Modulation of the input–output function by GABAA receptor-mediated currents in rat oculomotor nucleus motoneurons

The neuronal input–output function depends on recruitment threshold and gain of the firing frequency–current (f–I) relationship. These two parameters are positively correlated in ocular motoneurons (MNs) recorded in alert preparation and inhibitory inputs could contribute to this correlation. Phasic inhibition mediated by γ-amino butyric acid (GABA) occurs when a high concentration of GABA at the synaptic cleft activates postsynaptic GABAA receptors, allowing neuronal information transfer. In some neuronal populations, low concentrations of GABA activate non-synaptic GABAA receptors and generate a tonic inhibition, which modulates cell excitability. This study determined how ambient GABA concentrations modulate the input–output relationship of rat oculomotor nucleus MNs. Superfusion of brain slices with GABA (100 μm) produced a GABAA receptor-mediated current that reduced the input resistance, increased the recruitment threshold and shifted the f–I relationship rightward without any change in gain. These modifications did not depend on MN size. In absence of exogenous GABA, gabazine (20 μm; antagonist of GABAA receptors) abolished spontaneous inhibitory postsynaptic currents and revealed a tonic current in MNs. Gabazine increased input resistance and decreased recruitment threshold mainly in larger MNs. The f–I relationship shifted to the left, without any change in gain. Gabazine effects were chiefly due to MN tonic inhibition because tonic current amplitude was five-fold greater than phasic. This study demonstrates a tonic inhibition in ocular MNs that modulates cell excitability depending on cell size. We suggest that GABAA tonic inhibition acting concurrently with glutamate receptors activation could reproduce the positive covariation between threshold and gain reported in alert preparation.España, Ministerio de Ciencia y Tecnología BFU 2009-0786

Vitamin D deficiency as a potential risk factor for accelerated aging, impaired hippocampal neurogenesis and cognitive decline: a role for Wnt/β-catenin signaling

Vitamin D is an essential fat-soluble vitamin that participates in several homeostatic functions in mammalian organisms. Lower levels of vitamin D are produced in the older population, vitamin D deficiency being an accelerating factor for the progression of the aging process. In this review, we focus on the effect that vitamin D exerts in the aged brain paying special attention to the neurogenic process. Neurogenesis occurs in the adult brain in neurogenic regions, such as the dentate gyrus of the hippocampus (DG). This region generates new neurons that participate in cognitive tasks. The neurogenic rate in the DG is reduced in the aged brain because of a reduction in the number of neural stem cells (NSC). Homeostatic mechanisms controlled by the Wnt signaling pathway protect this pool of NSC from being depleted. We discuss in here the crosstalk between Wnt signaling and vitamin D, and hypothesize that hypovitaminosis might cause failure in the control of the neurogenic homeostatic mechanisms in the old brain leading to cognitive impairment. Understanding the relationship between vitamin D, neurogenesis and cognitive performance in the aged brain may facilitate prevention of cognitive decline and it can open a door into new therapeutic fields by perspectives in the elderly.Ministerio de Ciencia, Innovación y Universidades RTI2018-099908-B-C21FEDER-UCA18-1066

Acute Colon Inflammation Triggers Primary Motor Cortex Glial Activation, Neuroinflammation, Neuronal Hyperexcitability, and Motor Coordination Deficits

Neuroinflammation underlies neurodegenerative diseases. Herein, we test whether acute colon inflammation activates microglia and astrocytes, induces neuroinflammation, disturbs neuron intrinsic electrical properties in the primary motor cortex, and alters motor behaviors. We used a rat model of acute colon inflammation induced by dextran sulfate sodium. Inflammatory mediators and microglial activation were assessed in the primary motor cortex by PCR and immunofluorescence assays. Electrophysiological properties of the motor cortex neurons were determined by whole-cell patch-clamp recordings. Motor behaviors were examined using open-field and rotarod tests. We show that the primary motor cortex of rats with acute colon inflammation exhibited microglial and astrocyte activation and increased mRNA abundance of interleukin-6, tumor necrosis factor-alpha, and both inducible and neuronal nitric oxide synthases. These changes were accompanied by a reduction in resting membrane potential and rheobase and increased input resistance and action potential frequency, indicating motor neuron hyperexcitability. In addition, locomotion and motor coordination were impaired. In conclusion, acute colon inflammation induces motor cortex microglial and astrocyte activation and inflammation, which led to neurons’ hyperexcitability and reduced motor coordination performance. The described disturbances resembled some of the early features found in amyotrophic lateral sclerosis patients and animal models, suggesting that colon inflammation might be a risk factor for developing this disease.Ministerio de Ciencia e Innovación 18.06.07.3005 PID2019-105632RB-I00, Grant RTI-2018.099908-B-C21Agencia Estatal de Investigación AEI/10.13039/50110001103

Effects of classical PKC activation on hippocampal neurogenesis and cognitive performance: mechanism of action

Hippocampal neurogenesis has widely been linked to memory and learning performance. New neurons generated from neural stem cells (NSC) within the dentate gyrus of the hippocampus (DG) integrate in hippocampal circuitry participating in memory tasks. Several neurological and neuropsychiatric disorders show cognitive impairment together with a reduction in DG neurogenesis. Growth factors secreted within the DG promote neurogenesis. Protein kinases of the protein kinase C (PKC) family facilitate the release of several of these growth factors, highlighting the role of PKC isozymes as key target molecules for the development of drugs that induce hippocampal neurogenesis. PKC activating diterpenes have been shown to facilitate NSC proliferation in neurogenic niches when injected intracerebroventricularly. We show in here that long-term administration of diterpene ER272 promotes neurogenesis in the subventricular zone and in the DG of mice, affecting neuroblasts differentiation and neuronal maturation. A concomitant improvement in learning and spatial memory tasks performance can be observed. Insights into the mechanism of action reveal that this compound facilitates classical PKCα activation and promotes transforming growth factor alpha (TGFα) and, to a lesser extent, neuregulin release. Our results highlight the role of this molecule in the development of pharmacological drugs to treat neurological and neuropsychiatric disorders associated with memory loss and a deficient neurogenesis.Ministerio de Ciencia, Innovación y Universidades de España (MICINN) RTI-2018-099908-B-C21 y RTI-2018-099908-B-C22Ministerio de Ciencia, Innovación y Universidades de España y Fondos FEDER de la Unión Europea (MICINN/FEDER) BFU2016-75038RConsejería de Economía, Conocimiento, Empresas y Universidades de la Junta de Andalucía y Fondos FEDER. FEDER-UCA18-10664

Kit y método de cuantificación de la toxicidad en neuronas de la corteza cerebral para la detección de enfermedades neurodegenerativas

La presente invención escribe un método electrofisiológico y un kit consistente en una concentración de 10 µM de hidroperóxido de cumeno puro en líquido cefalorraquídeo para cuantificar los efectos de la toxicidad sobre las propiedades intrínsecas de las neuronas de la corteza motora a los 5 minutos de exposición a la acción tóxica y su uso en la detección de enfermedades neurodegenerativas, tal como la Esclerosis Lateral Amiotrófica. Esta invención se encuadra en las áreas analítica y científico-técnica farmacéutica, concretamente en el sector de actividad farmacéutica de evaluación de propiedades de fármacos neuroprotectores.Españ

Instagram como herramienta de aprendizaje en Fisiología: @fisiofarma_us

Las redes sociales (RR.SS.) forman parte de nuestra vida diaria convirtiéndose en una de las principales vías de comunicación y búsqueda de información, especialmente entre los más jóvenes. Entre los usuarios que usan de las RR.SS., un gran número son estudiantes universitarios; y entre los temas más tratados se encuentran aquellos relativos a temáticas de ciencias de la salud. Es por ello por lo que desde el Departamento de Fisiología de la Facultad de Farmacia de la Universidad de Sevilla se desarrolló un proyecto de innovación docente durante el curso 2021-2022 cuyo objetivo era la utilización de las RR.SS. para el aprendizaje de las materias impartidas en nuestro departamento, analizando los posibles beneficios derivado del uso de esta por parte de nuestros estudiantes y profesores. Esta actividad consistió en el desarrollo de contenido divulgativo relativo a la Fisiología por parte de estudiantes del Grado en Farmacia, Grado en Óptica-optometría y Doble Grado en ambos, de nuestro Centro para posteriormente ser publicado en una cuenta de Instagram creada para tal fin (@fisiofarma_us). La opinión tanto de los estudiantes como del profesorado sobre el proyecto fue recogida a través de la encuesta al finalizar el proyecto, y se realizó un registro del impacto en la RR.SS. (seguidores, interacciones, etc). Nuestra cuenta Instagram tuvo un gran impacto en RR.SS. Entre los resultados a destacar, los estudiantes consideran que esta actividad ha favorecido su interés por la Fisiología y tanto estudiantes como profesores creen que esta actividad favoreció diferentes herramientas de aprendizaje. Estos resultados nos hacen concluir que el uso adecuado de las RR.SS. puede ser un método efectivo de aprendizaje e incentivo para fomentar una mejor compresión de las asignaturas de Fisiología en grados universitarios de ciencias de la salud, como Farmacia u Óptica-optometría.: Social networks (RR.SS.) have become an integral part of our daily lives and serve as one of the primary means of communication and information retrieval, particularly among younger. A significant proportion of RR.SS. users are university students, and health science topics are among the most frequently discussed subjects. Considering this, the Department of Physiology at the Facultyof Pharmacy at the University of Seville initiated a teaching innovation project during the 2021-2022 academic year. This project aimed to use RR.SS. as a tool for learning the subjects taught within our department and to analyse the potential benefits that could be derived from its use by our students and members of the physiology department. This initiative involved the creation of informative content related to Physiology by students enrolled in the Degree in Pharmacy, Degree in OpticsOptometry, and Double Degree programs at our faculty. This content was subsequently published on an Instagram account created explicitly for this purpose (@fisiofarma_us). At the end of the project, feedback was obtained from both students and professors of the physiology department via a survey, and data about the impact of our initiative on RR.SS. (e.g., number of followers, interactions, and others) was recorded. Our Instagram account generated considerable interest on RR.SS. Notably, students reported that this activity increased their stake in Physiology, and both students and faculty members indicated that it facilitated the use of various learning tools. Based on these findings, we conclude that the use of RR.SS. can effectively enhance learning and promote a deeper understanding of Physiology-related subjects among students enrolled in university-level health science programs such as Pharmacy or Optics-Optometr

Electrofisiología y morfología de las motoneuronas del núcleo motor celular común durante el desarrollo postnatal

Con el desarrollo postnatal se producen transformaciones morfofuncionales que permiten a las motoneuronas (Mns) extraoculares adultas generar la actividad necesaria para producir los movimientos y fijaciones oculares. Las modificaciones electrofisiológicas y morfológicas que cursan con el desarrollo en Mns del núcleo motor ocular común (nMOC), utilizando la preparación de rodajas de tejido mantenidas “in vitro”, son el objeto de estudio de este trabajo. En la introducción, en primer lugar se describe al nMOC y a sus Mns como sistema eferente, y a continuación se revisan las modificaciones electrofisiológicas (apartado 1.3) y morfológicas (apartado 1.4) que se han descrito acompañando al desarrollo, tanto en Mns como en poblaciones de neuronas no motoras. En la sección de introducción se ha mostrado que el conocimiento de los cambios electrofisiológicos y morfológicos que ocurren durante el desarrollo postnatal es escaso. Los estudios más exhaustivos se han realizado principalmente en ciertas poblaciones de Mns como las del núcleo hipogloso. Las Mns de este núcleo modifican sus características electrofisiológicas y morfológicas de forma significativa con la maduración postnatal. Estudios similares en otras poblaciones de neuronas señalan también profundos cambios morfofuncionales con el desarrollo. El objetivo general de este estudio es determinar las modificaciones electrofisiológicas y morfológicas que tienen lugar en las Mns del nMOC durante el desarrollo postnatal. Con este trabajo se pretende conocer cómo se alcanzan las características de las Mns adultas, y si la secuencia de maduración postnatal es común en diferentes poblaciones de neuronas. Con el fin de avanzar en estos conocimientos se abordaron los siguientes objetivos específicos. - Caracterizar las siguientes propiedades electrofisiológicas en las Mns del nMOC con el desarrollo: * Resistencia de entrada y constante de tiempo. * Rectificación de voltaje por hiperpolarización o sag. * Potencial de acción. * Faase de posthiperpolarización del potencial de acción. * Frecuencia de disparo. * Rebote postinhibitorio. - Estudio morfológico de las Mns del nMOC con el desarrollo: * Caracterización de las Mns. * Caracterización del árbol dendrítico: + Complejidad. + Longitud y diámetro. * Caracterización de la superficie somática-dendrítica. * Acoplamiento eléctrico determinado con neurobiotina

Time and dose dependent effects of oxidative stress induced by cumene hydroperoxide in neuronal excitability of rat motor cortex neurons

It has been claimed that oxidative stress and the production of reactive oxygen radicals can contribute to neuron degeneration and might be one factor in the development of different neurological diseases. In our study, we have attempted to clarify how oxidative damage induces dose dependent changes in functional membrane properties of neurons by means of whole cell patch clamp techniques in brain slices from young adult rats. Our research demonstrates physiological changes in membrane properties of pyramidal motor cortex neurons exposed to 3 concentrations of cumene hydroperoxide (CH; 1, 10 and 100 μM) during 30 min. Results show that oxidative stress induced by CH evokes important changes, in a concentration and time dependent manner, in the neuronal excitability of motor cortex neurons of the rat: (i) Low concentration of the drug (μM) already blocks inward rectifications (sag) and decreases action potential amplitude and gain, a drug concentration which has no effects on other neuronal populations, (ii) 10 μM of CH depresses the excitability of pyramidal motor cortex neurons by decreasing input resistance, amplitude of the action potential, and gain and maximum frequency of the repetitive firing discharge, and (iii) 100 μM completely blocks the capability to produce repetitive discharge of action potentials in all cells. Both larger drug concentrations and/or longer times of exposure to CH narrow the current working range. This happens because of the increase in the rheobase, and the reduction of the cancelation current. The effects caused by oxidative stress, including those produced by the level of lipid peroxidation, are practically irreversible and, this, therefore, indicates that neuroprotective agents should be administered at the first symptoms of alterations to membrane properties. In fact, the pre-treatment with melatonin, acting as an antioxidant, prevented the lipid peroxidation and the physiological changes induced by CH. Larger cells (as estimated by their cell capacitance) were also more susceptible to oxidative stress. Our results provide previously unavailable observations that large size and high sensitivity to oxidative stress (even at low concentrations) make pyramidal neurons of the motor cortex, in particular corticofugal neurons, more susceptible to cell death when compared with other neuronal populations. These results could also shed some light on explaining the causes behind diseases such as Amyotrophic Lateral Sclerosis.European Regional Development Fund UNSE10-1E-094

The Use of an Escape Room As an Innovative Teaching Tool in Pharmacy Studies

Las Escape Rooms son un tipo de recurso que está siendo utilizado por muchos educadores, propiciando elementos de colaboración que ayudan a desarrollar habilidades sociales. En este estudio se ha desarrollado una Escape Room multidisciplinar como herramienta educativa con el fin de mejorar el aprendizaje de los estudiantes y prepararlos para el futuro de la práctica profesional. Participaron 145 alumnos y 12 profesores adscritos a 8 áreas de conocimiento distintas de la Facultad de Farmacia de la Universidad de Sevilla. Mediante esta innovación se ha producido una retroalimentación alumno-profesor, mejorando su relación y aprendiendo mutuamente. Los resultados obtenidos mediante encuestas de satisfacción muestran la gran aceptación que ha tenido la Escape Room entre los alumnos, siendo el estudio valorado con una puntuación general de 4,83/5. A pesar de que el 93% de los alumnos consideró la actividad de alta/muy alta dificultad, el 100% de los mismos destacan que esta herramienta fomenta el trabajo en equipo y el 86,9% considera que refuerza los conocimientos. Este estudio ha despertado en los alumnos la motivación e interés por las asignaturas implicadas, fortaleciendo el aprendizaje y conocimiento de los conceptos fundamentales adquiridos, y propiciando el trabajo en equipo y la resolución de problemas.Escape Rooms are educational resources that are being used by many educators, fostering elements of collaboration that help in social skills development. In this study, a multidisciplinary Escape Room has been developed as an educational tool in order to improve students learning and prepare them for the future of professional practice. 145 students and 12 professors belonging to 8 different areas of knowledge from the Faculty of Pharmacy of the University of Seville participated in this activity. Through this innovation, a student-teacher feedback has been created, improving their relationship and learning from each other. The results obtained through satisfaction surveys show the great acceptance that the escape room had among the students, being the study valued with an overall score of 4.83/5. Although 93% of the students considered the activity of high/very high difficulty, 100% of them emphasize that this tool encourages teamwork and 86.9% consider that it reinforces knowledge. This study has awakened students motivation and interest in the subjects involved, strengthening learning and knowledge of the fundamental concepts acquired, and promoting teamwork and problem solving