Estudio conductual, electrofisiológico e inmunohistoquímico del modelo de fibromialgia inducido por reserpina en rata

El síndrome de fibromialgia (FMS) es una patología de etiología desconocida caracterizada por dolor musculoesquelético generalizado acompañado de otros síntomas entre los que destacan las alteraciones del sueño y los trastornos depresivos, que afecta gravemente a la calidad de vida de los pacientes. Tiene una prevalencia relativamente importante en nuestra sociedad lo que determina que tenga un elevado impacto socio-económico. El desconocimiento de la causa que la genera y los recientes cambios en los criterios diagnósticos contribuyen a que, a pesar de los avances, actualmente el tratamiento del FMS no consiga alcanzar un grado de eficacia suficientemente satisfactorio. Es necesario el establecimiento de un modelo animal que sea capaz de reproducir no sólo la sintomatología de dolor, sino también los principales síntomas comórbidos, para poder profundizar en los mecanismos subyacentes a esta patología y poder avanzar en la investigación de terapias más efectivas. El objetivo del presente trabajo es aportar evidencias sobre la validez del modelo de FMS inducido por reserpina en rata propuesto por Nagakura et al. en 2009. Para ello, hemos analizado en este modelo la presencia de alteraciones en el procesamiento del dolor mediante pruebas conductuales de alodinia e hiperalgesia (mediante el Electrovonfrey test y el Randall y Selitto test, respectivamente), la presencia de sintomatología depresiva (mediante Forced Swimming test y Novelty-Suppressed Feeding test), y la presencia de alteraciones en la arquitectura del sueño que puedan justificar un sueño no reparador en las ratas (mediante estudios electrofisiológicos con implantación de electrodos crónicos). Asimismo, hemos analizado las modificaciones de los patrones de activación de los principales centros monoaminérgicos mediante técnicas de inmunodetección de c-fos. Los resultados obtenidos muestran que las ratas sometidas a la administración subcutánea de 1 mg/kg de reserpina durante tres días consecutivos siguiendo el procedimiento de Nagakura et al. (2009) muestran, tras la implantación del modelo, hiperalgesia y alodinia, sintomatología depresiva y alteraciones del sueño. También se muestra un aumento de la actividad en el locus coeruleus (LC), el núcleo del rafe dorsal (RD) y el área tegmental ventral (VTA) tras la administración aguda de 1 mg/kg de reserpina. En cambio, la administración de 1 mg/kg de reserpina durante tres días consecutivos produce un aumento de la actividad en el LC, pero una drástica disminución de la actividad en DR y VTA. Estos resultados inmunohistoquímicos evidencian el efecto de la reserpina sobre el sistema monoaminérgico, pero se requieren más pruebas para extraer de ellos resultados concluyentes. Tras el análisis de los resultados obtenidos, consideramos válido el modelo de FMS inducido por reserpina en rata propuesto por Nagakura et al. en 2009 para el estudio de este síndrome por reproducir tres de los síntomas más relevantes del FMS (dolor, síntomas depresivos y alteraciones del sueño), y por evidenciar alteraciones de los sistemas monoaminérgicos ampliamente relacionados con la regulación de estos síntomas en los pacientes con FMS.Fibromyalgia syndrome (FMS) is a disease of unknown etiology characterized by widespread musculoskeletal pain accompanied by other symptoms such as sleep disturbances and depressive disorders, which seriously affects the quality of life of patients. It has a relative high prevalence in our society, which determines a high socio-economic impact. Despite progress, the lack of knowledge of the manner of causation of FMS as well as recent changes in diagnostic criteria contribute to a not sufficiently satisfactory and ineffective treatment of FMS. The establishment of an animal model capable to reproduce both the symptoms of pain and major comorbid symptoms is needed in order to deepen into the mechanisms underlying this disease as well as to advance research for more effective therapies. The aim of this study is to provide evidence on the validity of the FMS induced by reserpine animal model proposed by Nagakura et al. in 2009. For this purpose, we analyzed the presence of abnormal pain processing through behavioral tests for allodynia and hyperalgesia (by Electrovonfrey test and the Randall and Selitto test, respectively), the presence of depressive symptoms (using Forced Swimming test and Novelty-Suppressed Feeding test), and the presence of sleep disturbances that can justify unrefreshed sleep in rats (by implantation of chronic electrodes in electrophysiological studies). We have also analyzed the changes in activation patterns of the major monoaminergic centers by performing c-fos immunohistochemical techniques. The results show that rats subjected to subcutaneous administration of 1 mg / kg reserpine for three consecutive days following the procedure used by Nagakura et al. (2009) present hyperalgesia and allodynia, depressive symptoms and sleep disturbances. In addition, an increased activity in the locus coeruleus (LC), the dorsal raphe nucleus (DR) and the ventral tegmental area (VTA) following acute administration of 1 mg / kg reserpine is also shown. However, administration of 1 mg / kg reserpine for three consecutive days results in an increased activity in the LC, but a drastic decline in activity of DR and VTA. Immunohistochemical results show the effect of reserpine on the monoaminergic system, but more evidence is required to draw conclusions from them. After analyzing the results, FMS induced by reserpine rat model proposed by Nagakura et al. in 2009 is considered valid for the study of this syndrome because it plays three of the most prominent symptoms of FMS (pain, depressive symptoms and sleep disturbances). Additionally, it shows changes in the monoamine systems broadly related to the regulation of these symptoms in patients with FMS

Prevalence and morphometric analysis of the retromolar canal in a Spanish population sample:a helical CT scan study

The retromolar canal (RMC) is an anatomical variation of the mandibular canal (MC) whose identification and study should be considered given its implication in the surgical procedures of the retromolar area. The prevalence of the RMC widely varies according to previous studies and may be influenced by the followed study method. This work aimed to evaluate the prevalence of the RMC in a Spanish population sample. For this purpose, 225 CT scan images (with a higher resolution than the cone beam CT used in other previous studies) from the Hospital Clínico Universitario de Valencia were analyzed. The Osirix MD® radiological image analysis system was applied to analyse the dimensions, location in the retromolar area and morphologic characteristics of the RMC by classifying them according to their typology. Furthermore, the relations between the RMC and gender, age and laterality were studied. RMC prevalence was 23.1%. No significant relation between the presence of the canal and gender, age or laterality was found. Type Ia was the commonest type with a prevalence of 40.8%. Based on the results of this study, the RMC should be considered a frequent anatomical variation whose complete study is very important in daily clinical practice

Deformidad tipo Checkrein del Hállux y dedos menores del pie sin fractura previa asociada.

We present a bibliographic review and a description of the surgical technique in checkrein deformity of the hallux and lesser toes. This dynamic deformity causes a significant difficulty in walking and prevents patients from practicing any sport, since in the stance phase of gait toes are forced into maximum plantar flexion and end up trapped under the foot. In cases in which this is not associated with a bone fracture, the clinical suspicion causing the injury is a subclinical compartment syndrome. Treatment described in this work consists of a Z-plasty and the application of a pulvertaft suture in the flexor hallux longus. In the rest of the toes, any additional surgical procedure is not needed, as the deformity is corrected at the retromalleolar level

Microvideos on social networks as a complement to Human Anatomy learning

[EN] In the training of university students of health sciences (medicine, physiotherapy, nursing, podiatry...) the knowledge of human anatomy in its various variants is fundamental; from anatomical dissection and prosection, surface anatomy and neuroanatomy, to clinical anatomy and bioscopic anatomy and diagnostic imaging. Given the observed trends in learning and behavior of the new generations of students, presenting additional or complementary information through game and gamification strategies, quizzes and social networks can be an exciting experience, positive in various academic aspects. By recording micro-videos and diverse posts distributed through social networks, students can have almost-unlimited access to additional, complementary and/or review content for their human anatomy classes.[ES] En la formación de los y las estudiantes universitarios de ciencias de la salud (medicina, fisioterapia, enfermería, podología…) es fundamental el conocimiento de la anatomía humana en sus diversas variantes; desde la disección y prosección anatómica, la anatomía de superficie y neuroanatomía, hasta la anatomía clínica y la anatomía bioscópica e imagen diagnóstica. Dadas las tendencias observadas en el aprendizaje y conductas de las nuevas generaciones de alumnos y alumnas, presentar información adicional o complementaria mediante estrategias de juego y gamificación, quizzes y redes sociales puede resultar una experiencia positiva en diversos aspectos académicos. Mediante la grabación de microvídeos y realización de posts distribuidos a través de redes sociales, los alumnos y las alumnas pueden acceder de forma casi ilimitada a contenido adicional, complementario y/o de repaso de sus clases de anatomía humana.González-Soler, E.; Blasco-Serra, A.; Higueras-Villar, C.; Blasco-Ausina, MC.; Alfosea-Cuadrado, GM.; Valverde-Navarro, A. (2022). Microvídeos en redes sociales como complemento del aprendizaje de la Anatomía Humana. Editorial Universitat Politècnica de València. 1350-1358. https://doi.org/10.4995/INRED2022.2022.158991350135

Structural connectivity and subcellular changes after antidepressant doses of ketamine and Ro 25-6981 in the rat: an MRI and immuno-labeling study

Ketamine has rapid and robust antidepressant effects. However, unwanted psychotomimetic effects limit its widespread use. Hence, several studies examined whether GluN2B-subunit selective NMDA antagonists would exhibit a better therapeutic profile. Although preclinical work has revealed some of the mechanisms of action of ketamine at cellular and molecular levels, the impact on brain circuitry is poorly understood. Several neuroimaging studies have examined the functional changes in the brain induced by acute administration of ketamine and Ro 25-6981 (a GluN2B-subunit selective antagonist), but the changes in the microstructure of gray and white matter have received less attention. Here, the effects of ketamine and Ro 25-6981 on gray and white matter integrity in male Sprague-Dawley rats were determined using diffusion-weighted magnetic resonance imaging (DWI). In addition, DWI-based structural brain networks were estimated and connectivity metrics were computed at the regional level. Immunohistochemical analyses were also performed to determine whether changes in myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) may underlie connectivity changes. In general, ketamine and Ro 25-6981 showed some opposite structural alterations, but both compounds coincided only in increasing the fractional anisotropy in infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increments of NF200 in deep layers of the infralimbic cortex (together with increased MBP) and the dorsal raphe nucleus. Our results suggest that the synthesis of NF200 and MBP may contribute to the formation of new dendritic spines and myelination, respectively. We also suggest that the increase of fractional anisotropy of the infralimbic and dorsal raphe nucleus areas could represent a biomarker of a rapid antidepressant response.Funding: Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grants from the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (PI13/00038, PI16/00217 and PI19/00170 to A.A.) that were co-funded by the European Regional Development Fund (‘A way to build Europe’); Generalitat Valenciana, Conselleria d’ Educació, Investigació, Cultura i Esport (GV/2018/049 to A.B-S.); Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00 to F.P.-C.). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged

Ketamine modifies the oscillatory effects of dorsal raphe stimulation in the infralimbic and prelimbic and cortex

Trabajo presentado en el 18th National Meeting of the Spanish Society of Neuroscience, celebrado en Santiago de Compostela (España), del 4 al 6 de abril de 2019Ketamine (NMDA antagonist) produces rapid (within hours) antidepressant actions, even in treatment resistant depression, and shows promise for suicidal ideationThis work was supported by the Fondo de Investigaciones Sanitarias Carlos III (FIS ISCIII PI16-00287

The oscillatory profile induced by the anxiogenic drug fg-7142 in the amygdala-hippocampal network is reversed by infralimbic deep brain stimulation: Relevance for mood disorders

Anxiety and depression exhibit high comorbidity and share the alteration of the amygdala-hippocampal-prefrontal network, playing different roles in the ventral and dorsal hippocampi. Deep brain stimulation of the infralimbic cortex in rodents or the human equivalent-the subgenual cingulate cortex-constitutes a fast antidepressant treatment. The aim of this work was: (1) to describe the oscillatory profile in a rodent model of anxiety, and (2) to deepen the therapeutic basis of infralimbic deep brain stimulation in mood disorders. First, the anxiogenic drug FG-7142 was administered to anaesthetized rats to characterize neural oscillations within the amygdala and the dorsoventral axis of the hippocampus. Next, deep brain stimulation was applied. FG-7142 administration drastically reduced the slow waves, increasing delta, low theta, and beta oscillations in the network. Moreover, FG-7142 altered communication in these bands in selective subnetworks. Deep brain stimulation of the infralimbic cortex reversed most of these FG-7142 effects. Cross-frequency coupling was also inversely modified by FG-7142 and by deep brain stimulation. Our study demonstrates that the hyperactivated amygdala-hippocampal network associated with the anxiogenic drug exhibits an oscillatory fingerprint. The study contributes to comprehending the neurobiological basis of anxiety and the effects of infralimbic deep brain stimulation.This work was funded by the Fondo de Investigaciones Sanitarias FIS—Instituto de Salud Carlos Tercero and FEDER funds of the EU (Reference FIS-ISCIII PI16/00287). Hanna Vila-Merkle’s PhD studies are funded by the Valencian Ministry of Education (Generalitat Valenciana; grant reference ACIF/2017/394)

Structural connectivity and subcellular changes after antidepressant doses of ketamine and Ro 25-6981 in the rat: an MRI and immuno-labeling study

© The Author(s) 2021.Ketamine has rapid and robust antidepressant effects. However, unwanted psychotomimetic effects limit its widespread use. Hence, several studies examined whether GluN2B-subunit selective NMDA antagonists would exhibit a better therapeutic profile. Although preclinical work has revealed some of the mechanisms of action of ketamine at cellular and molecular levels, the impact on brain circuitry is poorly understood. Several neuroimaging studies have examined the functional changes in the brain induced by acute administration of ketamine and Ro 25-6981 (a GluN2B-subunit selective antagonist), but the changes in the microstructure of gray and white matter have received less attention. Here, the effects of ketamine and Ro 25-6981 on gray and white matter integrity in male Sprague–Dawley rats were determined using diffusion-weighted magnetic resonance imaging (DWI). In addition, DWI-based structural brain networks were estimated and connectivity metrics were computed at the regional level. Immunohistochemical analyses were also performed to determine whether changes in myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) may underlie connectivity changes. In general, ketamine and Ro 25-6981 showed some opposite structural alterations, but both compounds coincided only in increasing the fractional anisotropy in infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increments of NF200 in deep layers of the infralimbic cortex (together with increased MBP) and the dorsal raphe nucleus. Our results suggest that the synthesis of NF200 and MBP may contribute to the formation of new dendritic spines and myelination, respectively. We also suggest that the increase of fractional anisotropy of the infralimbic and dorsal raphe nucleus areas could represent a biomarker of a rapid antidepressant response.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grants from the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (PI13/00038, PI16/00217 and PI19/00170 to A.A.) that were co-funded by the European Regional Development Fund (‘A way to build Europe’); Generalitat Valenciana, Conselleria d’ Educació, Investigació, Cultura i Esport (GV/2018/049 to A.B-S.); Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00 to F.P.-C.). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged