bifurcation and repaired with fibrin glue. Regeneration was assessed by applying retrograde tracers in the distal branches of the nerve 1 or 8 weeks after the lesion and counting the retrotraced somas and the axons in the branches. We found that cutaneous mechanoreceptors regenerated faster than other populations, followed by motoneurons and, lastly, proprioceptors. All neuron types had an early preference to regenerate into the cutaneous branch whereas, at long term, all neurons regenerated more through their original branch. Finally, we found that myelinated neurons extend more regenerative sprouts in the cutaneous than in the muscle branch of the femoral nerve and, particularly, that motoneurons have more collaterals than proprioceptors. Our findings reveal novel differences in regeneration dynamics and specificity, which indicate distinct regenerative mechanisms between neuron subtypes that can be potentially modulated to improve functional recovery after nerve injury