[Neurobiological basis of neonatal epilepsy and its comorbilities]. / Bases neurobiológicas de la epilepsia neonatal y sus comorbilidades.

The occurrence of seizures is frequent during the neonatal period due to the functional immaturity of the brain.The presence of these seizures may lead to a diagnosis of neonatal epilepsy, which is usually associated with structural alterations of the brain during neurodevelopment. Approximately 50% of people with active epilepsy have at least one comorbid medical disorder, and the existence of a comorbid process changes the course of the epilepsy. The presence of neurologic disorders preceding the onset of epilepsy indicates that underlying neurobiological alterations may independently cause the predisposition to epilepsy and comorbid processes. In this review we describe the structural and functional brain processes underlying the onset of neonatal epilepsy and its comorbidities.

La aparición de convulsiones es frecuente durante el periodo neonatal debido a las características de inmadurez funcional del cerebro es este periodo. La aparición de estas convulsiones puede llevar a un diagnóstico de epilepsia neonatal, que suele estar asociado a alteraciones estructurales del cerebro durante el neurodesarrollo. Aproximadamente el 50% de las personas con epilepsia activa padecen al menos un trastorno médico comórbido, y esto hace que cambie la evolución de la epilepsia. La presencia de trastornos neurológicos que preceden a la aparición de la epilepsia indica que alteraciones estructurales y/o funcionales del cerebro subyacentes pueden ser causa de la predisposición a padecer epilepsia y de los procesos comórbidos de manera independiente. En esta revisión describimos los procesos cerebrales estructurales y funcionales que subyacen a la aparición de epilepsia neonatal y sus comorbilidades.

Expresión de ACE2 en cerebro durante el desarrollo y susceptibilidad de infección cerebral por SARS-COV-2 / ACE2 expression in the brain during development and susceptibility to brain infection by SARS-COV-2

Resumen La pandemia COVID-19 se extendió por todo por a la enorme capacidad del coronavirus SARS-CoV-2 para transmitirse entre humanos. El COVID-19 es una amenaza para la salud pública mundial. La entrada de este virus en las células se ve muy facilitada por la presencia de la enzima convertidora de angiotensina 2 (ACE2) en la membrana celular. Hoy en día no tenemos un conocimiento preciso de cómo se expresa este receptor en el cerebro durante el desarrollo humano y, como consecuencia, no sabemos si las células neurales en desarrollo son susceptibles de ser infectadas a través de la transmisión de madre a feto. Revisamos en este artículo los conocimientos sobre la expresión de ACE2 en el cerebro humano en desarrollo, con especial atención a la etapa fetal. Esta etapa corresponde al periodo de formación de la corteza cerebral. La posibilidad de infección por SARS-CoV-2 durante el periodo fetal puede alterar el desarrollo normal de la corteza cerebral. Así pues, aunque se han publicado pocos casos demostrando la transmisión vertical de la infección por SARS-CoV-2, el gran número de jóvenes infectados puede representar un problema sanitario que necesite seguimiento, por la posibilidad de que se originen alteraciones cognitivas y anomalías en el desarrollo de los circuitos corticales, que pueden representar predisposición a padecer problemas mentales a lo largo de la vida.

Abstract The COVID-19 pandemic spread around the world due to the enormous transmission of the SARS-CoV-2 among humans. COVID-19 represents a threat to global public health. The entry of this virus into cells is greatly facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) in the cell membrane. Today we do not have a precise understanding of how this receptor expresses in the brain during human development and, as a consequence, we do not know whether neural cells in the developing brain are susceptible to infection. We review the knowledge about ACE2 expression in the developing human brain, with special attention to the fetal stage. This stage corresponds to the period of the cerebral cortex formation. Therefore, SARS-CoV-2 infection during the fetal period may alter the normal development of the cerebral cortex. Although few cases have been published demonstrating vertical transmission of SARS-CoV-2 infection, the large number of infected young people may represent a problem which requires health surveillance, due to the possibility of cognitive alterations and abnormalities in the development of cortical circuits that may represent a predisposition to mental problems later in life.

[ACE2 expression in the brain during development and susceptibility to brain infection by SARS-CoV-2]. / Expresión de ACE2 en cerebro durante el desarrollo y susceptibilidad de infección cerebral por SARS-CoV-2.

The COVID-19 pandemic spread around the world due to the enormous transmission of the SARSCoV-2 among humans. COVID-19 represents a threat to global public health. The entry of this virus into cells is greatly facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) in the cell membrane. Today we do not have a precise understanding of how this receptor expresses in the brain during human development and, as a consequence, we do not know whether neural cells in the developing brain are susceptible to infection. We review the knowledge about ACE2 expression in the developing human brain, with special attention to the fetal stage. This stage corresponds to the period of the cerebral cortex formation. Therefore, SARS-CoV-2 infection during the fetal period may alter the normal development of the cerebral cortex. Although few cases have been published demonstrating vertical transmission of SARS-CoV-2 infection, the large number of infected young people may represent a problem which requires health surveillance, due to the possibility of cognitive alterations and abnormalities in the development of cortical circuits that may represent a predisposition to mental problems later in life.

La pandemia COVID-19 se extendió por todo por a la enorme capacidad del coronavirus SARS-CoV-2 para transmitirse entre humanos. El COVID-19 es una amenaza para la salud pública mundial. La entrada de este virus en las células se ve muy facilitada por la presencia de la enzima convertidora de angiotensina 2 (ACE2) en la membrana celular. Hoy en día no tenemos un conocimiento preciso de cómo se expresa este receptor en el cerebro durante el desarrollo humano y, como consecuencia, no sabemos si las células neurales en desarrollo son susceptibles de ser infectadas a través de la transmisión de madre a feto. Revisamos en este artículo los conocimientos sobre la expresión de ACE2 en el cerebro humano en desarrollo, con especial atención a la etapa fetal. Esta etapa corresponde al periodo de formación de la corteza cerebral. La posibilidad de infección por SARS-CoV-2 durante el periodo fetal puede alterar el desarrollo normal de la corteza cerebral. Así pues, aunque se han publicado pocos casos demostrando la transmisión vertical de la infección por SARS-CoV-2, el gran número de jóvenes infectados puede representar un problema sanitario que necesite seguimiento, por la posibilidad de que se originen alteraciones cognitivas y anomalías en el desarrollo de los circuitos corticales, que pueden representar predisposición a padecer problemas mentales a lo largo de la vida.

Prosomeric Hypothalamic Distribution of Tyrosine Hydroxylase Positive Cells in Adolescent Rats.

Most of the studies on neurochemical mapping, connectivity, and physiology in the hypothalamic region were carried out in rats and under the columnar morphologic paradigm. According to the columnar model, the entire hypothalamic region lies ventrally within the diencephalon, which includes preoptic, anterior, tuberal, and mamillary anteroposterior regions, and sometimes identifying dorsal, intermediate, and ventral hypothalamic partitions. This model is weak in providing little or no experimentally corroborated causal explanation of such subdivisions. In contrast, the modern prosomeric model uses different axial assumptions based on the parallel courses of the brain floor, alar-basal boundary, and brain roof (all causally explained). This model also postulates that the hypothalamus and telencephalon jointly form the secondary prosencephalon, separately from and rostral to the diencephalon proper. The hypothalamus is divided into two neuromeric (transverse) parts called peduncular and terminal hypothalamus (PHy and THy). The classic anteroposterior (AP) divisions of the columnar hypothalamus are rather seen as dorsoventral subdivisions of the hypothalamic alar and basal plates. In this study, we offered a prosomeric immunohistochemical mapping in the rat of hypothalamic cells expressing tyrosine hydroxylase (TH), which is the enzyme that catalyzes the conversion of L-tyrosine to levodopa (L-DOPA) and a precursor of dopamine. This mapping was also combined with markers for diverse hypothalamic nuclei [agouti-related peptide (Agrp), arginine vasopressin (Avp), cocaine and amphetamine-regulated transcript (Cart), corticotropin releasing Hormone (Crh), melanin concentrating hormone (Mch), neuropeptide Y (Npy), oxytocin/neurophysin I (Oxt), proopiomelanocortin (Pomc), somatostatin (Sst), tyrosine hidroxilase (Th), and thyrotropin releasing hormone (Trh)]. TH-positive cells are particularly abundant within the periventricular stratum of the paraventricular and subparaventricular alar domains. In the tuberal region, most labeled cells are found in the acroterminal arcuate nucleus and in the terminal periventricular stratum. The dorsal retrotuberal region (PHy) contains the A13 cell group of TH-positive cells. In addition, some TH cells appear in the perimamillary and retromamillary regions. The prosomeric model proved useful for determining the precise location of TH-positive cells relative to possible origins of morphogenetic signals, thus aiding potential causal explanation of position-related specification of this hypothalamic cell type.

El cerebro ¿Una máquina analógica con funcionamiento cuántico? / The brain. An analogic machine with quantum functioning?

Resumen La neurociencia moderna aborda el problema de funcionamiento global del cerebro para poder comprender los procesos neurobiológicos que subyacen a las funciones mentales, y especialmente, a la consciencia. La actividad cerebral está basada en el intercambio de información entre neuronas a través de contactos llamados sinapsis. Las neuronas forman redes de conexión entre ellas (circuitos), que están dedicados a procesar una parcela específica de información (visual, auditiva, motora…). Los circuitos establecen redes entre ellos, combinando diferentes modalidades de información para generar lo que conocemos como actividad mental. El estudio de las conexiones entre regiones corticales, que se ha llamado conectoma, está siendo abordado mediante técnicas de neuroimagen como la resonancia magnética nuclear, que aportan datos sobre la densidad de conexiones del cerebro. La capacidad del cerebro de crear nuevas conexiones en función de la experiencia (plasticidad cerebral), sugiere que el conectoma es una estructura dinámica en constante interacción con estímulos externos e internos. La pregunta sobre si el conocimiento del conectoma de un individuo nos per mitiría predecir su conducta parece que todavía no tiene respuesta clara, porque no conocemos los parámetros físicos que ligan la complejidad de las conexiones del cerebro con la aparición de las funciones mentales y de la consciencia. Por el momento, parece que la compleja e impredecible conducta no es el simple resultado de procesos lineales de interacción neuronal. La incertidumbre prima al determinismo, lo que abre la puerta a la posibilidad de un mecanismo cuántico para explicar la consciencia.

Abstract Modern neuroscience addresses the problem of the global functioning of the brain in order to understand the neurobiological processes that underlie mental functions, and especially, consciousness. Brain activity is based on the exchange of infor mation between neurons through contacts or synapses. Neurons form networks of connection between them (circuits), which are dedicated to processing a specific type of information (visual, auditory, motor…). The circuits establish networks among themselves, combining different modalities of information to generate what we know as mental activity. The study of connections between cortical regions, which has been called connectome, is being approached through neuroimaging techniques such as nuclear magnetic resonance that provide data on the density of connections in the brain. The brain's ability to create new connections based on experience (brain plasticity) suggests that the connectome is a dynamic structure in constant interaction with external and internal stimuli. The question about whether knowledge of an individual's connectome would allow us to predict his or her behavior seems to have no clear answer yet, because we do not know the physical parameters that link the complexity of the brain's connections with the appearance of mental functions and consciousness. At the moment, it seems that the complex and unpredictable behavior is not the simple result of linear processes of neuronal interaction. Uncertainty prevails over determinism, which opens the door to the possibility of a quantum mechanism to explain consciousness.

[The brain. An analogic machine with quantum functioning?] / El cerebro ¿una máquina analógica con funcionamiento cuántico?

Modern neuroscience addresses the problem of the global functioning of the brain in order to understand the neurobiological processes that underlie mental functions, and especially, consciousness. Brain activity is based on the exchange of information between neurons through contacts or synapses. Neurons form networks of connection between them (circuits), which are dedicated to processing a specific type of information (visual, auditory, motor ...). The circuits establish networks among themselves, combining different modalities of information to generate what we know as mental activity. The study of connections between cortical regions, which has been called connectome, is being approached through neuroimaging techniques such as nuclear magnetic resonance that provide data on the density of connections in the brain. The brain's ability to create new connections based on experience (brain plasticity) suggests that the connectome is a dynamic structure in constant interaction with external and internal stimuli. The question about whether knowledge of an individual's connectome would allow us to predict his or her behavior seems to have no clear answer yet, because we do not know the physical parameters that link the complexity of the brain's connections with the appearance of mental functions and consciousness. At the moment, it seems that the complex and unpredictable behavior is not the simple result of linear processes of neuronal interaction. Uncertainty prevails over determinism, which opens the door to the possibility of a quantum mechanism to explain consciousness.

La neurociencia moderna aborda el problema de funcionamiento global del cerebro para poder comprender los procesos neurobiológicos que subyacen a las funciones mentales, y especialmente, a la consciencia. La actividad cerebral está basada en el intercambio de información entre neuronas a través de contactos llamados sinapsis. Las neuronas forman redes de conexión entre ellas (circuitos), que están dedicados a procesar una parcela específica de información (visual, auditiva, motora ...). Los circuitos establecen redes entre ellos, combinando diferentes modalidades de información para generar lo que conocemos como actividad mental. El estudio de las conexiones entre regiones corticales, que se ha llamado conectoma, está siendo abordado mediante técnicas de neuroimagen como la resonancia magnética nuclear, que aportan datos sobre la densidad de conexiones del cerebro. La capacidad del cerebro de crear nuevas conexiones en función de la experiencia (plasticidad cerebral), sugiere que el conectoma es una estructura dinámica en constante interacción con estímulos externos e internos. La pregunta sobre si el conocimiento del conectoma de un individuo nos permitiría predecir su conducta parece que todavía no tiene respuesta clara, porque no conocemos los parámetros físicos que ligan la complejidad de las conexiones del cerebro con la aparición de las funciones mentales y de la consciencia. Por el momento, parece que la compleja e impredecible conducta no es el simple resultado de procesos lineales de interacción neuronal. La incertidumbre prima al determinismo, lo que abre la puerta a la posibilidad de un mecanismo cuántico para explicar la consciencia.

Differentiation of human adult-derived stem cells towards a neural lineage involves a dedifferentiation event prior to differentiation to neural phenotypes.

Although it has been reported that mesenchymal stem cells isolated from adult tissues can be induced to overcome their mesenchymal fate and transdifferentiate into neural cells, the findings and their interpretation have been challenged. The main argument against this process is that the cells rapidly adopt neuron-like morphologies through retraction of the cytoplasm rather than active neurite extension. In this study, we examined the sequence of biological events during neural differentiation of human periodontal ligament-derived stem cells (hPDLSCs), human bone marrow-derived stem cells (hBMSCs) and human dental pulp-derived stem cells (hDPSCs) by time-lapse microscopy. We have demonstrated that hPDLSCs, hBMSCs and hDPSCs can directly differentiate into neuron-like cells without passing through a mitotic stage and that they shrink dramatically and change their morphology to that of neuron-like cells through active neurite extension. Furthermore, we observed micronuclei movement and transient cell nuclei lobulation concurrent to in vitro neurogenesis from hBMSCs and hDPSCs. Our results demonstrate that the differentiation of hPDLSCs, hBMSCs and hDPSCs towards a neural lineage occurs through a dedifferentiation step followed by differentiation to neural phenotypes, and therefore we definitively confirm that the rapid acquisition of the neural phenotype is via a differentiation trait.

A Handful of Details to Ensure the Experimental Reproducibility on the FORCED Running Wheel in Rodents: A Systematic Review.

A well-documented method and experimental design are essential to ensure the reproducibility and reliability in animal research. Experimental studies using exercise programs in animal models have experienced an exponential increase in the last decades. Complete reporting of forced wheel and treadmill exercise protocols would help to ensure the reproducibility of training programs. However, forced exercise programs are characterized by a poorly detailed methodology. Also, current guidelines do not cover the minimum data that must be included in published works to reproduce training programs. For this reason, we have carried out a systematic review to determine the reproducibility of training programs and experimental designs of published research in rodents using a forced wheel system. Having determined that most of the studies were not detailed enough to be reproducible, we have suggested guidelines for animal research using FORCED exercise wheels, which could also be applicable to any form of forced exercise.

[Mechanism of action of cell therapy in hereditary diseases]. / Mecanismo de acción de la terapia celular en enfermedades hereditarias.

Inherited metabolism disorders are serious childhood diseases that lead to significant cognitive impairment and regression of psychomotor development. The pathophysiology of the neural progressive deterioration is usually associated with severe neuroinflammation and demyelination, and as a consequence, neurodegeneration. At the moment they have no adequate treatment and require early and aggressive therapeutic approaches, which entail high mortality rates and, very frequently, low degrees of functional improvement and survival. Bone marrow transplantation and bone marrow mesenchymal cells grafts are therapeutic and experimental therapies that improve the course of these diseases through different mechanisms of action: enzyme replacement, membrane exchange and regulation of the inflammatory process.

Los trastornos heredados del metabolismo son enfermedades graves de la infancia que cursan con un gran deterioro cognitivo y del desarrollo psicomotor. La fisiopatología del progresivo deterioro del sistema nervioso suele estar asociada a una severa neuroinflamación y desmielinización, y como consecuencia, neurodegeneración. Por el momento no tienen cura y precisan de actitudes terapéuticas precoces y agresivas, que conllevan altas tasas de mortalidad y, muy frecuentemente, escasos grados de mejoría funcional y supervivencia. El trasplante de médula ósea y de células mesenquimales de médula ósea son terapias de elección y experimentales que consiguen mejorar el curso de estas enfermedades mediante diferentes mecanismos de acción: remplazo de enzima deficiente, intercambio de membranas y regulación del proceso inflamatorio.

Mecanismo de acción de la terapia celular en enfermedades hereditarias / Mechanism of action of cell therapy in hereditary diseases

Los trastornos heredados del metabolismo son enfermedades graves de la infancia que cursan con un gran deterioro cognitivo y del desarrollo psicomotor. La fisiopatología del progresivo deterioro del sistema nervioso suele estar asociada a una severa neuroinflamación y desmielinización, y como consecuencia, neurodegeneración. Por el momento no tienen cura y precisan de actitudes terapéuticas precoces y agresivas, que conllevan altas tasas de mortalidad y, muy frecuentemente, escasos grados de mejoría funcional y supervivencia. El trasplante de médula ósea y de células mesenquimales de médula ósea son terapias de elección y experimentales que consiguen mejorar el curso de estas enfermedades mediante diferentes mecanismos de acción: remplazo de enzima deficiente, intercambio de membranas y regulación del proceso inflamatorio.

Inherited metabolism disorders are serious childhood diseases that lead to significant cognitive impairment and regression of psychomotor development. The pathophysiology of the neural progressive deterioration is usually associated with severe neuroinflammation and demyelination, and as a consequence, neurodegeneration. At the moment they have no adequate treatment and require early and aggressive therapeutic approaches, which entail high mortality rates and, very frequently, low degrees of functional improvement and survival. Bone marrow transplantation and bone marrow mesenchymal cells grafts are therapeutic and experimental therapies that improve the course of these diseases through different mechanisms of action: enzyme replacement, membrane exchange and regulation of the inflammatory process.

Non-proliferative neurogenesis in human periodontal ligament stem cells.

Understanding the sequence of events from undifferentiated stem cells to neuron is not only important for the basic knowledge of stem cell biology, but also for therapeutic applications. In this study we examined the sequence of biological events during neural differentiation of human periodontal ligament stem cells (hPDLSCs). Here, we show that hPDLSCs-derived neural-like cells display a sequence of morphologic development highly similar to those reported before in primary neuronal cultures derived from rodent brains. We observed that cell proliferation is not present through neurogenesis from hPDLSCs. Futhermore, we may have discovered micronuclei movement and transient cell nuclei lobulation coincident to in vitro neurogenesis. Morphological analysis also reveals that neurogenic niches in the adult mouse brain contain cells with nuclear shapes highly similar to those observed during in vitro neurogenesis from hPDLSCs. Our results provide additional evidence that it is possible to differentiate hPDLSCs to neuron-like cells and suggest the possibility that the sequence of events from stem cell to neuron does not necessarily requires cell division from stem cell.

Bases neurobiológicas del autismo y modelos celulares para su estudio experimental / Neurobiological bases of autism and cellular models for its experimental study

Los trastornos del espectro autista (TEA) son una alteración funcional de la corteza cerebral, que presenta anomalías estructurales del neurodesarrollo que afectan fundamentalmente a la función sináptica y el patrón de conexiones dentro y entre columnas corticales. Desde su aspecto etiológico, el TEA tiene una importante carga genética, considerándose un desorden derivado de una combinación de mutaciones "de novo", asociadas a una predisposición derivada de variaciones comunes heredadas. Las principales anomalías genéticas asociadas a TEA implican genes que codifican proteínas de la sinapsis. Así, en pacientes con TEA se han descrito alteraciones del desarrollo inicial de las sinapsis en los circuitos de conexión entre áreas corticales de procesamiento complejo. La complejidad molecular observada en la predisposición a desarrollar un TEA, junto con la diversidad de fenotipos estructurales neuronales, ha hecho que los modelos animales reproduzcan solo parcialmente el TEA. Para avanzar en el estudio experimental se hace pues necesario desarrollar modelos más representativos, como son los modelos celulares derivados de células humanas. En las últimas décadas, el desarrollo de la biología de las células madre nos da medios para acceder a paradigmas experimentales sobre células derivadas de individuos con TEA. Actualmente, los modelos de células plutipotentes inducidas (IPs) derivadas de células humanas permiten profundizar en el estudio de las bases moleculares y celulares del TEA. Sin embargo, presentan problemas inherentes derivados de la manipulación experimental que conlleva la reprogramación de la expresión génica, por lo que otros modelos celulares se están también postulando como válidos.

Autism Spectrum Disorders (ASD) are a functional alteration of the cerebral cortex, which presents structural neurodevelopmental anomalies that affect synaptic function and the pattern of connections within and between cortical columns. From its etiological aspect, ASD has an important genetic load, considering a polygenic disorder, derived from a combination of "de novo" genetic mutations, associated to a predisposition derived from common inherited variations. The main genetic anomalies associated with ASD involve genes that encode proteins of the synapse. Thus, in patients with ASD, alterations in the initial development of the synapses have been described in the connection circuits between complex processing cortical areas. The molecular complexity observed in the predisposition to develop an ASD, together with the diversity of structural phenotypes, has made animal models reproduce only partially the ASD. To advance in the experimental study it is therefore necessary to develop representative models, such as cellular models derived from human cells. In recent decades, the advances in stem cell biology give us a way to apply experimental paradigms in cells derived from individuals with ASD. Currently, induced pluripotent cells (IPs) derived from human adult cells allow deepening the study of molecular and cellular bases of the neuronal development in humans, as well as the anomalies in this development, which give rise to disorders such as ASD. However, they present inherent problems derived from the experimental manipulation that involves the reprogramming of gene expression, therefore other models are also been explored.

[Neurobiological bases of autism and cellular models for its experimental study]. / Bases neurobiológicas del autismo y modelos celulares para su estudio experimental.

Autism Spectrum Disorders (ASD) are a functional alteration of the cerebral cortex, which presents structural neurodevelopmental anomalies that affect synaptic function and the pattern of connections within and between cortical columns. From its etiological aspect, ASD has an important genetic load, considering a polygenic disorder, derived from a combination of "de novo" genetic mutations, associated to a predisposition derived from common inherited variations. The main genetic anomalies associated with ASD involve genes that encode proteins of the synapse. Thus, in patients with ASD, alterations in the initial development of the synapses have been described in the connection circuits between complex processing cortical areas. The molecular complexity observed in the predisposition to develop an ASD, together with the diversity of structural phenotypes, has made animal models reproduce only partially the ASD. To advance in the experimental study it is therefore necessary to develop representative models, such as cellular models derived from human cells. In recent decades, the advances in stem cell biology give us a way to apply experimental paradigms in cells derived from individuals with ASD. Currently, induced pluripotent cells (IPs) derived from human adult cells allow deepening the study of molecular and cellular bases of the neuronal development in humans, as well as the anomalies in this development, which give rise to disorders such as ASD. However, they present inherent problems derived from the experimental manipulation that involves the reprogramming of gene expression, therefore other models are also been explored.

Los trastornos del espectro autista (TEA) son una alteración funcional de la corteza cerebral, que presenta anomalías estructurales del neurodesarrollo que afectan fundamentalmente a la función sináptica y el patrón de conexiones dentro y entre columnas corticales. Desde su aspecto etiológico, el TEA tiene una importante carga genética, considerándose un desorden derivado de una combinación de mutaciones "de novo", asociadas a una predisposición derivada de variaciones comunes heredadas. Las principales anomalías genéticas asociadas a TEA implican genes que codifican proteínas de la sinapsis. Así, en pacientes con TEA se han descrito alteraciones del desarrollo inicial de las sinapsis en los circuitos de conexión entre áreas corticales de procesamiento complejo. La complejidad molecular observada en la predisposición a desarrollar un TEA, junto con la diversidad de fenotipos estructurales neuronales, ha hecho que los modelos animales reproduzcan solo parcialmente el TEA. Para avanzar en el estudio experimental se hace pues necesario desarrollar modelos más representativos, como son los modelos celulares derivados de células humanas. En las últimas décadas, el desarrollo de la biología de las células madre nos da medios para acceder a paradigmas experimentales sobre células derivadas de individuos con TEA. Actualmente, los modelos de células plutipotentes inducidas (IPs) derivadas de células humanas permiten profundizar en el estudio de las bases moleculares y celulares del TEA. Sin embargo, presentan problemas inherentes derivados de la manipulación experimental que conlleva la reprogramación de la expresión génica, por lo que otros modelos celulares se están también postulando como válidos.

Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients.

The engrailed homeobox protein (EN) plays an important role in the regionalization of the neural tube. EN distribution regulates the cerebellum and midbrain morphogenesis, as well as retinotectal synaptogenesis. In humans, the EN1 and EN2 genes code for the EN family of transcription factors. Genetic alterations in the expression of EN2 have been related to different neurologic conditions and more particularly to autism spectrum disorders (ASD). We aimed to study and compare the phenotypes of three series of patients: (1) patients with encephalic structural anomalies (ESA) and abnormalities in the genomic (DNA) and/or transcriptomic (RNAm) of EN2 (EN2-g), (2) ESA patients having other gene mutations (OG-g), and (3) ESA patients free of these mutations (NM-g). Subjects and Methods: We have performed a descriptive study on 109 patients who suffer from mental retardation (MR), cerebral palsy (CP), epilepsy (EP), and behavioral disorders (BD), showing also ESA in their encephalic MRI. We studied genomic DNA and transcriptional analysis (cDNA) on EN2 gene (EN2), and in other genes (OG): LIS1, PTAFR, PAFAH1B2, PAFAH1B3, FGF8, PAX2, D17S379, D17S1866, and SMG6 (D17S5), as a routine genetic diagnosis in ESA patients. Results: From 109 patients, fifteen meet the exclusion criteria. From the remaining 94 patients, 12 (12.8%) showed mutations in EN2 (EN2-g), 20 showed mutations in other studied genes (OG-g), and 62 did not showed any mutation (NM-g). All EN2-g patients, suffered from MR, nine EP, seven BD and four CP. The proportions of these phenotypes in EN2-g did not differ from those in the OG-g, but it was significantly higher when comparing EN2-g with NM-g (MR: p = 0.013; EP: p = 0.001; BD: p = 0.0001; CP: p = 0.07, ns). Groups EN2-g and OG-g showed a 100 and a 70% of comorbidity, respectively, being significantly (p = 0.04) greater than NM-group (62.9%). Conclusion: Our series reflects a significant effect of EN2 gene alterations in neurodevelopmental abnormalities associated to ESA. Conversely, although these EN2 related anomalies might represent a predisposition to develop brain diseases, our results did not support direct relationship between EN2 mutations and specific clinical phenotypes.

Bases neurobiológicas del trastorno del espectro autista y del trastorno por déficit de atención/hiperactividad: diferenciación neural y sinaptogénesis / Neurobiological bases of autistic spectrum disorder and attention deficit hyperactivity disorder: neural differentiation and synaptogenesis

Objetivo. Conocer los procesos neurales ligados a la formación de sinapsis y circuitos cerebrales para entender su papel en las enfermedades del neurodesarrollo, como el trastorno del espectro autista (TEA) y el trastorno por déficit de atención/hiperactividad (TDAH). Desarrollo. La actividad de los circuitos neuronales es la base neurobiológica de la conducta y la actividad mental (emociones, memoria y pensamientos). Los procesos de diferenciación de las células neurales y la formación de circuitos por contactos sinápticos entre neuronas (sinaptogénesis) ocurren en el sistema nervioso central durante las últimas fases del desarrollo prenatal y los primeros meses después del nacimiento. Los TEA y el TDAH comparten rasgos biológicos, relacionados con alteraciones en los circuitos cerebrales y la función sináptica, que permiten tratarlos científicamente de forma conjunta. Desde el aspecto neurobiológico, el TEA y el TDAH son manifestaciones de anomalías en la formación de circuitos y contactos sinápticos en regiones cerebrales implicadas en la conducta social, especialmente en la corteza cerebral prefrontal. Estas anomalías son causadas por mutaciones en genes involucrados en la formación de sinapsis y plasticidad sináptica, la regulación de la morfología de las espinas dendríticas, la organización del citoesqueleto y el control del equilibrio excitador e inhibidor en la sinapsis. Conclusiones. El TEA y el TDAH son alteraciones funcionales de la corteza cerebral, que presenta anomalías estructurales en la disposición de las neuronas, en el patrón de conexiones de las columnas corticales y en la estructura de las espinas dendríticas. Estas alteraciones afectan fundamentalmente a la corteza prefrontal y sus conexiones (AU)

Aim. To know the neural processes linked to the activity of brain circuits in order to understand the consequences of their dysfunction and their role in the development of neurodevelopmental diseases, such as autistic spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). Development. The activity of neuronal circuits is the neurobiological basis of behavior and mental activity (emotions, memory and thoughts). The processes of differentiation of neural cells and the formation of circuits by synaptic contacts between neurons (synaptogenesis) occur in the central nervous system during the late stages of prenatal development and the first months after birth. ASD and ADHD share biological features, mainly related to alterations in brain circuits and synaptic function, which allow us to treat them scientifically together. From the neurobiological aspect, ASD and ADHD are manifestations of anomalies in the formation of circuits and synaptic contacts in the brain regions involved in social behavior, and especially in the prefrontal cerebral cortex. These anomalies are caused by mutations in genes involved synaptogenesis and synaptic plasticity, regulation of dendritic spine morphology, synaptic cytoskeletal organization, synthesis and degradation of synaptic proteins, and control of excitatory and inhibitory balance in the synaptic function. Conclusions. ASD and ADHD are functional alterations of the cerebral cortex, which present structural anomalies in the arrangement of neurons, in the pattern of connections of cortical columns and in the structure of dendritic spines. These alterations affect mainly the prefrontal cortex and its connections (AU)

Plasticidad neural: la sinaptogénesis durante el desarrollo normal y su implicación en la discapacidad intelectual / Neuroplasticity: synaptogenesis during normal development and its implication in intellectual disability

La neuroplasticidad es la capacidad biológica que tiene el sistema nervioso de modificar su estructura y función para adaptarse a las variaciones del entorno, tanto fisiológicas como patológicas. Sus principales consecuencias fisiológicas son el aprendizaje y la memoria, y las patológicas, la rehabilitación neurológica. El continuo cambio y la fragilidad inicial del cerebro en desarrollo hacen especialmente plásticos los períodos embrionario y fetal (lo que se conoce como neuroplasticidad del desarrollo). Ahora bien, la reducción progresiva de la plasticidad nunca es total, permaneciendo a lo largo de toda la vida la capacidad de modificar los circuitos cerebrales en respuesta a nuevos aprendizajes (neuroplasticidad adaptativa) o a lesiones cerebrales (neuroplasticidad reactiva). El principal mecanismo neurobiológico de la neuroplasticidad es la formación de contactos sinápticos entre neuronas. Los trastornos del neurodesarrollo están asociados a anomalías funcionales del cerebro, muchas veces derivadas de la falta de capacidad adaptativa o reactiva del cerebro para modificar los circuitos malformados o dañados por anomalías genéticas o ambientales. Clásicamente se asocian con la aparición de discapacidad intelectual y enfermedades mentales. Esta revisión trata sobre el desarrollo de la neuroplasticidad cerebral y sus mecanismos neurobiológicos. También se analizan algunos de los procesos celulares y moleculares que están implicados en su desarrollo normal y las posibles consecuencias derivadas de sus alteraciones (AU)

Neuroplasticity is the biological capacity of the nervous system to modify its structure and functioning to adapt to both physiological and pathological variations in the environment. Its main physiological consequences are learning and memory, and its pathological outcome is neurological rehabilitation. The continuous change and initial fragility of the developing brain make the embryonic and foetal periods especially plastic (what is known as developmental neuroplasticity). The progressive reduction in plasticity, however, is never complete and the capacity to modify the brain circuits in response to new learning (adaptive neuroplasticity) or brain injuries (reactive neuroplasticity) remains throughout the individual’s entire lifespan. The main neurobiological mechanism underlying neuroplasticity is the formation of synaptic contacts between neurons. Neurodevelopmental disorders are associated to functional anomalies of the brain, often derived from the lack of adaptive or reactive capacity of the brain to modify circuits that are malformed or damaged by genetic or environmental anomalies. They are traditionally associated with the appearance of intellectual disability and mental illnesses. This review deals with the development of the neuroplasticity of the brain and its neurobiological mechanisms. Some of the cellular and molecular processes involved in its normal development are also examined, together with the possible consequences deriving from alterations affecting them (AU)

Desarrollo y plasticidad del cerebro / Brain development and plasticity

Los trastornos de neurodesarrollo están asociados a anomalías funcionales del cerebro que se manifiestan de forma temprana en la vida. Clásicamente se asociaban de manera casi exclusiva con la aparición de discapacidad intelectual y retraso en el desarrollo psicomotor. Las causas de estos trastornos se han descrito parcialmente, incluyendo anomalías por causas genéticas (síndrome de Down, X frágil, etc.), por exposición a factores tóxicos durante el embarazo (síndrome alcohólico fetal), infecciones (citomegalovirus, toxoplasmosis, etc.) o por otras alteraciones, entre las que cabe citar la gran inmadurez en el momento del nacimiento (grandes prematuros). Datos epidemiológicos apoyados en un mejor conocimiento de las enfermedades del sistema nervioso central indican que algunos trastornos mentales, que aparecen en la adolescencia o la madurez temprana, están originados también por anomalías del desarrollo cerebral. Esta revisión pretende dar una visión general del desarrollo cerebral. También se analizan algunos de los procesos celulares y moleculares que pueden explicar las similitudes y diferencias en los fenotipos que generan las alteraciones del desarrollo normal. Todo ello con el objetivo de identificar claramente los procesos sensibles a ser modificados con la actuación terapéutica de un programa de atención temprana (AU)

Neurodevelopmental disorders are associated to functional anomalies of the brain that become manifest early on in life. Traditionally, they have been related almost exclusively to the appearance of intellectual disability and delayed psychomotor development. The causes of these disorders have been partially described, and include anomalies due to genetic causes (Down syndrome, fragile X syndrome, etc.), exposure to toxic factors during pregnancy (foetal alcohol syndrome), infections (cytomegalovirus, toxoplasmosis, etc.) or other alterations, including a status of great immaturity at birth (very preterm). Epidemiological data based on a better knowledge of the diseases affecting the central nervous system suggest that some mental disorders, which appear in adolescence or early adulthood, also have their origin in anomalies in brain development. This review aims to offer an overview of brain development. Some of the cellular and molecular processes that may account for the similarities and differences in the phenotypes that generate alterations affecting normal development are also analysed. The study is conducted with a view to clearly identifying processes that are susceptible to modification by means of therapeutic intervention consisting in an early care programme (AU)

Desarrollo del dimorfismo sexual en el cerebro: el origen de la identidad y la conducta sexual / Sexual dimorphism development in the brain: the origin of sexual identity and behavior

El cerebro es el órgano más complejo del organismo del que dependen las funciones mentales y la conducta. Es evidente que las diferencias que caracterizan el comportamiento de machos y hembras en los vertebrados son debidas a la existencia de diferencias estructurales en el cerebro. Hoy en día se conoce bastante sobre las bases moleculares y celulares que subyacen al desarrollo y mantenimiento de estas diferencias, y por lo tanto, de las bases neurobiológicas del comportamiento diferencial entre machos y hembras de una misma especie. Nos proponemos revisar los últimos hallazgos que explican el desarrollo y las principales características del dimorfismo sexual en el cerebro de mamíferos y del hombre. Veremos cómo la producción de hormonas gonadales durante el desarrollo actúa sobre receptores específicos que regulan procesos fundamentales en el desarrollo genital durante la etapa precoz del desarrollo, y del sistema nervioso central durante la etapa perinatal. En el cerebro embrionario la acción de estas hormonas regula la neurogenesis y la muerte celular en regiones localizadas. Las neuronas y los circuitos neuronales de estas regiones están fundamentalmente implicados en el control de respuestas autónomas y reflejos motores con claro dimorfismo sexual, así como en funciones cerebrales más complejas que determinan la identidad y la conducta sexual del individuo. Por otro lado, el dimorfismo sexual del cerebro es aparente en otras regiones, explicando la respuesta diferente de machos y hembras a procesos que producen alteraciones generales de la función cerebral (AU)

Mental functions and behavior are consequence of the complex brain structure and function. Therefore, the differences that characterize the behavior of males and females in vertebrates are due to the existence of structural differences in the brain. Today our knowledge about the molecular and cellular processes underlying the development and maintenance of these differences is progressively increasing, and thus, the understanding of the neurobiological basis of differential behavior between males and females. We propose to review the latest findings that explain the development and the main features of sexual dimorphism in the brain of mammals. We will see how the production of gonadal hormones during development, acting on specific receptors, regulates key processes in the central nervous system during the perinatal period. In embryonic brain the action of these hormones modulate neurogenesis and cell death in specific neural regions. Neurons and neural circuitry of these regions are primarily involved in the control of autonomous sexual dimorphic motor reflex responses, as well as more complex brain functions as sexual identity and behavior. Moreover, the brain sexual dimorphism is also apparent in other regions, which explain the different response of males and females to general processes that produce alterations in brain function (AU)