Spike burst-pause dynamics of Purkinje cells regulate sensorimotor adaptation

Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of target medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.This work was supported by the European Union (www.europa.eu), Project SpikeControl 658479 (recipient NL), the Spanish Agencia Estatal de Investigacio´n and European Regional Development Fund (www.ciencia.gob.es/ portal/site/MICINN/aei), Project CEREBROT TIN2016-81041-R (recipient ER), and the French National Research Agency (www.agence-nationalerecherche. fr) – Essilor International (www.essilor. com), Chair SilverSight ANR-14-CHIN-0001 (recipient AA)

Ética en la docencia. El profesor universitario como modelo de actuación personal y profesional

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524El profesor universitario debe ser un modelo de actuación personal y profesional para sus alumnos; un ejemplo que estimule a los estudiantes tanto en el ejercicio de la profesión, como con el respeto por su entorno. De tal modo que el conocimiento que adquieran los alumnos puedan aplicarlo a la vida cotidiana. Esta práctica se ha llevado a cabo en la asignatura de Trabajo Dirigido. El profesor debe manifestar una coherencia entre acción y el pensamiento, debe ser justo y equitativo en la evaluación y tener en cuenta las necesidades particulares de los alumnos; también debe conseguir motivarlos, de forma amigable, con el fin que ellos se esfuercen para lograr las metas académicas. El objetivo es fomentar el logro de competencias transversales tales como responsabilidad, igualdad y capacidad de trabajo en equipo; mediante la realización de sesiones de debate entre el alumno, el tutor, y/o otros investigadores. Por otra parte, también se pretende un análisis reflexivo de nuestra propia actividad docente con el fin de tener en cuenta el potencial y necesidades particulares de cada alumno para lograr una mejora continua. Para alcanzar estos objetivos, el método consiste en la colaboración directa del alumno con los investigadores de la Unidad en proyectos reales y, sesiones semanales de discusión de los resultados que se van obteniendo. De forma que los alumnos desarrollan capacidad de trabajar en equipo, responsabilidad, respeto entre géneros, pensamiento crítico y una verdadera integración. Finalmente, creemos que la ética en la docencia también se pone de manifiesto a la hora de evaluar el aprendizaje de los alumnos. Por este motivo, es de vital importancia que el profesor universitario fomente un clima de integración, de comunicación y de trabajo en equipo en las sesiones docentes. El análisis reflexivo que ha realizado el grupo docente ha permitido examinar las debilidades, las fortalezas y oportunidades acaecidas de la actividad docente para potenciar mejoras en el nuevo curso

A Metric for Evaluating Neural Input Representation in Supervised Learning Networks

Supervised learning has long been attributed to several feed-forward neural circuits within the brain, with particular attention being paid to the cerebellar granular layer. The focus of this study is to evaluate the input activity representation of these feed-forward neural networks. The activity of cerebellar granule cells is conveyed by parallel fibers and translated into Purkinje cell activity, which constitutes the sole output of the cerebellar cortex. The learning process at this parallel-fiber-to-Purkinje-cell connection makes each Purkinje cell sensitive to a set of specific cerebellar states, which are roughly determined by the granule-cell activity during a certain time window. A Purkinje cell becomes sensitive to each neural input state and, consequently, the network operates as a function able to generate a desired output for each provided input by means of supervised learning. However, not all sets of Purkinje cell responses can be assigned to any set of input states due to the network's own limitations (inherent to the network neurobiological substrate), that is, not all input-output mapping can be learned. A key limiting factor is the representation of the input states through granule-cell activity. The quality of this representation (e.g., in terms of heterogeneity) will determine the capacity of the network to learn a varied set of outputs. Assessing the quality of this representation is interesting when developing and studying models of these networks to identify those neuron or network characteristics that enhance this representation. In this study we present an algorithm for evaluating quantitatively the level of compatibility/interference amongst a set of given cerebellar states according to their representation (granule-cell activation patterns) without the need for actually conducting simulations and network training. The algorithm input consists of a real-number matrix that codifies the activity level of every considered granule-cell in each state. The capability of this representation to generate a varied set of outputs is evaluated geometrically, thus resulting in a real number that assesses the goodness of the representation

Reinforcement Learning in a Spiking Neural Model of Striatum Plasticity

The basal ganglia (BG), and more specifically the striatum, have long been proposed to play an essential role in action-selection based on a reinforcement learning (RL) paradigm. However, some recent findings, such as striatal spike-timing-dependent plasticity (STDP) or striatal lateral connectivity, require further research and modelling as their respective roles are still not well understood. Theoretical models of spiking neurons with homeostatic mechanisms, lateral connectivity, and reward-modulated STDP have demonstrated a remarkable capability to learn sensorial patterns that statistically correlate with a rewarding signal. In this article, we implement a functional and biologically inspired network model of the striatum, where learning is based on a previously proposed learning rule called spike-timing-dependent eligibility (STDE), which captures important experimental features in the striatum. The proposed computational model can recognize complex input patterns and consistently choose rewarded actions to respond to such sensorial inputs. Moreover, we assess the role different neuronal and network features, such as homeostatic mechanisms and lateral inhibitory connections, play in action-selection with the proposed model. The homeostatic mechanisms make learning more robust (in terms of suitable parameters) and facilitate recovery after rewarding policy swapping, while lateral inhibitory connections are important when multiple input patterns are associated with the same rewarded action. Finally, according to our simulations, the optimal delay between the action and the dopaminergic feedback is obtained around 300 ms, as demonstrated in previous studies of RL and in biological studies

Ex-Vivo and In-Vivo Assessment of Cyclamen europaeum Extract After Nasal Administration

Rhinosinusitis is a prevalent disorder with a severe impact on the health-related quality of life. Saponins of Cyclamen europaeum exert a clinically proven curative effect on rhinosinusitis symptoms when instilled into the nasal cavity, however, more extensive preclinical assessment is required to better characterize the efficacy of this botanical extract. This work evaluates the potential use of a natural freeze-dried extract of C. europaeum given as topical nasal administration. Permeation experiment on porcine nasal mucosa was performed with Franz diffusion cells. Experiments in rabbits were performed to test for any toxicological, hematological, biochemical or histological evidence of systemic action. No theoretical levels of saponins were found in the receptor chamber of Franz diffusion cells. Hematological data did not show significant differences between control and experimental animals (p > 0.05). Histological studies also showed that enhanced secretory activity in response to intranasal administration was not accompanied by any visible signs of injury. An examination of the brain, lungs, liver, kidneys, spleen, and gastrointestinal organs did not reveal any abnormality. The absence of mucosal permeation of saponins and negligible probability of C. europaeum saponins absorption in the course of a therapeutic application was demonstrated

Spiking Neural Network With Distributed Plasticity Reproduces Cerebellar Learning in Eye Blink Conditioning Paradigms

In this study, we defined a realistic cerebellar model through the use of artificial spiking neural networks, testing it in computational simulations that reproduce associative motor tasks in multiple sessions of acquisition and extinction. Methods: By evolutionary algorithms, we tuned the cerebellar microcircuit to find out the near-optimal plasticity mechanism parameters that better reproduced human-like behavior in eye blink classical conditioning, one of the most extensively studied paradigms related to the cerebellum. We used two models: one with only the cortical plasticity and another including two additional plasticity sites at nuclear level. Results: First, both spiking cerebellar models were able to well reproduce the real human behaviors, in terms of both "timing" and "amplitude", expressing rapid acquisition, stable late acquisition, rapid extinction, and faster reacquisition of an associative motor task. Even though the model with only the cortical plasticity site showed good learning capabilities, the model with distributed plasticity produced faster and more stable acquisition of conditioned responses in the reacquisition phase. This behavior is explained by the effect of the nuclear plasticities, which have slow dynamics and can express memory consolidation and saving. Conclusions: We showed how the spiking dynamics of multiple interactive neural mechanisms implicitly drive multiple essential components of complex learning processes. Significance: This study presents a very advanced computational model, developed together by biomedical engineers, computer scientists, and neuroscientists. Since its realistic features, the proposed model can provide confirmations and suggestions about neurophysiological and pathological hypotheses and can be used in challenging clinical application

Novel Polymeric Formulation for Removal of Gastrointestinal Polyps by Digestive Endoscopy

Álvaro Gimeno Sandig from Animal House Bellvitge University of Barcelona is acknowledged for his technical support.Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are two techniques used in the resection of gastrointestinal mucosal polyps. The aim of this work is the development and evaluation of an innovative polymeric solution containing sodium carboxymethylcellulose and hyaluronic acid. For this purpose, several mixtures of these two main components, as well as other components such as fructose, citric acid, and zinc, are evaluated in terms of physicochemical and microbiological properties, rheological behavior, extensibility, syringeability, and stability at different storage conditions. Furthermore, the potential production of mucosal elevation and duration is also studied by an ex vivo model using porcine stomach and colon. Results show that the developed polymeric solutions possess optimal values of pH, from 4.58 to 6.63, for their use in the gastrointestinal tract. The formulations exhibit both Newtonian and pseudoplastic behaviors with different viscosity values as a function of their composition. All formulations exhibit high stability properties and no bacterial or fungal growth is detected. MCS01 and MCS05 are the polymeric solutions with the best syringeability results. In this line, MCS05 is the formulation that provides the highest, 2.20 ± 0.18 cm and 1.40 ± 0.11 cm, and longest-lasting, for more than 120 min, elevation effect on porcine submucosal stomach and colon tissues, respectively. Thus, it can be concluded that polymeric solution MCS05 might be considered as a promising tool for use in human EMR and ESD.This research was funded by the local Regional Government of Andalusia (Junta de Andalucía), grant number PIN-0479-2016

Nano-engineering of ketorolac tromethamine platforms for ocular treatment of inflammatory disorders

Aim: The development and optimization of Ketorolac tromethamine-loaded polylactic-co-glycolic acid nanoparticles (KT-NPs) for the treatment of inflammatory processes of the eye. Materials & methods: KT-NPs were developed by factorial design and characterized by assessing their physicochemical properties. Biopharmaceutical behavior studies, ocular tolerance, anti-inflammatory efficacy and bioavailability tests were performed on pigs. Results: Optimized KT-NPs of 112 nm, narrow distribution with encapsulation efficiency near 100% were obtained. KT release followed the Weibull model and there was significantly greater retention in the cornea and sclera than in the commercial reference. KT-NPs showed no signs of ocular irritancy and similar anti-inflammatory efficacy to the commercial reference. Conclusion: KT-NPs were a suitable alternative for the treatment of inflammatory disorders of the anterior and posterior segments of the eye as an alternative to conventional topical formulations

Efficacy and Safety of a Novel Submucosal Injection Solution for Resection of Gastrointestinal Lesions

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are minimally invasive and efficient techniques for the removal of gastrointestinal (GI) mucosal polyps. In both techniques, submucosal injection solutions are necessary for complete effectiveness and safety during the intervention to be obtained. The main objective of this study was to evaluate the efficacy and safety of a new sterile submucosal injection solution for EMR/ESD used within a clinical protocol in patients with intestinal polyps. We carried out a prospective study between 2016 and 2017 with patients who attended the Endoscopy Consultation—Digestive Department of Primary Hospital. Patients were selected for EMR/ESD after the application of clinical protocols. Thirty-six patients were selected (≥ 66 years with comorbidities and risk factors). Lesions were located mainly in the colon. Our solution presented an intestinal lift ≥ 60 min in EMR/ESD and a high expansion of tissue, optimum viscosity, and subsequent complete resorption. The genes S100A9 and TP53 presented an expression increase in the distal regions. TP53 and PCNA were the only genes whose expression was increased in polyp specimens vs. the surrounding tissue at the mRNA level. In EMR/ESD, our solution presented a prolonged effect at the intestinal level during all times of the intervention. Thus, our solution seems be an effective and safe alternative in cases of flat lesions in both techniques.Study co-financed by the Junta de Andalucia (PIN-0479-2016, CTS676, CTS235, CTS164), the Ministry of Economy and Competitivity, Spain (SAF2017-88457-R, AGL2017-85270-R), Nakafarma S.L and CIBERehd is funded by Instituto de Salud Carlos III, Spain. The sponsors had no role in the design, execution, interpretation, or writing of the study