HDAC2 Inhibits Hippocampal Neurogenesis and Impairs the Cognitive Function in Prenatally Stressed Adult Offspring / HDAC2 Inhibe la Neurogénesis del Hipocampo y Afecta la Función Cognitiva en la Descendencia Adulta Estresada Prenatalmente

SUMMARY: The objective of this study was to investigate the mechanism of prenatal stress on the cognitive function of offspring, and clarify the change of histone deacetylase 2 (HDAC2) expression in hippocampal neurons of offspring. 16 pregnant SD rats were randomly divided into control group and stress group, with eight rats in each group. The stress group received restrained stress from 15 to 21 days of pregnancy, while the control group did not receive any treatment. Anxiety-like behavior and spatial memory, learning and memory ability were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. Nissl staining was used to detect the function of hippocampal neurons. Western blot was used to detect the expression of HDAC2 protein in hippocampal neurons of adult offspring. Immunofluorescence staining was used to detect the expression of HDAC2 protein and hippocampal neurogenesis. The learning and memory ability of adult offspring was decreased. The prenatal stress damaged the function of hippocampal neurons , the expression of HDAC2 was down-regulated, and the number of neurons was reduced. Maternal prenatal stress can down- regulate the expression of HDAC2 in the hippocampus of offspring, inhibits hippocampal neurogenesis and impairs the cognitive function.

El objetivo de este estudio fue investigar el mecanismo del estrés prenatal en la función cognitiva de la descendencia y aclarar el cambio de la expresión de la histona desacetilasa 2 (HDAC2) en las neuronas del hipocampo de la descendencia. 16 ratas SD preñadas se dividieron aleatoriamente en un grupo de control y un grupo de estrés, con ocho ratas en cada grupo. El grupo de estrés recibió estrés durante 15 a 21 días de pre, preñez, mientras que el grupo de control no recibió ningún tratamiento. El comportamiento similar a la ansiedad y la memoria espacial, el aprendizaje y la capacidad de memoria se detectaron en campo abierto, laberinto en cruz elevado, prueba de reconocimiento de objetos novedosos y laberinto de Barnes. La tinción de Nissl se utilizó para detectar la función de las neuronas del hipocampo. Se utilizó Western blot para detectar la expresión de la proteína HDAC2 en las neuronas del hipocampo de la descendencia adulta. La tinción de inmunofluorescencia se utilizó para detectar la expresión de la proteína HDAC2 y la neurogénesis del hipocampo. La capacidad de aprendizaje y memoria de la descendencia adulta se redujo. El estrés prenatal dañó la función de las neuronas del hipocampo, se reguló negativamente la expresión de HDAC2 y se redujo el número de neuronas. El estrés prenatal materno puede regular a la baja la expresión de HDAC2 en el hipocampo de la descendencia, inhibe la neurogénesis del hipocampo y deteriora la función cognitiva.

Effect of fish oil on oxidative stress markers in patients with probable Alzheimer´s disease

High intake of omega-3 fatty acids has been associated with synaptic plasticity, neurogenesis and memory in several experimental models. To assess the efficacy of fish oil supplementation on oxidative stress markers in patients diagnosed with probable Alzheimer´s disease (AD) we conducted a double blind, randomized, placebo controlled clinical trial. AD patients who met the inclusive criteria were given fish oil (containing 0.45 g eicosapentaenoic acid and 1 g docosahexaenoic acid) or placebo daily for 12 months. Oxidative stress markers [lipoperoxides, nitric oxide catabolites levels, oxidized/reduced glutathione ratio, and membrane fluidity] and fatty acid profile in erythrocytes were assessed at enrollment, and 6 and 12 months after the start of the testing period. At the end of the trial, in patients who received fish oil, we detected a decrease in the omega 6/omega 3 ratio in erythrocyte membrane phospholipids. This change was parallel with decreases in plasma levels of lipoperoxides and nitric oxide catabolites. Conversely, the ratio of reduced to oxidized glutathione was significantly increased. In addition, membrane fluidity was increased significantly in plasma membrane samples. In conclusion fish oil administration has a beneficial effect in decreasing the levels of oxidative stress markers and improving the membrane fluidity in plasma(AU)

El alto consumo de ácidos grasos omega-3 se asocia con la plasticidad sináptica, neurogénesis y memoria en varios modelos experimentales. Para evaluar la eficacia de la suplementación con aceite de pescado en los marcadores de estrés oxidativo en pacientes con diagnóstico de la enfermedad de Alzheimer (EA) probable realizamos un ensayo clínico doble ciego, aleatorizado, controlado con placebo. A los pacientes con la EA que cumplían los criterios de inclusión se les administró aceite de pescado (que contenía 0,45 g de ácido eicosapentaenoico y 1 g de ácido docosahexaenoico) o placebo diariamente durante 12 meses. Los marcadores de estrés oxidativo plasmático [niveles de lipoperóxidos y catabolitos del óxido nítrico, cociente de glutatión reducido a glutatiónoxidado) y fluidez de la membrana] y el perfil de ácidos grasos en los eritrocitos se evaluaron al inicio, 6 meses y alos 12 meses. Al final del ensayo, en pacientes que recibieron aceite de pescado detectamos una disminución en el cociente de ácidos grasos omega 6/omega 3 en los fosfolípidos de la membrana eritrocitaria. Este cambio ocurrió en paralelo a la disminución de los niveles plasmáticos de lipoperóxidos y catabolitos del óxido nítrico. Por el contrario, el cociente de glutatión reducido a glutatión oxidado se incrementó significativamente. Además, la fluidez de la membrana aumentó significativamente en las muestras analizadas. En conclusión, la administración de aceite de pescado tiene un efecto beneficioso al disminuir los niveles de marcadores de estrés oxidativo plasmático y mejorar la fluidez de la membrana plasmática(AU)

The neurogenic effects of rosmarinic acid in a mouse model of type 2 diabetes mellitus

There is emerging evidence for a dysregulation of insulin signaling in the brains of patients with Alzheimer's disease (AD) with overlapping molecular features to Type 2 Diabetes Mellitus (T2DM). In addition, T2DM is a known risk factor of AD. The goal of this study was to investigate the neurogenic and neuroprotective potential of rosmarinic acid (RA) in a streptozotocin (STZ)-induced combined with high fat diet (HFD) mouse model of diabetes. Animals were divided into four experimental groups (control, diabetic, diabetic + RA, RA only). Behavioral analysis was performed to assess spatial learning and anxiety levels of animals, whereas quantitative real time PCR was carried out to assess the gene expression levels of neuronal markers of neurogenesis (Ki67, DCX and NeuN). A significant decrease in memory and spatial learning was observed in the diabetic mice, which was substantially improved by RA treatment. RA also increased the gene expression of NeuN, DCX and Ki67, which were dysregulated in the diabetic model. This study proposes RA as a potential therapeutic agent to mitigate neuronal dysfunction associated with T2DM by promoting adult hippocampal neurogenesis.

Neurogenesis and gliogenesis modulation in cerebral ischemia by CDK5 RNAi-based therapy / Modulación de la neurogénesis y la gliogénesis en la isquemia cerebral mediante una terapia basada en la interferencia de CDK5

Abstract Introduction: Cerebral ischemia is the third cause of death risk in Colombia and the first cause of physical disability worldwide. Different studies on the silencing of the cyclin-dependent kinase 5 (CDK5) have shown that reducing its activity is beneficial in ischemic contexts. However, its effect on neural cell production after cerebral ischemia has not been well studied yet. Objective: To evaluate CDK5 silencing on the production of neurons and astrocytes after a focal cerebral ischemia in rats. Materials and methods: We used 40 eight-week-old male Wistar rats. Both sham and ischemia groups were transduced at CA1 hippocampal region with an adeno-associated viral vector using a noninterfering (shSCRmiR) and an interfering sequence for CDK5 (shCDK5miR). We injected 50 mg/kg of bromodeoxyuridine intraperitoneally from hour 24 to day 7 post-ischemia. We assessed the neurological abilities during the next 15 days and we measured the immunoreactivity of bromodeoxyuridine (BrdU), doublecortin (DCX), NeuN, and glial fibrillary acid protein (GFAP) from day 15 to day 30 post-ischemia. Results: Our findings showed that CDK5miR-treated ischemic animals improved their neurological score and presented increased BrdU+ cells 15 days after ischemia, which correlated with higher DCX and lower GFAP fluorescence intensities, and, although mature neurons populations did not change, GFAP immunoreactivity was still significantly reduced at 30 days post-ischemia in comparison with untreated ischemic groups. Conclusion: CDK5miR therapy generated the neurological recovery of ischemic rats associated with the induction of immature neurons proliferation and the reduction of GFAP reactivity at short and longterm post-ischemia.

Resumen Introducción. La isquemia cerebral es la tercera causa de riesgo de muerte en Colombia y la primera causa de discapacidad física en el mundo. En diversos estudios en los que se silenció la cinasa 5 dependiente de la ciclina (CDK5) se ha demostrado que la reducción de su actividad es beneficiosa frente a la isquemia. Sin embargo, su efecto sobre la neurogénesis después de la isquemia no se ha dilucidado suficientemente. Objetivo. Evaluar el silenciamiento de la CDK5 en la neurogénesis y la gliogénesis después de la isquemia cerebral focal en ratas. Materiales y métodos. Se usaron 40 machos de rata Wistar de ocho semanas de edad. Los grupos de control y los isquémicos sometidos a transducción en la región del hipocampo CA1, se inyectaron intraperitonealmente por estereotaxia con 50 mg/kg de bromodesoxiuridina (BrdU) a partir de las 24 horas y hasta el día 7 después de la isquemia, con un vector viral asociado a adenovirus usando una secuencia no interferente (SCRmiR) y una interferente (CDK5miR). Se evaluó la capacidad neurológica durante los quince días siguientes y se detectó la capacidad de inmunorreacción para la BrdU, la proteína doblecortina (DCX), los núcleos neuronales (NeuN), y la proteína fibrilar acídica de la glía (Glial Fibrillary Acidic Protein, GFAP) a los 15 y 30 días de la isquemia. Resultados. Los animales isquémicos tratados con CDK5miR mejoraron su puntuación neurológica y presentaron un incremento de la BrdU+ a los 15 días de la isquemia, lo cual se correlacionó con una mayor intensidad de la DCX+ y una menor de la GFAP+. No hubo modificación de los NeuN+, pero sí una reducción significativa de la GFAP+ a los 30 días de la isquemia en los animales tratados comparados con los animales isquémicos no tratados. Conclusión. La terapia con CDK5miR generó la recuperación neurológica de ratas isquémicas asociada con la inducción de la neurogénesis y el control de la capacidad de reacción de la proteína GFAP a corto y largo plazo después de la isquemia.

Desarrollo neuroembriológico: el camino desde la proliferación hasta la perfección / Neuronal Embryonic Development: A Pathway from Proliferation to Perfection

El desarrollo neurológico humano requiere una serie de pasos que permitan orientar, regular y diferenciar los diversos componentes cerebrales, para así garantizar, de una manera bastante precisa, la correcta organización y funcionamiento de las estructuras neuronales. La neurogénesis está clásicamente dividida en cuatro etapas consecutivas: proliferación, migración, diferenciación y maduración. En los humanos, estas ocurren desde la tercera semana de gestación hasta la vida adulta y precisan de un complejo grupo de paquetes genéticos, así como de algunos factores asociados, que se han ido descubriendo gracias a los avances en la biología molecular. El artículo es una revisión acerca del desarrollo neuroembriológico humano y los componentes genéticos más relevantes encontrados en la literatura.

The human neuronal development requires a number of concrete steps which lead to orientation, regulation and differentiation of several brain components. They must be done to guarantee, in a very precise way, the correct organization and functioning of the neuronal structures. Neurogenesis is commonly divided into four consecutive stages: proliferation, migration, differentiation and maturation. In humans, those stages take place since the third week of prenatal Iife until the adult Iife. They also require a complex group of genetic packs and associated molecular factors, most of which have been recen tly discovered by the molecular biology technology. A review was made about the human neuronal and embryological development and the most relevant genetic components described by the literature so far.

Células-tronco derivadas do epitélio olfatório: perspectivas terapêuticas na medicina veterinária / Stem cells derived from olfactory epithelium: therapeutic perspectives in veterinary medicine

O epitélio olfatório (EO) é uma fonte promissora de células-tronco (CTEO) para o uso terapêutico na medicina veterinária e humana, especialmente em doenças correlacionadas com o sistema nervoso periférico (medula espinhal) e central (cérebro e tronco encefálico) , pois as CTEO possuem a capacidade de se diferenciar em células do sistema nervoso, tais como: neurônios, oligodendrócitos e astrócitos. Em humanos estas células são utilizadas em ensaios terapêuticos de doenças degenerativas como o Alzheimer e Parkinson. Em animais a casuística relativa das doenças neurodegenerativas crônicas ou agudas é baixa, devido à dificuldade de diagnóstico definitivo, desta forma o enfoque das pesquisas com terapia celular são em sua grande maioria em lesões mecânicas na medula espinhal. Devido à falta de padronização e seleção das melhores metodologias que permitam confrontação de estudos, esta revisão busca reunir as mais recentes publicações, descrevendo o potencial uso das células-tronco do epitélio olfatório em terapias celulares, discutindo os principais desafios e perspectivas futuras com enfoque na medicina veterinária.(AU)

The olfactory epithelium (OE) is a promising source of stem cells (OESC) for therapeutic use in veterinary and human medicine, especially in diseases correlated with the peripheral (spinal cord) and central (brain and brainstem) nervous system (CNS), because of its ability to differentiate into neurons, astrocytes and oligodendrocytes cells. In humans, OESC has been used primarily in therapeutic trials for degenerative diseases such as Alzheimer and Parkinson. In animals, the frequency of corresponding cases of chronic or acute neurodegenerative diseases is very low, because of the difficulty of a definitive diagnosis; thus, the focus of cell therapy research are mostly mechanical spinal cord injuries. Due to the lack of normalization and selection of the best methodologies for comparative studies, this review aims to analyze recent reports on the potential use of stem cells from the olfactory epithelium in cell therapies and to discuss the main challenges and future prospects in veterinary medicine.(AU)

A atividade física voluntária e suas relações sobre a neurogênese hipocampal em roedores adultos ­ Uma revisão de literatura / Voluntary physical activity and its relationship to hippocampal neurogenesis in adult rodents ­ A literature review

Esta revisão objetivou sistematizar as informações sobre a atividade física voluntária em roda de correr e sua relação com a neurogênese hipocampal na fase adulta. A pesquisa foi realizada na base de dados eletrônica US National Library of Medicine (PubMED). Foram incluídos artigos originais que abordassem o uso de roedores e a corrida voluntária como modelo de exercício; que relatassem a ocorrência de neurogênese hipocampal na fase adulta; publicados nos últimos cinco anos; disponíveis na íntegra; em inglês ou português. Foram excluídos: artigos de revisão; que abordassem a neurogênese humana; que se utilizassem de outros modelos de exercício físico; que não obedecessem aos critérios de inclusão. A busca eletrônica identificou 28 artigos relevantes, dos quais três não analisaram a ocorrência de neurogênese hipocampal e três não avaliaram a ocorrência da neurogênese na fase adulta, sendo então excluídos e restando 22 publicações. Os estudos avaliaram um total de 16 espécies diferentes de roedores, com predominância da linhagem de camundongos C57BL/6. O tempo de exposição à roda de corrida variou entre três dias e seis meses. Em conclusão, fatores como diferenças genéticas, neurotrofinas e a relação com o desenvolvimento de um comportamento ansioso interferem na expressão da neurogênese hipocampal na fase adulta após a atividade física voluntária. Essas evidências servem para nortear novos estudos a fim de melhor elucidar os mecanismos pelos quais esses fenômenos ocorrem, contudo, é indubitável o benefício que a prática regular de exercício físico, pode trazer aos indivíduos com neuropatologias.

This review aimed to systematize information about the voluntary physical activity in wheel running and its relationship to adult hippocampal neurogenesis. The search was conducted in the electronic database US National Library of Medicine (PubMED). It were included original articles that addressed the use of rodents and the voluntary running as an exercise model; who reported the occurrence of hippocampal adult neurogenesis; published in the last five years; full text available; in English or Portuguese. The exclusion criteria were: review articles; that addressed the human neurogenesis; that used other exercise models; that not met the inclusion criteria. The electronic search identified 28 relevant articles, of which three did not analyze the occurrence of hippocampal neurogenesis and three did not evaluate the occurrence of neurogenesis in adults, being excluded and therefore remaining 22 publications. The studies evaluated a total of 16 different species of rodents, especially the C57BL/6 mouse strain. The running wheel exposure time ranged between three days and six months. In conclusion, factors such as genetic differences, neurotrophins and their relationship with the development of an anxious behavior interfere in the expression of hippocampal neurogenesis in adulthood after the voluntary physical activity. This evidence serve to guide further studies to further elucidate the mechanisms by which these phenomena occur, however, is undoubtedly the benefit that regular physical exercise can bring to individuals with neuropathology.

Fatores psicossociais e socioeconômicos relacionados à insônia e menopausa: Estudo Pró-Saúde / Psychosocial and socioeconomic factors related to insomnia and menopause: Pró-Saúde Study / Factores psicosociales y socioeconómicos relacionados con el insomnio y la menopausia: Estudio Pro-Salud

Foi avaliada a associação entre menopausa e insônia e a influência de variáveis socioeconômicas e psicossociais, em estudo transversal com 2.190 funcionárias de uma universidade (Estudo Pró-Saúde), a partir de um questionário autopreenchível com variáveis sobre menopausa, insônia, transtorno mental comum, eventos de vida estressantes, apoio social e variáveis socioeconômicas. Odds ratios foram calculados por meio de regressão logística multivariada, com desfecho politômico. Após ajuste para potenciais confundidoras sociodemográficas, mulheres na menopausa há mais de 60 meses apresentaram maior chance de reportar queixas de sono frequentes (OR entre 1,53 e 1,86) do que as que estavam na menopausa há menos de 60 meses. Após os ajustes, no primeiro grupo, para as variáveis psicossociais, a magnitude dos ORs reduziu para 1,53 (IC95%: 0,92-2,52) para dificuldade em iniciar o sono, 1,81 (IC95%: 1,09-2,98) para dificuldade em manter o sono e 1,71 (IC95%: 1,08-2,73) para queixa geral de insônia. Fatores psicossociais podem mediar a manifestação da insônia em mulheres na menopausa.

This study evaluated the association between insomnia and menopausal status and the influence of socioeconomic and psychosocial variables on this association in a cross-sectional analysis of 2,190 university employees (the Pró-Saúde Study). A self-administered questionnaire was used, covering menopausal status, complaints of insomnia, common mental disorders, stressful life events, social support, and socioeconomic variables. Odds ratios were calculated using logistic regression with a polytomous outcome. After adjusting for potential socio-demographic confounders, women who had entered menopause more than 60 months previously were more likely to report complaints with sleep (OR 1.53-1.86) as compared to women in menopause for less than 60 months. After adjusting for psychosocial variables, in the first group the ORs decreased to 1.53 (95%CI: 0.92-2.52) for difficulty initiating sleep, 1.81 (95%CI: 1.09-2.98) for difficulty maintaining sleep, and 1.71 (95%CI: 1.08-2.73) for general complaints of insomnia. Psychosocial factors can mediate the manifestation of insomnia among menopausal women.

En este estudio se evaluó la asociación entre insomnio y menopausia y la influencia de las variables socioeconómicas y psicosociales, en un estudio transversal con 2.190 mujeres de una universidad (Estudio Pro-Salud), a partir de un cuestionario autoadministrado con variables de la menopausia, insomnio, trastornos mentales, situaciones de estrés vital, apoyo social y variables socioeconómicas. Se calcularon los odds ratio mediante regresión logística multivariante con desenlace politómico. Después de ajustar por factores de confusión sociodemográficos potenciales, las mujeres menopáusicas desde hace más de 60 meses fueron más propensas a reportar quejas frecuentes de sueño (OR entre 1,53 y 1,86) que las menopáusicas hace menos de 60 meses. Después de los ajustes, en el primer grupo, para las variables psicosociales la magnitud de los OR se redujo a 1,53 (IC95%: 0,92-2,52) para la dificultad para iniciar el sueño, un 1,81 (IC95%: 1,09-2,98) para mantener el sueño y un 1,71 (IC95%: 1,08-2,73) para las quejas de insomnio en general. Los factores psicosociales pueden mediar en la manifestación del insomnio en las mujeres menopáusicas.

Ejercicio físico: su rol en la neurogénesis inducida por BDNF y VEGF / Exercise: your role in neurogenesis induced by BDNF and VEGF

Durante los últimos 100 años se asumió que la neurogénesis se limitaba al desarrollo del sistema nervioso central. Sin embargo, en la actualidad se acepta ampliamente que la neurogénesis también se produce en los períodos de la vida adulta y se observa en diversas regiones del cerebro. Evidencia reciente muestra que la neurogénesis puede ser aumentada por el ejercicio, no obstante, los mecanismos y tiempos de maduración de este proceso no están del todo claros, por esta razón, la presente revisión implica una actualización en el conocimiento de la neurogénesis inducida por el ejercicio físico, abarcando los mecanismos mediadores y su proceso de maduración. En los últimos años se han propuesto diversas moléculas que podrían mediar el efecto del ejercicio físico en la neurogénesis adulta, siendo los más estudiados BDNF (factor neurotrófico derivado del cerebro) y VEGF (factor de crecimiento de endotelio vascular), ya que se observó que ambas moléculas aumentan en respuesta al ejercicio, y estos aumento se relacionaron con el aumento de la proliferación celular en el giro dentado. En cuanto a los períodos de maduración, se ha observado en diferentes especies que fluctúa en un rango entre 30 y 23 semanas, sin embargo, hay una escasez de datos de informes de la dinámica de la maduración en los seres humanos. En consecuencia, la neurogénesis representa un modelo natural para la comprensión de cómo regenerar e incorporar nuevas neuronas en circuitos cerebrales, lo que constituye un potencial terapéutico en el retraso o reparación de daño cerebral causado por una lesión o enfermedad.

During the last hundred years it was assumed that neurogenesis process was limited to the development of the central nervous system. Nevertheless, currently it is widely accepted that neurogenesis also occurs in periods of adult life and observed in various brain regions. Recent evidence shows that neurogenesis can be increased by exercise. The mechanisms and maturation times of this increase are not entirely clear, for this reason the present review involve an update in the knowledge of neurogenesis induced by physical exercise, covering mediating mechanisms and their maturation process. In recent years it has been proposed various molecules that could mediate the effect of physical exercise on adult neurogenesis, the most studied BDNF (brain-derived neurotrophic factor) and VEGF (vascular endothelial growth factor) both molecules have been observed to increase in response to exercise, and correlating with increased cell proliferation in the dentate gyru. Regarding to the maturation periods it has been observed in different species that they fluctuate in a range between 30 and 23 weeks, however, there is a limited data reporting the dynamics of maturation in humans. Consequently, neurogenesis represents a natural model for the understanding of how to regenerate and incorporate new neurons in brain circuits, which represents a potential therapeutic delay and repair of brain damage caused by injury or disease.

Environmental enrichment restores cognitive deficits induced by experimental childhood meningitis

Objective: To evaluate the influence of environmental enrichment (EE) on memory, cytokines, and brain-derived neurotrophic factor (BDNF) in the brain of adult rats subjected to experimental pneumococcal meningitis during infancy. Methods: On postnatal day 11, the animals received either artificial cerebrospinal fluid (CSF) or Streptococcus pneumoniae suspension intracisternally at 1 × 106 CFU/mL and remained with their mothers until age 21 days. Animals were divided into the following groups: control, control + EE, meningitis, and meningitis + EE. EE began at 21 days and continued until 60 days of age (adulthood). EE consisted of a large cage with three floors, ramps, running wheels, and objects of different shapes and textures. At 60 days, animals were randomized and subjected to habituation to the open-field task and the step-down inhibitory avoidance task. After the tasks, the hippocampus and CSF were isolated for analysis. Results: The meningitis group showed no difference in performance between training and test sessions of the open-field task, suggesting habituation memory impairment; in the meningitis + EE group, performance was significantly different, showing preservation of habituation memory. In the step-down inhibitory avoidance task, there were no differences in behavior between training and test sessions in the meningitis group, showing aversive memory impairment; conversely, differences were observed in the meningitis + EE group, demonstrating aversive memory preservation. In the two meningitis groups, IL-4, IL-10, and BDNF levels were increased in the hippocampus, and BDNF levels in the CSF. Conclusions: The data presented suggest that EE, a non-invasive therapy, enables recovery from memory deficits caused by neonatal meningitis. .

Neurotoxicidad de los plaguicidas como agentes disruptores endocrinos: una revisión / Neurotoxicity of pesticides as endocrine disruptors agents: a review

Los plaguicidas se encuentran en el medio ambiente como contaminantes formando mezclas complejas, los estudios recientes se han centrados en la evaluación de los efectos y riesgos que pueden causar estas mezclas de plaguicidas en el ser humano y los ecosistemas.Esta revisión hace hincapié a tres plaguicidas específicos, representativos de los grupos químicos organofosforados, carbamato de tipo ditiocarbamato y triazinas, como son: Paratión® etílico, Mancozeb® y Atrazina®, respectivamente. Ha sido demostrado en animales de experimentación la neurotoxicidad de estos plaguicidas por alteración de la transmisión sináptica y de los mecanismos de la homeostasis del sistema neuroendocrino, lo cual explica la acción de estos plaguicidas como disruptores endocrinos. Varios trabajos demuestran que estos plaguicidas son potencialmente tóxicos a la salud humana, y aún en bajas concentraciones, pueden afectar al organismo causando alteraciones en el sistema neuroendocrino, especialmente en los ejes hipotálamo-hipófisis-gónada e hipotálamo-hipófisis-tiroides. Los investigadores destacan que los momentos de particular sensibilidad de la exposición a plaguicidas disruptores endocrinos son las etapas tempranas de la vida como: durante el desarrollo embrionario y la primera infancia, períodos en los cuales los procesos de crecimiento son controlados por las hormonas afectando el desarrollo del cerebro, el sistema inmune y otros órganos como el sistema reproductor y tiroideo. Los cambios neuroquímicos provocados por la exposición a estos plaguicidas durante el desarrollo cerebral constituyen un alto riesgo porque son capaces de interferir en los procesos de neurogénesis y sinaptogénesis, afectando de manera adversa las funciones cognitivas y motoras, cuyos efectos se observan durante las etapas posteriores de la vida.

Pesticides are found in the environment as complex mixtures forming pollutants, recent studies have focused on evaluating the effects and risks that may cause these mixtures of pesticides on humans and ecosystems. This review highlights three specific, representative of organophosphorus pesticide chemical groups carbamate, dithiocarbamate and triazine type, such as: ethyl Paratión®, Mancozeb® and Atrazina®, respectively.It has been demonstrated in experimental animal’s neurotoxicity of these pesticides by altering synaptic transmission and mechanisms of homeostasis of the neuroendocrine system, which explains the action of these pesticides as endocrine disruptors. Several studies show that these pesticides are potentially toxic to human health, and even in low concentrations, can affect the body causing alterations in the neuroendocrine system, especially in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid axis. The researchers point out that the moments of particular sensitivity of exposure Endocrine disruptor pesticide are the early stages of life as during embryonic development and early childhood periods in which growth processes are controlled by hormones affecting the development brain, immune system and other organs such as the thyroid and reproductive system. The neurochemical changes induced by exposure to these pesticides during brain development are at high risk because they are able to interfere with the processes of neurogenesis and synaptogenesis, adversely affecting cognitive and motor functions, whose effects are observed during the later stages of life.

Efectos del estrés sobre los procesos de plasticidad y neurogénesis: una revisión / Effects of Stress on Plasticity and Neurogenesis: A Review

Grandes esfuerzos han sido llevados a cabo para entender los componentes psicobiológicos del estrés y de algunas de las psicopatologías relacionadas con él, tales como los trastornos de ansiedad (ansiedad generalizada o crisis de pánico) e incluso la depresión. Existen evidencias de que procesos como la neurogénesis y la plasticidad se ven enormemente afectados por muchos factores, entre ellos el estrés. En esta revisión se presentan algunos de los principales conceptos sobre la relación entre estrés, plasticidad y neurogénesis, a los que se ha llegado a partir de investigaciones realizadas -principalmente en modelos animales-, desde hace algunas décadas. Se realizará una diferenciación entre los efectos ocasionados por estrés crónico y agudo, tratando de establecer las interacciones que sobre estos efectos ejercen algunas variables tales como el género o el rango de edad, se enfatizarán los efectos comportamentales para finalmente revisar algunas de las formas de intervención actualmente más usadas para el tratamiento del estrés.

There is a growing interest in the comprehension of psychobiological mechanisms underlying stress and its relationships with many psychopathologies such as anxiety (i.e. generalized anxiety and panic attacks) or depression. There are several reports on the effects of stress on neurogenesis and plasticity. This review will discuss some of the core concepts on the relation between stress, plasticity and neurogenesis obtained during the last decades from research - mainly based in the use of animal models. The distinguishable effects between acute and chronic stress will also be discussed in relation to other factors as genre and age with an emphasis on behavioral effects. Some current therapeutic approaches will be reviewed as well.

Alteraciones hipocampales y cambios cognitivos preceden al deposito de placas amiloides en un modelo murino de la enfermedad de Alzheimer

Existen múltiples evidencias de alteraciones neuronales y gliales en etapas avanzadas de la enfemedad de Alzheimer con abundantes depósitos cerebrales de beta amiloide, aunque hay pocos datos de cambios tempranos que podrían contribuir al desarrollo de la enfermedad. Evaluamos alteraciones morfológicas neuronales y gliales, y cambios cognitivos y emocionales tempranos en ratones transgénicos PDAPP-J20 (Tg), portadores del gen humano de APP (amyloid precursor protein) mutado, a los 5 meses de edad, aún sin depósitos amiloides en el hipocampo y con niveles bajos de péptidos amiloides cerebrales. Mediante inmunohistoquímica para NeuN, los Tg presentaron menor número de neuronas piramidales y granulares en el hipocampo, junto con un menor volumen de la estructura, en comparación con los controles no transgénicos. La neurogénesis se encontró afectada, evidenciada por reducido número de neuronas DCX+ en el giro dentado. En la región CA3, hubo una menor densidad de sinaptofisina sugiriendo alteraciones sinápticas entre neuronas granulares y piramidales, sin cambios en la densidad de espinas dendríticas en CA1. Utilizando microscopía confocal, observamos una disminución del número de astrocitos GFAP+ con una reducción de la complejidad celular, sugiriendo atrofia glial. Se detectó un déficit cognitivo (reconocimiento de localización novedosa de un objeto) y un aumento de la ansiedad (campo abierto) en los Tg, con aumento en los núcleos c-Fos+ en amígdala, evidenciando el papel de la emocionalidad en los inicios de la enfermedad. El estudio de las alteraciones iniciales en la enfermedad amiloide podría contribuir al desarrollo de métodos de diagnóstico temprano y de terapéutica preventiva.

Although there is strong evidence about neuronal and glial disturbances at advanced stages of Alzheimer’s disease, less attention has been directed to early, pre-amyloid changes that could contribute to the progression of the disease. We evaluated neuronal and glial morphological changes and behavioral disturbances in PDAPP-J20 transgenic (Tg) mice, carrying mutated human APP gene (amyloid precursor protein), at 5 months of age, before brain amyloid deposition occurs. Using NeuN immunohistochemistry we found decreased numbers of pyramidal and granular neurons in the hippocampus associated with a reduction of hippocampal volume in Tg mice compared with controls. Neurogenesis was impaired, evidenced by means of DCX immunohistochemistry in the dentate gyrus. In the CA3 region we found a decreased density of synaptophysin, suggesting synaptic disturbance, but no changes were found in CA1 synaptic spine density. Using confocal microscopy we observed decreased number and cell complexity of GFAP+ astrocytes, indicating potential glial atrophy. Cognitive impairment (novel location recognition test) and increased anxiety (open field) were detected in Tg mice, associated with more c-Fos+ nuclei in the amygdala, possibly indicating a role for emotionality in early stages of the disease. The study of early alterations in the course of amyloid pathology could contribute to the development of diagnostic and preventive strategies.

Mapeamento de potencial nicho neurogênico no lobo temporal humano / Mapping of potential neurogenic niche in the human temporal lobe

No final do século 19, o neurônio foi descrito como a unidade funcional básica do sistema nervoso e sua formação era considerada inexistente na fase adulta, explicando a ausência de recuperação significativa em doenças neurológicas. Evidências de geração de neurônios em mamíferos adultos surgiram na década de 1960 e foram confirmadas três décadas depois. Atualmente, predomina a visão de que mamíferos adultos possuem dois nichos neurogênicos independentes: a zona subventricular (ZSV) e a zona subgranular (ZSG) do giro denteado. No entanto, a existência de nichos neurogênicos em humanos adultos é controversa. Nossa hipótese foi de que o mapeamento de nichos neurogênicos no lobo temporal humano poderia esclarecer aspectos sobre a neurogênese adulta. A detecção destes nichos foi buscada em 28 lobos temporais através de imuno-histoquímica para nestina, o marcador mais comum de células-tronco neurais, que são aquelas capazes de se autorrenovar e de gerar novas células neurais. A neurogênese foi pesquisada no hipocampo pelo uso de DCX (do inglês "doublecortin"), o principal marcador de neuroblastos e neurônios imaturos. Nestina foi observada em uma camada contínua formada pela ZSV, zona subpial do lobo temporal medial e ZSG, terminando no subículo. A partir do subículo, uma intensa expressão de DCX ocorreu através da principal via eferente do hipocampo até a fímbria. A visão panorâmica das marcações por nestina e DCX mostrava em conjunto uma linha que circundava as estruturas límbicas do lobo temporal. Por isto, foi denominada linha externa de células do sistema límbico (LECEL). Uma possível explicação para os resultados é que a LECEL seja um nicho neurogênico no qual a ZSV, a zona subpial do lobo temporal medial e a ZSG formam uma unidade contendo células-tronco neurais que se diferenciam em neurônios no subículo. Curiosamente, a área identificada previamente como sendo a corrente migratória rostral humana (formada por células neurais imaturas migrando a partir da...

At the end of the 19th century, the neuron was described as the basic functional unit of the nervous system. The formation of neurons was thought to be absent in adulthood, thus explaining the lack of significant recovery from neurological diseases. Evidence for the generation of neurons in adult mammals was reported in the 1960s and confirmed three decades later. Currently, the prevailing view is that adult mammals harbour two neurogenic niches: the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ). Nonetheless, the existence of these niches in adult humans is controversial. We hypothesised that mapping neurogenic niches in the human temporal lobe could clarify this issue. The presence of neurogenic niches was examined in 28 temporal lobes via immunostaining for nestin, the most common marker for neural stem cells, which are cells with the capacities of self-renewal and the generation of neural cells. The presence of neurogenesis was examined in the hippocampus with doublecortin (DCX), a prominent marker for neuroblasts and immature neurons. Nestin was observed in a continuous layer that was formed by the SVZ, the subpial zone of the medial temporal lobe and the SGZ, terminating in the subiculum. In the subiculum, remarkable DCX expression was observed through the principal efferent pathway of the hippocampus to the fimbria. A panoramic view of nestin and DCX staining collectively displayed a line that surrounded the limbic structures of the temporal lobe. Hence, we termed it the external line of cells of the limbic system (EXCEL). A possible explanation for the results is that the EXCEL is a neurogenic niche, in which the SVZ, the subpial zone of the medial temporal lobe and the SGZ form a unit containing neural stem cells that differentiate into neurons in the subiculum. Curiously, the area previously identified as the human rostral migratory stream (formed by immature neural cells that migrate from the SVZ of the frontal horn)...

Morphological characterization of gecko's (eublepharis macularius) glial cells in culture / Caracterización morfológica de las células gliales del gecko (eublepharis macularius) en cultivo

Central nervous system of reptiles has the ability to grow and regenerate during adult life of the animal. Therefore, cells creating CNS of this animal class should compound substances or molecules enabling neuroregeneration. Cells directly involved in this process have not been clearly characterized, especially in cell culture environment. Morphology of reptilian glial adherent cells should be known better to find any differences from mammalian CNS cells. We isolated glial cells from olfactory bulb and cerebrum from gecko (Eublepharis macularius) and cultured separately. We have observed populations of cells with proliferative capacity in both types of cultures. Also, we have detected lipid molecules deposits within their cytoplasm, which localization was correlated with mitochondria position. This information can be helpful in searching new bioactive substances involved in regeneration of central nervous system.

El sistema nervioso central de los reptiles tiene la capacidad de crecer y regenerarse durante la vida adulta del animal. Por lo tanto, las células de SNC creadas de esta clase de animales deberían componerse de sustancias o moléculas que permiten la neuroregeneración. Las células que participan directamente en este proceso no han sido claramente caracterizadas, especialmente en el entorno de cultivo celular. La morfología de las células adherentes gliales de reptiles deben ser reconocidas y diferenciarse respecto a las células del SNC de mamíferos. Se aislaron células gliales del bulbo olfatorio y el cerebro del Gecko (Eublepharis macularius) y se cultivaron por separado. Se observaron poblaciones de células con capacidad proliferativa en ambos tipos de cultivos. Además, se detectaron moléculas de depósitos lipídicos dentro de su citoplasma, y su localización se correlacionó con la posición de las mitocondrias. Esta información puede ser útil en la búsqueda de nuevas sustancias bioactivas que participan en la regeneración del sistema nervioso central.

NF-kB (Nuclear factor kappa B) su relación con aprendizaje, memoria y neurogénesis en el hipocampo / NF-kB (nuclear factor NF-kB) its relationship with learning, memory and neurogenesis in the hippocampus

En esta revisión bibliográfica focalizaremos sobre la importancia del factor de transcripción NF-kB en el sistema nervioso. NF-kB es una familia de factores de transcripción, conservada evolutivamente, involucrada en los mecanismos básicos celulares de la respuesta inmune, la inflamación, el desarrollo y la apoptosis, que también se expresa en el sistema nervioso central, especialmente en las áreas implicadas en el procesamiento de la memoria, y es activado por señales como el glutamato y el Ca2+. En los últimos años, numerosas investigaciones han comprobado su rol fundamental como parte de la vía de señalización en la regulación de la expresión de genes implicados en la memoria de largo término. Se comprobó la importancia del NF-kB en el neurodesarrollo, en la regulación de la supervivencia neuronal y de la neurogénesis en el hipocampo del adulto. También se comprobó un aumento de la actividad del NF-kB en el cerebro en modelos animales de depresión. Este efecto estaría mediado por el incremento de la IL-6, proinflamatoria. En el modelo de depresión de oscuridad constante también se observaron alteraciones en los niveles de las proteínas hipocampales per2 y npas2, vinculadas al ritmo circadiano. El conocimiento de la neurobiología de este factor de transcripción nos permitirá vislumbrar sus potenciales implicaciones clínicas, así como la posibilidad de influir farmacológicamente: en las memorias traumáticas, en la declinación cognitiva y en los trastornos del ánimo.

In this literature review, we will focus on the importance of the transcription factor NF-kB in the nervous system. NF-kB is a transcription factor family, evolutionarily conserved, which is involved in the basic mechanisms involved in the cellular immune response, inflammation, development and apoptosis, which is also expressed in the Central Nervous System, especially in the areas involved in the processing of memory, and it is activated by signals such as glutamate and Ca2+. In recent years, numerous studies have proven its key role as part of the signaling path in the regulation of the expression of genes in the long-term memory. The importance of NF-kB in neurodevelopment has also been verified in relation to the regulation of neuronal survibal and the neurogenesis in the adult hippocampus. An increase in the NF-kB activity in the brain has also been found in animal models of depression. This effect would be mediated by an increase in pro-inflammatory IL-6. In the model of Constant Drkness Depression, an alteration of the hippocampal protein levels per2 and npas2 linked to circadian rhythm was also observed. Knowing the neurobiology of this transcription factor will allow us to glimpse their potential clinical implications, and the possibility to influence pharmacologically in traumatic memories, in cognitive decline, and mood disorders.

Desarrollo de la médula espinal de salmón (Salmo salar) durante el período post-eclosional / Development of spinal cord of the salmon (Salmo salar) during the period post eclosional

En este estudio se describe el desarrollo post-eclosional de la médula espinal del salmón. Salmo salar. Se utilizaron 200 alevines recién eclosionados, los que fueron cultivados en el Centro de Estudios Acuícolas de la Universidad de Chile. Las condiciones ambientales de cultivo fueron de un 90% de saturación de oxigeno. La temperatura ambiental se mantuvo en 7°C. A los días 1, 3, 5 7 ds post-eclosión, 50 alevines por grupo etario fueron anestesiados y sacrificados por exposición a 5% Benzocaina diluida en agua (Kalmagin 20®, Farquímica). Posteriormente fueron fijados en formalina tamponada al 10% y procesados mediante técnica histológica. Para cada alevín se tomaron a nivel de la aleta dorsal un total de 40 cortes coronales seriados de 5µm de grosor, los que fueron procesados de acuerdo a las técnicas Cresil violeta. La cuantificación neuronal se realizó sobre imágenes microscópicas mediante el método del disector. Los resultados obtenidos se sometieron a una prueba de Coeficiente de Kurtosis con el propósito de analizar el grado de concentración que presentan los valores alrededor de la zona central de la distribución. La médula espinal de los alevines de 1 día es poco diferenciada. En los alevines de 3, 5 y 7 días se diferencian gradualmente las neuronas de la sustancia gris, pero no presenta la distribución característica en forma de "Y" invertida del salmón adulto. El número de neuronas aumenta desde 67+1.7 en el día 1 hasta 88+2.1 en el día 7. Esta observación se puede relacionar con la ausencia de movimientos natatorios de los peces durante los primeros días ya que estos caen sobre la gravilla al fondo de las bateas. Un factor determinante en la adquisición de la morfología de la médula espinal es el inicio de los movimientos natatorios, lo que ocurre aproximadamente al quinto día post-eclosión. La actividad motriz activa permite que las neuronas de la médula espinal sean reclutadas y se formen y activen las redes neurales, permaneciendo finalmente los circuitos más eficientes. El aumento del número de neuronas se puede explicar por neurogénesis post-eclosión, como ocurre en otros teleósteos. Este estudio indica que al momento de la eclosión, el sistema nervioso está muy indiferenciando, y que durante las primeras semanas de vida del alevín ocurre la diferenciación de las neuronas y neurogénesis. Este conocimiento es muy importante debido a que en las pisciculturas se cuidan las ovas, y se descuida la fase del alevinaje en la creencia que los tejidos están constituidos.

We describe the development of the spinal cord during the post eclosion period of the salmon (Salmo salar).We used a total of 200 newly hatched fry grown in the Aquaculture Research Center of the Universidad de Chile. Environmental conditions were of 90% oxygen saturation. Ambient temperature was maintained at 7° C. At days, 1, 3, 5 and 7, post-hatching, 50 fry were anesthetized and sacrificed by exposure to 5% benzocaine diluted in water, (Kalmagin 20 ®, Farquímica). They were then fixed in 10% buffered formalin and processed by histological technique. For each juvenile a total of 40 serial coronal sections of 5µm were taken at the level of the dorsal fin, which were then processed according to cresyl violet techniques.Neuronal quantitation was performed on microscopic images by dissector method. The results obtained were subjected to coefficient Kurtosis test in order to analyze the degree of concentration of values around the central distribution area.The spinal cord of the one-day fry is poorly differentiated. In fry of 3, 5 and 7 days neurons are gradually differentiated, they do not however present the characteristic neuronal distribution inverted "Y" of the adult salmon. The number of neurons increases from 67±1.7 on day one, to 88±2.1 on day 7.This observation may be related to the absence of fish swimming movements during days one and three as these fall on the gravel at the bottom of the trays. A determining factor in the acquisition of the morphology of the spinal cord is the start of swimming movements, which occur at around the fifth day post-hatching.Active motor activity allows spinal cord neurons to be recruited and form to activate neural networks, to remain finally in the most efficient circuits. Increasing the number of neurons can be explained by post-hatching neurogenesis as in other teleosts.This study indicates that at the time of hatching, the nervous system is very undifferentiated and that neuron differentiation and neurogenesis occur during the first weeks of life. This knowledge is very important as fish farms take care of eggs, neglecting the nursery stage in the belief that tissues are formed.