14-3-3 proteins interact with the beta-thymosin repeat protein Csp24.

Conditioned stimulus pathway protein 24 (Csp24) is a beta-thymosin-like protein that is homologous to other members of the family of beta-thymosin repeat proteins that contain multiple actin binding domains. Actin co-precipitates with Csp24 and co-localizes with it in the cytosol of type-B photoreceptor cell bodies. Several signal transduction pathways have been shown to regulate the phosphorylation of Csp24 and contribute to cellular plasticity. Here, we report the identification of the adapter protein 14-3-3 in lysates of the Hermissenda circumesophageal nervous system and its interaction with Csp24. Immunoprecipitation experiments using an antibody that is broadly reactive with several isoforms of the 14-3-3 family of proteins showed that Csp24 co-precipitates with 14-3-3 protein, and nervous systems stimulated with 5-HT exhibited a significant increase in co-precipitated Csp24 probed with a phosphospecific antibody as compared with controls. These results indicate that post-translational modifications of Csp24 regulate its interaction with 14-3-3 protein, and suggest that this mechanism may contribute to the control of intrinsic enhanced excitability.

Infection of organotypic slice cultures from rat central nervous tissue with Neospora caninum: an alternative approach to study host-parasite interactions

Neospora caninum is an apicomplexan parasite which has emerged as an important cause of bovine abortion worldwide. Abortion is usually triggered by reactivation of dormant bradyzoites during pregnancy and subsequent congenital infection of the foetus, where the central nervous system appears to be most frequently affected. We here report on an organotypic tissue culture model for Neospora infection which can be used to study certain aspects of the cerebral phase of neosporosis within the context of a three-dimensionally organised neuronal network. Organotypic slice cultures of rat cortical tissue were infected with N. caninum tachyzoites, and the kinetics of parasite proliferation, as well as the proliferation-inhibitory effect of interferon-gamma (IFN-gamma), were monitored by either immunofluorescence, transmission electron microscopy, and a quantitative PCR-assay using the LightCycler instrument, respectively. In addition, the neuronal cytoskeletal elements, namely glial acidic protein filaments as well as actin microfilament bundles were shown to be largely colocalising with the pseudocyst periphery. This organotypic culture model for cerebral neosporosis provides a system, which is useful to study the proliferation, ultrastructural characteristics, development, and the interactions of N. caninum within the context of neuronal tissue, which at the same time can be modulated and influenced under controlled conditions, and will be useful in the future to gain more information on the cerebral phase of neosporosis.

The Gut Microbiome and Cirrhosis: Basic Aspects

In this chapter the basic aspects helping to understand the microbiome in terms of quantity, diversity, complexity, function, and interaction with the host are discussed. First the nomenclature, definitions of taxa, and measures of diversity as well as methods to unravel this kingdom are outlined. A brief summary on its physiological relevance for general health and the functions exerted specifically by the microbiome is presented. Differences in the composition of the microbiome along the gastrointestinal tract and across the gut wall and its interindividual variations, enterotypes, and stability are highlighted. The reader will be familiarized with all different modulators impacting on the microbiome, namely, intrinsic and extrinsic factors. Intrinsic factors include gastrointestinal secretions (gastric acid, bile, pancreatic juice, mucus), antimicrobial peptides, motility, enteric nervous system, and host genotype. Extrinsic factors are mainly dietary choices, hygiene, stress, alcohol consumption, exercise, and medications. The second part of the chapter focuses on quantitative and qualitative changes in microbiome in liver cirrhosis. The mechanisms contributing to dysbiosis, small intestinal bacterial overgrowth, and bacterial translocation are delineated underscoring their role for the liver-gut axis.

A novel motion tracking system for evaluation of functional rehabilitation of the upper limbs

Upper limb function impairment is one of the most common sequelae of central nervous system injury, especially in stroke patients and when spinal cord injury produces tetraplegia. Conventional assessment methods cannot provide objective evaluation of patient performance and the tiveness of therapies. The most common assessment tools are based on rating scales, which are inefficient when measuring small changes and can yield subjective bias. In this study, we designed an inertial sensor-based monitoring system composed of five sensors to measure and analyze the complex movements of the upper limbs, which are common in activities of daily living. We developed a kinematic model with nine degrees of freedom to analyze upper limb and head movements in three dimensions. This system was then validated using a commercial optoelectronic system. These findings suggest that an inertial sensor-based motion tracking system can be used in patients who have upper limb impairment through data integration with a virtual reality-based neuroretation system.

Modelado y Evaluación de Entornos Virtuales Interactivos para Rehabilitación Cognitiva en Daño Cerebral

El Daño Cerebral (DC) se refiere a cualquier lesión producida en el cerebro y que afecta a su funcionalidad. Se ha convertido en una de las principales causas de discapacidad neurológica de las sociedades desarrolladas. Hasta la más sencilla de las actividades y acciones que realizamos en nuestro día a día involucran a los procesos cognitivos. Por ello, la alteración de las funciones cognitivas como consecuencia del DC, limita no sólo la calidad de vida del paciente sino también la de las persona de su entorno. La rehabilitación cognitiva trata de aumentar la autonomía y calidad de vida del paciente minimizando o compensando los desórdenes funciones causados por el episodio de DC. La plasticidad cerebral es una propiedad intrínseca al sistema nervioso humano por la que en función a la experiencia se crean nuevos patrones de conectividad. El propósito de la neurorrehabilitación es precisamente modular esta propiedad intrínseca a partir de ejercicios específicos, los cuales podrían derivar en la recuperación parcial o total de las funciones afectadas. La incorporación de la tecnología a las terapias de rehabilitación ha permitido desarrollar nuevas metodologías de trabajo. Esto ha ayudado a hacer frente a las dificultades de la rehabilitación que los procesos tradicionales no logran abarcar. A pesar del gran avance realizado en los Ãoltimos años, todavía existen debilidades en el proceso de rehabilitación; por ejemplo, la trasferencia a la vida real de las habilidades logradas durante la terapia de rehabilitación, así como su generalización a otras actividades cotidianas. Los entornos virtuales pueden reproducir situaciones cotidianas. Permiten simular, de forma controlada, los requisitos conductuales que encontramos en la vida real. En un contexto terapéutico, puede ser utilizado por el neuropsicólogo para corregir en el paciente comportamientos patológicos no deseados, realizar intervenciones terapéuticas sobre Actividades de Vida Diaria que estimulen conductas adaptativas. A pesar de que las tecnologías actuales tienen potencial suficiente para aportar nuevos beneficios al proceso de rehabilitación, existe cierta reticencia a su incorporación a la clínica diaria. A día de hoy, no se ha podido demostrar que su uso aporte una mejorar significativa con respecto a otro tipo de intervención; en otras palabras, no existe evidencia científica de la eficacia del uso de entornos virtuales interactivos en rehabilitación. En este contexto, la presente Tesis Doctoral trata de abordar los aspectos que mantienen a los entornos virtuales interactivos al margen de la rutina clínica diaria. Se estudian las diferentes etapas del proceso de rehabilitación cognitiva relacionado con la integración y uso de estos entornos: diseño de las actividades, su implementación en el entorno virtual, y finalmente la ejecución por el paciente y análisis de los respectivos datos. Por tanto, los bloques en los que queda dividido el trabajo de investigación expuesto en esta memoria son: 1. Diseño de las AVD. La definición y configuración de los elementos que componen la AVD permite al terapeuta diseñar estrategias de intervención terapéutica para actuar sobre el comportamiento del paciente durante la ejecución de la actividad. En esta parte de la tesis se pretende formalizar el diseño de las AVD de tal forma que el terapeuta pueda explotar el potencial tecnológico de los entornos virtuales interactivos abstrayéndose de la complejidad implícita a la tecnología. Para hacer viable este planteamiento se propone una metodología que permita modelar la definición de las AVD, representar el conocimiento implícito en ellas, y asistir al neuropsicólogo durante el proceso de diseño de la intervención clínica. 2. Entorno virtual interactivo. El gran avance tecnológico producido durante los Ãoltimos años permite reproducir AVD interactivas en un contexto de uso clínico. El objetivo perseguido en esta parte de la Tesis es el de extraer las características potenciales de esta solución tecnológica y aplicarla a las necesidades y requisitos de la rehabilitación cognitiva. Se propone el uso de la tecnología de Vídeo Interactivo para el desarrollo de estos entornos virtuales. Para la evaluación de la misma se realiza un estudio experimental dividido en dos fases con la participación de sujetos sanos y pacientes, donde se valora su idoneidad para ser utilizado en terapias de rehabilitación cognitiva. 3. Monitorización de las AVD. El uso de estos entornos virtuales interactivos expone al paciente ante una gran cantidad de estímulos e interacciones. Este hecho requiere de instrumentos de monitorización avanzado que aporten al terapeuta información objetiva sobre el comportamiento del paciente, lo que le podría permitir por ejemplo evaluar la eficacia del tratamiento. En este apartado se propone el uso de métricas basadas en la atención visual y la interacción con el entorno para conocer datos sobre el comportamiento del paciente durante la AVD. Se desarrolla un sistema de monitorización integrado con el entorno virtual que ofrece los instrumentos necesarios para la evaluación de estas métricas para su uso clínico. La metodología propuesta ha permitido diseñar una AVD basada en la definición de intervenciones terapéuticas. Posteriormente esta AVD has sido implementada mediante la tecnología de vídeo interactivo, creando así el prototipo de un entorno virtual para ser utilizado por pacientes con déficit cognitivo. Los resultados del estudio experimental mediante el cual ha sido evaluado demuestran la robustez y usabilidad del sistema, así como su capacidad para intervenir sobre el comportamiento del paciente. El sistema monitorización que ha sido integrado con el entorno virtual aporta datos objetivos sobre el comportamiento del paciente durante la ejecución de la actividad. Los resultados obtenidos permiten contrastar las hipótesis de investigación planteadas en la Tesis Doctoral, aportando soluciones que pueden ayudar a la integración de los entornos virtuales interactivos en la rutina clínica. Esto abre una nueva vía de investigación y desarrollo que podría suponer un gran progreso y mejora en los procesos de neurorrehabilitación cognitiva en daño cerebral. ABSTRACT Brain injury (BI) refers to medical conditions that occur in the brain, altering its function. It becomes one of the main neurological disabilities in the developed society. Cognitive processes determine individual performance in Activities of Daily Living (ADL), thus, the cognitive disorders after BI result in a loss of autonomy and independence, affecting the patient’s quality of life. Cognitive rehabilitation seeks to increase patients’ autonomy and quality of life minimizing or compensating functional disorders showed by BI patients. Brain plasticity is an intrinsic property of the human nervous system whereby its structure is changed depending on experience. Neurorehabilitation pursuits a precise modulation of this intrinsic property, based on specific exercises to induce functional changes, which could result in partial or total recovery of the affected functions. The new methodologies that can be approached by applying technologies to the rehabilitation process, permit to deal with the difficulties which are out of the scope of the traditional rehabilitation. Despite this huge breakthrough, there are still weaknesses in the rehabilitation process, such as the transferring to the real life those skills reached along the therapy, and its generalization to others daily activities. Virtual environments reproduce daily situations. Behavioural requirements which are similar to those we perceive in real life, are simulated in a controlled way. In these virtual environments the therapist is allowed to interact with patients without even being present, inhibiting unsuitable behaviour patterns, stimulating correct answers throughout the simulation and enhancing stimuli with supplementary information when necessary. Despite the benefits which could be brought to the cognitive rehabilitation by applying the potential of the current technologies, there are barriers for widespread use of interactive virtual environments in clinical routine. At present, the evidence that these technologies bring a significant improvement to the cognitive therapies is limited. In other words, there is no evidence about the efficacy of using virtual environments in rehabilitation. In this context, this work aims to address those issues which keep the virtual environments out of the clinical routine. The stages of the cognitive rehabilitation process, which are related with the use and integration of these environments, are analysed: activities design, its implementation in the virtual environment, and the patient’s performance and the data analysis. Hence, the thesis is comprised of the main chapters that are listed below: 1. ADL Design.Definition and configuration of the elements which comprise the ADL allow the therapist to design intervention strategies to influence over the patient behaviour along the activity performance. This chapter aims to formalise the AVD design in order to help neuropsychologists to make use of the interactive virtual environments’ potential but isolating them from the complexity of the technology. With this purpose a new methodology is proposed as an instrument to model the ADL definition, to manage its implied knowledge and to assist the clinician along the design process of the therapeutic intervention. 2. Interactive virtual environment. Continuous advancements make the technology feasible for re-creating rehabilitation therapies based on ADL. The goal of this stage is to analyse the main features of virtual environments in order to apply them according to the cognitive rehabilitation’s requirements. The interactive video is proposed as the technology to develop virtual environments. Experimental study is carried out to assess the suitability of the interactive video to be used by cognitive rehabilitation. 3. ADL monitoring system. This kind of virtual environments bring patients in front lots of stimuli and interactions. Thus, advanced monitoring instruments are needed to provide therapist with objective information about patient’s behaviour. This thesis chapter propose the use of metrics rely on visual patients’ visual attention and their interactions with the environment. A monitoring system has been developed and integrated with the interactive video-based virtual environment, providing neuropsychologist with the instruments to evaluate the clinical force of this metrics. Therapeutic interventions-based ADL has been designed by using the proposed methodology. Interactive video technology has been used to develop the ADL, resulting in a virtual environment prototype to be use by patients who suffer a cognitive deficits. An experimental study has been performed to evaluate the virtual environment, whose overcomes show the usability and solidity of the system, and also its capacity to have influence over patient’s behaviour. The monitoring system, which has been embedded in the virtual environment, provides objective information about patients’ behaviour along their activity performance. Research hypothesis of the Thesis are proven by the obtained results. They could help to incorporate the interactive virtual environments in the clinical routine. This may be a significant step forward to enhance the cognitive neurorehabilitation processes in brain injury.

The oculomotor system as a model for the study of neuronal interaction processes

Identified neurons that control eye movements offer an excellent experimental target for the study of Information coding and neuronal interaction processes wíthin the central nervous system. Here are presented some prelimínary results of the motoneuron behaviour during steady eye fíxation, obtained by regressíon and analysis of variance techniques. A flexible information system intended for the systematic acquisitíon and analysis of simultaneous records of neuronal activity and both eyes angular position in a great amount of cells, oriented to the defínition of mathematical models, is also briefly outlíned.

Activity-dependent regulation of synaptic clustering in a hippocampal culture system

Currently, there is a limited understanding of the factors that influence the localization and density of individual synapses in the central nervous system. Here we have studied the effects of activity on synapse formation between hippocampal dentate granule cells and CA3 pyramidal neurons in culture, taking advantage of FM1–43 as a fluorescent marker of synaptic boutons. We observed an early tendency for synapses to group together, quickly followed by the appearance of synaptic clusters on dendritic processes. These events were strongly influenced by N-methyl-d-aspartic acid receptor- and cyclic AMP-dependent signaling. The microstructure and localization of the synaptic clusters resembled that found in hippocampus, at mossy fiber synapses of stratum lucidum. Activity-dependent clustering of synapses represents a means for synaptic targeting that might contribute to synaptic organization in the brain.

Reconstitution of the hippocampal mossy fiber and associational-commissural pathways in a novel dissociated cell culture system.

Synapses of the hippocampal mossy fiber pathway exhibit several characteristic features, including a unique form of long-term potentiation that does not require activation of the N-methyl-D-aspartate receptor by glutamate, a complex postsynaptic architecture, and sprouting in response to seizures. However, these connections have proven difficult to study in hippocampal slices because of their relative paucity (<0.4%) compared to commissural-collateral synapses. To overcome this problem, we have developed a novel dissociated cell culture system in which we have enriched mossy fiber synapses by increasing the ratio of granule-to-pyramidal cells. As in vivo, mossy fiber connections are composed of large dynorphin A-positive varicosities contacting complex spines (but without a restricted localization). The elementary synaptic connections are glutamatergic, inhibited by dynorphin A, and exhibit N-methyl-D-aspartate-independent long-term potentiation. Thus, the simplicity and experimental accessibility of this enriched in vitro mossy fiber pathway provides a new perspective for studying nonassociative plasticity in the mammalian central nervous system.

Motor learning by field approximation.

We investigated how human subjects adapt to forces perturbing the motion of their ams. We found that this kind of learning is based on the capacity of the central nervous system (CNS) to predict and therefore to cancel externally applied perturbing forces. Our experimental results indicate: (i) that the ability of the CNS to compensate for the perturbing forces is restricted to those spatial locations where the perturbations have been experienced by the moving arm. The subjects also are able to compensate for forces experienced at neighboring workspace locations. However, adaptation decays smoothly and quickly with distance from the locations where disturbances had been sensed by the moving limb. (ii) Our experiments also how that the CNS builds an internal model of the external perturbing forces in intrinsic (muscles and / or joints) coordinates.

Cell fate determination in the vertebrate retina.

In the vertebrate central nervous system, the retina has been a useful model for studies of cell fate determination. Recent results from studies conducted in vitro and in vivo suggest a model of retinal development in which both the progenitor cells and the environment change over time. The model is based upon the notion that the mitotic cells within the retina change in their response properties, or "competence", during development. These changes presage the ordered appearance of distinct cell types during development and appear to be necessary for the production of the distinct cell types. As the response properties of the cells change, so too do the environmental signals that the cells encounter. Together, intrinsic properties and extrinsic cues direct the choice of cell fate.

Emergence of order in visual system development.

Neural connections in the adult central nervous system are highly precise. In the visual system, retinal ganglion cells send their axons to target neurons in the lateral geniculate nucleus (LGN) in such a way that axons originating from the two eyes terminate in adjacent but nonoverlapping eye-specific layers. During development, however, inputs from the two eyes are intermixed, and the adult pattern emerges gradually as axons from the two eyes sort out to form the layers. Experiments indicate that the sorting-out process, even though it occurs in utero in higher mammals and always before vision, requires retinal ganglion cell signaling; blocking retinal ganglion cell action potentials with tetrodotoxin prevents the formation of the layers. These action potentials are endogenously generated by the ganglion cells, which fire spontaneously and synchronously with each other, generating "waves" of activity that travel across the retina. Calcium imaging of the retina shows that the ganglion cells undergo correlated calcium bursting to generate the waves and that amacrine cells also participate in the correlated activity patterns. Physiological recordings from LGN neurons in vitro indicate that the quasiperiodic activity generated by the retinal ganglion cells is transmitted across the synapse between ganglion cells to drive target LGN neurons. These observations suggest that (i) a neural circuit within the immature retina is responsible for generating specific spatiotemporal patterns of neural activity; (ii) spontaneous activity generated in the retina is propagated across central synapses; and (iii) even before the photoreceptors are present, nerve cell function is essential for correct wiring of the visual system during early development. Since spontaneously generated activity is known to be present elsewhere in the developing CNS, this process of activity-dependent wiring could be used throughout the nervous system to help refine early sets of neural connections into their highly precise adult patterns.

Multi-agent system for control of robots inspired on the distributed activity and hormonal regulation of humans

Robotics is an emerging field with great activity. Robotics is a field that presents several problems because it depends on a large number of disciplines, technologies, devices and tasks. Its expansion from perfectly controlled industrial environments toward open and dynamic environment presents a many new challenges. New uses are, for example, household robots or professional robots. To facilitate the low cost, rapid development of robotic systems, reusability of code, its medium and long term maintainability and robustness are required novel approaches to provide generic models and software systems who develop paradigms capable of solving these problems. For this purpose, in this paper we propose a model based on multi-agent systems inspired by the human nervous system able to transfer the control characteristics of the biological system and able to take advantage of the best properties of distributed software systems. Specifically, we model the decentralized activity and hormonal variation.

The ubiquitin-proteasome system in retinal health and disease

The ubiquitin–proteasome system (UPS) is the main intracellular pathway for modulated protein turnover, playing an important role in the maintenance of cellular homeostasis. It also exerts a protein quality control through degradation of oxidized, mutant, denatured, or misfolded proteins and is involved in many biological processes where protein level regulation is necessary. This system allows the cell to modulate its protein expression pattern in response to changing physiological conditions and provides a critical protective role in health and disease. Impairments of UPS function in the central nervous system (CNS) underlie an increasing number of genetic and idiopathic diseases, many of which affect the retina. Current knowledge on the UPS composition and function in this tissue, however, is scarce and dispersed. This review focuses on UPS elements reported in the retina, including ubiquitinating and deubiquitinating enzymes (DUBs), and alternative proteasome assemblies. Known and inferred roles of protein ubiquitination, and of the related, SUMO conjugation (SUMOylation) process, in normal retinal development and adult homeostasis are addressed, including modulation of the visual cycle and response to retinal stress and injury. Additionally, the relationship between UPS dysfunction and human neurodegenerative disorders affecting the retina, including Alzheimer's, Parkinson's, and Huntington's diseases, are dealt with, together with numerous instances of retina-specific illnesses with UPS involvement, such as retinitis pigmentosa, macular degenerations, glaucoma, diabetic retinopathy (DR), and aging-related impairments. This information, though still basic and limited, constitutes a suitable framework to be expanded in incoming years and should prove orientative toward future therapy design targeting sight-affecting diseases with a UPS underlying basis.

Rôle des cellules endothéliales dans l’immunité innée précoce induite lors d’infections par des coronavirus murins

Les cellules endothéliales (EC) constituent une première barrière physique à la dissémination de virus pléiotropiques circulant par voie hématogène mais leur contribution à la défense innée anti-virale est peu connue. Des dysfonctions des EC de la barrière hémato-encéphalique (BMEC) et des sinusoïdes hépatiques (LSEC) ont été rapportées dans des neuropathologies et des hépatites aiguës ou chroniques d’origine virale, suggérant que des atteintes à leur intégrité contribuent à la pathogenèse. Les sérotypes de coronavirus de l’hépatite murine (MHV), se différenciant par leur capacité à induire des hépatites et des maladies neurologiques de sévérité variable et/ou leur tropisme pour les EC, représentent des modèles viraux privilégiés pour déterminer les conséquences de l’infection des EC sur la pathogenèse virale. Lors d’infection par voie hématogène, le sérotype MHV3, le plus virulent des MHV, induit une hépatite fulminante, caractérisée par une réponse inflammatoire sévère, et des lésions neurologiques secondaires alors que le sérotype moins virulent, MHV-A59, induit une hépatite modérée sans atteintes secondaires du système nerveux central (SNC). Par ailleurs, le sérotype MHV3, à la différence du MHV-A59, démontre une capacité à stimuler la production de cytokines par la voie TLR2. Les variants atténués du MHV3, les virus 51.6-MHV3 et YAC-MHV3, sont caractérisés par un faible tropisme pour les LSEC et induisent respectivement une hépatite modérée et subclinique. Compte tenu de l’importance des LSEC dans le maintien de la tolérance hépatique et de l’élimination des pathogènes circulants, il a été postulé que la sévérité de l’hépatite et de la réponse inflammatoire lors d’infections par les MHV est associée à la réplication virale et à l’altération des propriétés tolérogéniques et vasculaires des LSEC. Les désordres inflammatoires hépatiques pourraient résulter d’une activation différentielle du TLR2, plutôt que des autres TLR et des hélicases, selon les sérotypes. D’autre part, compte tenu du rôle des BMEC dans la prévention des infections du SNC, il a été postulé que l’invasion cérébrale secondaire par les coronavirus est reliée à l’infection des BMEC et le bris subséquent de la barrière hémato-encéphalique (BHE). À l’aide d’infections in vivo et in vitro par les différents sérotypes MHV, chez des souris ou des cultures de BMEC et de LSEC, nous avons démontré, d’une part, que l’infection in vitro des LSEC par le sétotype MHV3, à la différence des variants 51.6- et YAC-MHV3, altérait la production du facteur vasodilatant NO et renversait leur phénotype tolérogénique en favorisant la production de cytokines et de chimiokines inflammatoires. Ces dysfonctions se traduisaient in vivo par une réponse inflammatoire incontrôlée et une dérégulation du recrutement intrahépatique de leucocytes, favorisant la réplication virale et les dommages hépatiques. Nous avons aussi démontré, à l’aide de souris TLR2 KO et de LSEC dont l’expression du TLR2 a été abrogée par des siRNA, que la sévérité de l’hépatite et de la réponse inflammatoire induite par le sérotype MHV3, dépendait en partie de l’induction et de l’activation préférentielle du TLR2 par le virus dans le foie. D’autre part, la sévérité de la réplication virale au foie et des désordres dans le recrutement leucocytaire intrahépatique induits par le MHV3, et non par le MHV-A59 et le 51.6-MHV3, corrélaient avec une invasion virale subséquente du SNC, au niveau de la BHE. Nous avons démontré que l’invasion cérébrale du MHV3 était associée à une infection productive des BMEC et l’altération subséquente des protéines de jonctions serrées occludine, VE-cadhérine et ZO-1 se traduisant par une augmentation de la perméabilité de la BHE et l’entrée consécutive du virus dans le cerveau. Dans l’ensemble, les résultats de cette étude mettent en lumière l’importance du maintien de l’intégrité structurale et fonctionnelle des LSEC et des BMEC lors d’infections virales aigües par des MHV afin de limiter les dommages hépatiques associés à l’induction d’une réponse inflammatoire exagérée et de prévenir le passage des virus au cerveau suite à une dissémination par voie hématogène. Ils révèlent en outre un nouveau rôle aggravant pour le TLR2 dans l’évolution de l’hépatite virale aigüe ouvrant la voie à de nouvelles avenues thérapeutiques visant à moduler l’activité inflammatoire du TLR2.

The Ets domain transcription factor Erm distinguishes rat satellite glia from Schwann cells and is regulated in satellite cells by neuregulin signaling

Distinct glial cell types of the vertebrate peripheral nervous system (PNS) are derived from the neural crest. Here we show that the expression of the Ets domain transcription factor Erm distinguishes satellite glia from Schwann cells beginning early in rat PNS development. In developing dorsal root ganglia (DRG), Erm is present both in presumptive satellite glia and in neurons. In contrast, Erm is not detectable at any developmental stage in Schwann cells in peripheral nerves. In addition, Erm is downregulated in DRG-derived glia adopting Schwann cell traits in culture. Thus, Erm is the first described transcription factor expressed in satellite glia but not in Schwann cells. In culture, the Neuregulin1 (NRG1) isoform GGF2 maintains Erm expression in presumptive satellite cells and reinduces Erm expression in DRG-derived glia but not in Schwann cells from sciatic nerve. These data demonstrate that there are intrinsic differences between these glial subtypes in their response to NRG1 signaling. In neural crest cultures, Erm-positive progenitor cells give rise to two distinct glial subtypes: Erm-positive, Oct-6-negative satellite glia in response to GGF2, and Erm-negative, Oct-6-positive Schwann cells in the presence of serum and the adenylate cyclase activator forskolin. Thus, Erm-positive neural crest-derived progenitor cells and presumptive satellite glia are able to acquire Schwann cell features. Given the in vivo expression of Erm in peripheral ganglia, we suggest that ganglionic Erm-positive cells may be precursors of Schwann cells.