Expression of Pax6 and Pax7 proteins during the central nervous system development in human embryos / Expresión de proteínas Pax6 y Pax7 durante el desarrollo del sistema central nervioso en embriones humanos

The family of paired box (Pax) genes encodes the transcription factors that have been emphasized for the particular importance to embryonic development of the CNS, with the evidence obtained from various animal models. Human embryos have rarely been available for the detection of the expression of Pax family members. In this study 32 human embryos of Carnegie (CS) stages 10-20 were investigated to find the differences in the expression of Pax6 and Pax7 proteins in different regions of the neural tube and the caudal spinal cord. The expression of Pax6 and Pax7, as determined by immunohistochemistry, showed a tendency to increase in the later stages of the development both in the spinal cord and the brain. Significantly weaker expression of Pax6 and Pax7 was observed at CS 10 as compared to the later stages. At CS 10-12 weak expression of Pax6 was noticed in both dorsal and ventral parts of the developing spinal cord, while the expression of Pax7 was restricted to the cells in the roof plate and the dorsal part of the spinal cord. At CS 14-20 in the developing spinal cord Pax6 and Pax7 were detected mostly in the neuroepithelial cells of the ventricular layer, while only weak expression characterized the mantle and the marginal layers. At the same stages in the developing brain Pax6 and Pax7 were expressed in the different regions of the forebrain, the midbrain and the hindbrain suggesting for their involvement in the differentiation of neurons in specific parts of the developing brain.

La familia de genes Pax del inglés (Paired box) codifica los factores de transcripción debido a la particular importancia en el desarrollo embrionario del SNC, con la evidencia obtenida de varios modelos animales. Rara vez han estado disponibles embriones humanos para la detección de la expresión de genes de la familia Pax. En este estudio, se investigaron 32 embriones humanos de Carnegie (CS) etapas 10-20 para encontrar las diferencias en la expresión de las proteínas Pax6 y Pax7 en diferentes regiones del tubo neural y la médula espinal caudal. La expresión de Pax6 y Pax7, según la inmunohistoquímica, se observó una tendencia a aumentar en las etapas posteriores del desarrollo, tanto en la médula espinal como en el cerebro. Se observó una expresión significativamente más débil de Pax6 y Pax7 en CS 10 en comparación con las etapas posteriores. En CS 10-12 se notó una expresión débil de Pax6 en las partes dorsal y ventral de la médula espinal en desarrollo, mientras que la expresión de Pax7 se limitó a células en la placa del techo y dorsal de la médula espinal. En CS 14-20 en la médula espinal en desarrollo, Pax6 y Pax7 se observó principalmente en las células neuroepiteliales de la capa ventricular, mientras que expresión débil se caracterizó en las capas marginales. En las mismas etapas en el cerebro en desarrollo, Pax6 y Pax7 se expresaron en las diferentes áreas del prosencéfalo, el mesencéfalo y el mesencéfalo, lo que sugiere su participación en la diferenciación de las neuronas en partes específicas del cerebro en desarrollo.

Clinical and subclinical maternal hypothyroidism and their effects on neurodevelopment, behavior and cognition

ABSTRACT Clinical and subclinical hypothyroidism are the most common hormonal dysfunctions during pregnancy. Insufficient maternal thyroid hormones (THs) in the early stages of pregnancy can lead to severe impairments in the development of the central nervous system because THs are critical to central nervous system development. In the fetus and after birth, THs participate in neurogenic processes, cell differentiation, neuronal activation, axonal growth, dendritic arborization, synaptogenesis and myelination. Although treatment is simple and effective, approximately 30% of pregnant women in Brazil with access to prenatal care have their first consultation after the first trimester of pregnancy, and any delay in diagnosis and resulting treatment delay may lead to cognitive impairment in children. This review summarizes the effects of clinical and subclinical hypothyroidism on fetal neurodevelopment, behavior and cognition in humans and rodents. Arch Endocrinol Metab. 2020;64(1):89-95

Vesicles stage of camel brain development / Etapas del desarrollo de las vesículas cerebrales del camello

A successive embryonic developmental study was conducted on the brain of twenty eight embryos and fetuses of one humped camel (Camelus Dromedarius), whose crown vertebral rump lengths (CVRL) ranged from 9 to 80 mm, collected from the El-Basateen (Cairo) and Belbees (ElSharqya) Slaughterhouse. The current investigation revealed that camel brain was found to consist of fore, mid and hind brains. The fore brain is divided into telencephalon and diencephalon while the rhombencephalon divided into metencephalon and myelencephalon. Flexures appeared between the vesicles are cervical flexure between the rhomencephalon and the spinal cord, cephalic flexure in the mesencephalon and pontine flexure between the metencephalon, and the myelencephalon of the hind brain (rhombencephalon). The cavity of the rhombencephalon is the fourth ventricle, while that of the diencephalon is the third ventricle, and those of the telencephalon are the lateral ventricles but that of mid brain is the cerebral aqueduct. myelencephalon becomes medulla oblongata and metencephalon developed to pons and cerebellum while mesencephalon gives rise to the cerebral crura and anterior and a posterior colliculus. Diencephalon gives the thalamus, hypothalamus, mamillary body, infundibulum and pineal body while telencephalon becomes the cerebral hemispheres and corpus striatum.

Se llevó a cabo un estudio del desarrollo embrionario cerebral de veintiocho embriones y fetos de camello jorobado (Camelus dromedarius). Las muestras fueron recolectadas en los mataderos de El-Basateen (El Cairo) y Belbees (ElSharqya). La investigación reveló que el cerebro de camello posee un cerebro anterior, medio y posterior. El cerebro anterior se divide en telencéfalo y diencéfalo, mientras que el rombencéfalo se divide en metencéfalo y mielencéfalo. Las flexiones encontradas entre las vesículas son la flexión cervical entre el rombencéfalo y la médula espinal; la flexión cefálica en el mesencéfalo; y la flexión pontina entre el metencéfalo y el mielencéfalo del cerebro posterior (rombencéfalo). La cavidad del rombencéfalo conforma el cuarto ventrículo, la del diencéfalo forma el tercer ventrículo, y las del telencéfalo a los ventrículos laterales. En el cerebro medio, la cavidad corresponde al acueducto cerebral. El mielencéfalo se convierte en médula oblonga y el metencéfalo deriva en puente y cerebelo, mientras que el mesencéfalo da lugar a la crura cerebral y a los colículos anterior y posterior. El diencéfalo origina el tálamo, el hipotálamo, el cuerpo mamilar, el infundíbulo y la hipófisis, mientras que del telencéfalo se originan los hemisferios cerebrales y el cuerpo estriado.

Zika virus damages the human placental barrier and presents marked fetal neurotropism

An unusually high incidence of microcephaly in newborns has recently been observed in Brazil. There is a temporal association between the increase in cases of microcephaly and the Zika virus (ZIKV) epidemic. Viral RNA has been detected in amniotic fluid samples, placental tissues and newborn and fetal brain tissues. However, much remains to be determined concerning the association between ZIKV infection and fetal malformations. In this study, we provide evidence of the transplacental transmission of ZIKV through the detection of viral proteins and viral RNA in placental tissue samples from expectant mothers infected at different stages of gestation. We observed chronic placentitis (TORCH type) with viral protein detection by immunohistochemistry in Hofbauer cells and some histiocytes in the intervillous spaces. We also demonstrated the neurotropism of the virus via the detection of viral proteins in glial cells and in some endothelial cells and the observation of scattered foci of microcalcifications in the brain tissues. Lesions were mainly located in the white matter. ZIKV RNA was also detected in these tissues by real-time-polymerase chain reaction. We believe that these findings will contribute to the body of knowledge of the mechanisms of ZIKV transmission, interactions between the virus and host cells and viral tropism.

Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior

Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.

Comparison of cerebral artery angle in adults and fetuses / Comparación del ángulo de arteria cerebral en adultos y fetos

In this study we generated casting specimens of human cerebral blood vessels for twenty-five fetuses and thirty-six adults. The degrees of the angles were measured and comprised for those blood vessels frequently involved in the interventional catheterization.

En este estudio generamos muestras de los vasos sanguíneos cerebrales humanos en veinticinco fetos y treinta y seis adultos. Fueron medidos y comprendidos los ángulos de aquellos vasos sanguíneos implicados frecuentemente en intervenciones de cateterismo.

Sleep deprivation, pain and prematurity: a review study / Privação do sono, dor e prematuridade: um estudo de revisão

The aim was to describe current reports in the scientific literature on sleep in the intensive care environment and sleep deprivation associated with painful experiences in premature infant. A systematic search was conducted for studies on sleep, pain, premature birth and care of the newborn. Web of Knowledge, MEDLINE, LILACS, Cochrane Library, PubMed, EMBASE, Scopus, VHL and SciELO databases were consulted. The association between sleep deprivation and pain generates effects that are observed in the brain and the behavioral and physiological activity of preterm infants. Polysomnography in intensive care units and pain management in neonates allow comparison with the first year of life and term infants. We have found few references and evidence that neonatal care programs can influence sleep development and reduce the negative impact of the environment. This evidence is discussed from the perspective of how hospital intervention can improve the development of premature infants.

O objetivo foi descrever o estado atual na literatura científica sobre privação do sono associado a experiências dolorosas no prematuro e o papel na evolução do sono em ambiente de terapia intensiva. Realizou-se uma busca sistemática para estudos sobre sono, dor, prematuridade e programas de atenção ao neonato. Foram consultados as bases Web-of-Knowledge, MEDLINE, LILACS, Biblioteca Cochrane, PubMed, EMBASE, Scopus, BVS e SciELO. A associação entre privação do sono e dor gera efeitos que são observados na atividade cerebral, fisiológica e comportamental dos prematuros. A polissonografia nas unidades intensivas e o manejo da dor em neonatos permitem comparação no primeiro ano de vida com crianças nascidas a termo. Encontraram-se poucas evidências de que programas de cuidado neonatal podem influenciar o desenvolvimento do sono e diminuir o impacto negativo do ambiente. Estas evidências são discutidas na perspectiva de como a intervenção hospitalar pode melhorar o desenvolvimento do prematuro.

Fatores associados com centralização fetal em pacientes com hipertensão arterial na gestação / Factors associated with fetal brain-sparing effect in patients with hypertension in pregnancy

OBJETIVOS: Descrever os resultados perinatais e os fatores associados à centralização fetal diagnosticado pelo exame doplervelocimétrico em gestantes com hipertensão arterial. MÉTODOS: Realizou-se um estudo de corte transversal, retrospectivo, incluindo 129 gestantes com hipertensão arterial submetidas à análise doplervelocimétrica, até quinze dias antes do parto. Mulheres com gravidez múltipla, malformações fetais, sangramento genital, descolamento prematuro de placenta, rotura prematura das membranas, tabagismo, uso ilícito de drogas e doenças crônicas foram excluídas. Foram analisadas as características biológicas, sociodemográficas, obstétricas e os resultados perinatais. Para determinar a associação entre as variáveis, foram utilizados os testes χ² exato de Fisher e t de Student. Realizou-se análise de regressão logística múltipla para determinar fatores associados com a centralização fetal. RESULTADOS: Pré-eclâmpsia grave foi a síndrome hipertensiva mais frequente (53,5%) e a centralização fetal foi observada em 24,0% dos fetos. Os fatores pré-natais associados com centralização fetal foram a persistência da incisura protodiastólica bilateral na artéria uterina (OR 3,6; IC95% 1,4 - 9,4; p=0,009) e a restrição de crescimento intrauterino (RCIU) (OR 3,3; IC95% 1,2 - 9,3; p=0,02). Os desfechos perinatais associados à centralização fetal foram idade gestacional <32ª semana, recém-nascido (RN) pequeno para a idade gestacional (PIG), peso do RN<2.500 g e morte perinatal. Não se encontrou associação com outras variáveis maternas e neonatais. CONCLUSÕES: Os fatores associados à centralização fetal foram persistência da incisura protodiastólica bilateral na artéria uterina, RCIU e aumento da frequência de desfechos perinatais adversos.

PURPOSE: To determine perinatal outcomes and factors associated with fetal brain sparing effect diagnosed by Doppler flow velocimetry in patients with arterial hypertension. METHODS: We performed a cross-sectional retrospective study including 129 pregnant women with arterial hypertension and submitted to Doppler flow velocimetry, within fifteen days before delivery. Women with multiple pregnancies, fetal malformations, genital bleeding, placenta praevia, premature rupture of membranes, smoking, illicit drug use and chronic diseases were excluded. We analyzed the biological, socio-demographic and obstetric characteristics, as well the perinatal outcomes. To determine the association between variables, we used the χ² test, Fisher's exact test and Student's t-test. Multiple logistic regression analysis was performed to determine the factors associated with fetal centralization. RESULTS: Pre-eclampsia was the most frequent hypertensive disorder (53.5%) and fetal brain sparing effect was observed in 24.0% of fetuses. The prenatal factors associated with fetal brain sparing were the persistence of bilateral protodiastolic notches in uterine arteries (OR 3.6; 95%CI 1.4 - 9.4; p=0.009) and intrauterine growth restriction (IUGR) (OR 3.3; 95%CI 1.2 - 9.3; p=0.02). The perinatal outcomes associated with fetal brain sparing were gestational age <32 weeks, small for gestational age (SGA) infants, birth weight <2,500 g and perinatal death. There was no association with other maternal or neonatal variables. CONCLUSIONS: The main factors associated with fetal brain sparing were persistence of uterine arteries notches, IUGR, and increased frequency of adverse perinatal outcomes.

Typical and atypical stem cells in the brain, vitamin C effect and neuropathology

Stem cells are considered a valuable cellular resource for tissue replacement therapies in most brain disorders. Stem cells have the ability to self-replicate and differentiate into numerous cell types, including neurons, oligodendrocytes and astrocytes. As a result, stem cells have been considered the "holy grail" of modern medical neuroscience. Despite their tremendous therapeutic potential, little is known about the mechanisms that regulate their differentiation. In this review, we analyze stem cells in embryonic and adult brains, and illustrate the differentiation pathways that give origin to most brain cells. We also evaluate the emergent role of the well known anti-oxidant, vitamin C, in stem cell differentiation. We believe that a complete understanding of all molecular players, including vitamin C, in stem cell differentiation will positively impact on the use of stem cell transplantation for neurodegenerative diseases.

JNK/stress-activated protein kinase associated protein 1 is required for early development of telencephalic commissures in embryonic brains

We previously reported that mice lacking JSAP1 (jsap1-/-) were lethal and the brain of jsap1-/- at E18.5 exhibited multiple types of developmental defects, which included impaired axon projection of the corpus callosum and anterior commissures. In the current study, we examined whether the early telencephalic commissures were formed abnormally from the beginning of initial development or whether they arose normally, but have been progressively lost their maintenance in the absence of JSAP1. The early corpus callosum in the brain of jsap1+/+ at E15.5-E16.5 was found to cross the midline with forming a distinct U-shaped tract, whereas the early axonal tract in jsap1-/- appeared to cross the midline in a diffuse manner, but the lately arriving axons did not cross the midline. In the brain of jsap1-/- at E17.5, the axon terminals of lately arriving collaterals remained within each hemisphere, forming an early Probst's bundle-like shape. The early anterior commissure in the brain of jsap1+/+ at E14.5-E15.5 crossed the midline, whereas the anterior commissure in jsap1-/- developed, but was deviated from their normal path before approaching the midline. The axon tracts of the corpus callosum and anterior commissure in the brain of jsap1-/- at E16.5-E17.5 expressed phosphorylated forms of FAK and JNK, however, their expression levels in the axonal tracts were reduced compared to the respective controls in jsap1+/+. Considering the known scaffolding function of JSAP1 for the FAK and JNK pathways, these results suggest that JSAP1 is required for the pathfinding of the developing telencephalic commissures in the early brains.

Effects of fluoxetine and imipramine in rat fetuses treated during a critical gestational period: a macro and microscopic study / Efeitos da fluoxetina e imipramina em fetos de ratas tratadas durante o período crítico da gestação: estudo macro e microscópico

OBJECTIVE: To evaluate morphological alterations in rat fetuses treated with fluoxetine and imipramine during the "critical" period of gestation. METHOD: Fifteen female rats were separated into three groups (n = 5) and treated with 10 mg/kg/day of test substances on the ninth, tenth and eleventh day of pregnancy: G1, fluoxetine; G2, imipramine hydrochloride; G3 (control), saline. On day 21, cesarean sections were performed to release the fetuses, whose bodies were weighed and macroscopically analyzed. The placenta was also weighed. The fetuses were then fixed and their encephala removed and weighed. Sections of the frontal lobe were taken for histological neuron counting. RESULTS: G1 and G2 showed the highest fetal body weight. Placental weight showed statistical differences (p < 0.01): G1 weighed more than G2 and G3. Otherwise, G2 exhibited the highest encephalon weight, statistically differing from G3 (control) and fluoxetine-treated G1 (p < 0.01). However, G1 did not statistically (p > 0.01) differ from the control group. G3 showed the highest number of neurons per area when compared to G1 and G2 (p < 0.01). CONCLUSION: The use of antidepressants in rats caused an increase in fetal weight and a decrease in the number of fetal frontal lobe neurons, thus suggesting that the use of antidepressants by pregnant women can induce depression in fetuses due to alterations in their neural development.

OBJETIVO: Avaliar as possíveis alterações ocorridas em nível macroscópico e microscópico de fetos de ratas submetidas ao tratamento com fluoxetina e imipramina durante o período "crítico" da gestação. MÉTODO: Quinze ratas, posteriormente ao acasalamento, foram divididas em três grupos experimentais (n = 5): G1, tratadas com 10mg/kg/dia de fluoxetina; G2, tratadas com 10mg/kg/dia de cloridrato de imipramina, e G3 (controle), tratadas com 10mg/kg/dia de solução fisiológica a 0,9 por cento, no 9º, 10º e 11º dias de prenhez das ratas. Posteriormente à cesária, no 21º dia de prenhez, analisou-se macroscopicamente o peso fetal e placentário. Os fetos foram fixados e houve a remoção do encéfalo para pesagem e preparação das lâminas do tecido neuronal para contagem de neurônios do lobo frontal. RESULTADOS: O G1 e G2 apresentaram maior peso fetal. O G1 apresentou maior peso placentário, diferindo do G2 e G3 (p < 0,01). De forma diferente, o G2 possuiu maior peso encefálico, diferindo do G3 e G1 (p < 0,01). G1 não diferiu estatisticamente do grupo controle (p > 0,01). O G3 exibiu maior número de neurônios, por área, do lobo frontal em relação a G1 e G2 (p < 0,01). CONCLUSÃO: A adoção dos antidepressivos causou, nos fetos, aumento de peso e redução da contagem de neurônios do lobo frontal, sugerindo que a indicação de antidepressivos às gestantes pode induzir a depressão nos fetos por alterações em seu neurodesenvolvimento.

Centralização de fluxo sanguíneo fetal: comparação entre os índices diagnósticos / Brain-sparing effect: comparison of diagnostic indices

OBJETIVO: descrever os resultados perinatais adversos em pacientes com centralização de fluxo sanguíneo fetal, utilizando a relação entre os índices de pulsatilidade das artérias cerebral média e umbilical (IPACM/IPAU) e entre os índices de resistência das artérias cerebral média e umbilical (IRACM/IRAU), assim como comparar os dois índices diagnósticos. MÉTODOS: foram incluídas 151 gestantes com diagnóstico de centralização de fluxo sanguíneo atendidas na maternidade da Universidade Estadual de Campinas, cujo parto ocorreu até 15 dias após o diagnóstico ultrassonográfico. Foram considerados como resultados perinatais adversos: índice de Apgar inferior a sete no quinto minuto, internação em UTI neonatal, concepto pequeno para a idade gestacional, sofrimento fetal agudo, mortalidade perinatal, hipoglicemia, policitemia, enterocolite necrosante, hemorragia cerebral, hemorragia pulmonar, anemia, septicemia, doença de membrana hialina, síndromes convulsivas, síndrome de hiper-reflexia e insuficiência renal. As frequências dos resultados perinatais adversos (RPA) para as relações cérebro-placentária foram comparadas utilizando-se o teste exato de Fisher ou o do χ2 de Pearson, considerando-se como estatisticamente significativo o nível de 5 por cento. Os resultados perinatais adversos foram avaliados de acordo com a idade gestacional, utilizando-se o teste de tendência de Cochrane-Armitage. RESULTADOS: os resultados perinatais adversos para o grupo em que os dois índices apresentaram-se alterados constatou que 62,5 por cento dos recém-natos necessitaram de internação em UTI, conceptos pequenos para a idade gestacional (PIG) ocorreram em 75,2 por cento, sofrimento fetal agudo em 35,3 por cento, hipoglicemia em 84,4 por cento, policitemia em 8,3 por cento, enterocolite necrosante em 4,2 por cento e hemorragia cerebral em 2,1 por cento. Constatou-se associação significativa das relações IPACM/IPAU e IRACM/IRAU, no decorrer da idade gestacional, ...

PURPOSE: to describe adverse perinatal outcomes in patients with fetal blood flow centralization, using the relationship between the pulsatility indexes of the middle cerebral and umbilical arteries (MCAPI/UAPI), and between the resistance indexes of the middle cerebral and umbilical arteries (MCARI/UARI), as well as to compare both diagnostic indexes. METHODS: 151 pregnant women with diagnosis of blood flow centralization, attended to at the maternity hospital of Universidade Estadual de Campinas, whose delivery occurred up to 15 days after the ultrasonographic diagnosis, were included. It was considered as adverse perinatal outcomes: Apgar index lower than 7 at the fifth minute, permanence in neonatal ICU, small fetus for the gestational age, severe fetal suffering, perinatal death, hypoglycemia, polycythemia, necrotizing enterocolitis, brain hemorrhage, lung hemorrhage, anemia, septicemia, hyaline membrane disease, convulsive syndromes, hyperreflexia syndrome and kidney insufficiency. Rates of the perinatal adverse outcomes (PAO) for the brain-placentary ratios have been compared, using Fisher's exact or Pearson's χ2 tests, at 5 percent significance level. Adverse perinatal outcomes according to the gestational age have been evaluated using the Cochrane-Armitage test for trend. RESULTS: the adverse perinatal outcomes for the group with the two indexes altered were: 62.5 percent of the newborns needed to be placed in an ICU, 75.2 percent were small for the gestational age (SGA), 35.3 percent were under severe fetal suffering, 84.4 percent had hypoglycemia, 8.3 percent polycythemia, 4.2 percent necrotizing enterocolitis, and 2.1 percent brain hemorrhage. There has been significant association between the MCAPI/UAPI and MCARI/UARI ratios along the gestational age, and the need for neonatal intensive care, small fetuses for the gestational age, septicemia, necrotizing enterocolitis, kidney insufficiency, hyaline membrane disease, ...

Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice

Neural progenitor cells (NPs) have shown several promising benefits for the treatment of neurological disorders. To evaluate the therapeutic potential of human neural progenitor cells (hNPs) in amyotrophic lateral sclerosis (ALS), we transplanted hNPs or growth factor (GF)-expressing hNPs into the central nervous system (CNS) of mutant Cu/Zn superoxide dismutase (SOD(1G93A)) transgenic mice. The hNPs were engineered to express brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), VEGF, neurotrophin-3 (NT-3), or glial cell-derived neurotrophic factor (GDNF), respectively, by adenoviral vector and GDNF by lentiviral vector before transplantation. Donor-derived cells engrafted and migrated into the spinal cord or brain of ALS mice and differentiated into neurons, oligodendrocytes, or glutamate transporter-1 (GLT1)-expressing astrocytes while some cells retained immature markers. Transplantation of GDNF- or IGF-1-expressing hNPs attenuated the loss of motor neurons and induced trophic changes in motor neurons of the spinal cord. However, improvement in motor performance and extension of lifespan were not observed in all hNP transplantation groups compared to vehicle-injected controls. Moreover, the lifespan of GDNF-expressing hNP recipient mice by lentiviral vector was shortened compared to controls, which was largely due to the decreased survival times of female animals. These results imply that although implanted hNPs differentiate into GLT1-expressing astrocytes and secrete GFs, which maintain dying motor neurons, inadequate trophic support could be harmful and there is sexual dimorphism in response to GDNF delivery in ALS mice. Therefore, additional therapeutic approaches may be required for full functional recovery.

Development of fetal nicotine and muscarinic receptors in utero

The role of acetylcholine in the central and peripheral nervous systems is well established in adults. Cholinergic modulation of vascular functions and body fluid balance has been extensively studied. In the embryo-fetus, cholinergic receptors are widespread in the peripheral and central systems, including smooth muscle and the epithelial lining of the cardiovascular, digestive, and urinary systems, as well as in the brain. Fetal nicotine and muscarinic receptors develop in a pattern (e.g., amount and distribution) related to gestational periods. Cholinergic mechanisms have been found to be relatively intact and functional in the control of vascular homeostasis during fetal life in utero at least during the last third of gestation. This review focuses on the development of fetal nicotine and muscarinic receptors, and provides information indicating that central cholinergic systems are well developed in the control of fetal blood pressure and body fluid balance before birth. Therefore, the development of cholinergic systems in utero plays an important role in fetal vascular regulation, gastrointestinal motility, and urinary control.

Identification and characterization of scirr1, a novel gene up-regulated after spinal cord injury

Spinal cord injury and regeneration involves transcriptional activity of many genes, of which many remain unknown. Using the rat spinal cord full- transection model, bioinformatics, cloning, expression assays, fusion proteins, and transfection techniques, we identified and characterized one such differentially expressed gene, termed scirr1 (spinal cord injury and/or regeneration related gene 1). Fourteen orthologs were found in 13 species from echinoderm to insect and human by Blast search of NCBI protein reference sequence database. However, no further information is available for these homologues. Using whole-mount in situ hybridization, mouse scirr1 mRNA was expressed temporally and spatially in accordance with the early development sequence of the central nervous system. In adult rat spinal cord, expression of scirr1 mRNA was localized to neurons of gray matter by in situ hybridization. Using immunohistochemistry, SCIRR1 protein was found to be up-regulated and expressed more highly in spinal cord neurons farther from the epicenter of injury. Although the precise function of SCIRR1 is unknown, its unique pattern of expression during CNS early development and up-regulation after spinal cord injury suggest that SCIRR1 should be involved in the succeeding injury and/or repair processes of the injured spinal cord. Also, the typical F-box and leucine-rich repeat (LRR) architecture of rat SCIRR1 indicated that it may play an important substrate recruiting role in the pleiotropic ubiquitin/proteasome pathway. All these make scirr1 a new interesting start to study the spinal cord injury and regeneration mechanism.

Upregulation of Proinflammatory Cytokines in the Fetal Brain of the Gaucher Mouse

Gaucher disease is caused by a deficiency of glucocerebrosidase. Patients with Gaucher disease are divided into three major phenotypes: chronic nonneuronopathic, acute neuronopathic, and chronic neuronopathic, based on symptoms of the nervous system, the severity of symptoms, and the age of disease onset. The characteristics of patients with acute neuronopathic- and chronic neuronopathic-type Gaucher disease include oculomotor abnormalities, bulbar signs, limb rigidity, seizures and occasional choreoathetoid movements, and neuronal loss. However, the mechanisms leading to the neurodegeneration of this disorder remain unknown. To investigate brain dysfunction in Gaucher disease, we studied the possible role of inflammation in neurodegeneration during development of Gaucher disease in a mouse model. Elevated levels of the proinflammatory cytokines, IL-1alpha, IL-1beta, IL-6, and TNF-alpha, were detected in the fetal brains of Gaucher mice. Moreover, the levels of secreted nitric oxide and reactive oxygen species in the brains of Gaucher mice were higher than in wild-type mice. Thus, accumulated glucocerebroside or glucosylsphingosine, caused by glucocerebrosidase deficiency, may mediate brain inflammation in the Gaucher mouse via the elevation of proinflammatory cytokines, nitric oxide, and reactive oxygen species.

Distribution of microglial cells in the cerebral hemispheres of embryonic and neonatal chicks

The distribution, morphology and morphometry of microglial cells in the chick cerebral hemispheres from embryonic day 4 (E4) to the first neonatal day (P1) were studied by histochemical labeling with a tomato (Lycopersicon esculentum) lectin. The histochemical analysis revealed lectin-reactive cells in the nervous parenchyma on day E4. Between E4 (5.7 ± 1.35 mm length) and E17 (8.25 ± 1.2 mm length), the lectin-reactive cells were identified as ameboid microglia and observed starting from the subventricular layer, distributed throughout the mantle layer and in the proximity of the blood vessels. After day E13, the lectin-reactive cells exhibited elongated forms with small branched processes, and were considered primitive ramified microglia. Later, between E18 (5.85 ± 1.5 mm cell body length) and P1 (3.25 ± 0.6 mm cell body length), cells with more elongated branched processes were observed, constituting the ramified microglia. Our findings provide additional information on the migration and differentiation of microglial cells, whose ramified form is observed at the end of embryonic development. The present paper focused on the arrangement of microglial cells in developing cerebral hemispheres of embryonic and neonatal chicks, which are little studied in the literature. Details of morphology, morphometry and spatial distribution of microglial cells contributed to the understanding of bird and mammal central nervous system ontogeny. Furthermore, the identification and localization of microglial cells during the normal development could be used as a morphological guide for embryonic brain injury researches.

La dieta como determinante del desarrollo del sistema nervioso central: rol de los ácidos grasos asenciales / Diet as a determinant of the central nervous system development: role of essential fatty acids

El sistema nervioso central es el segundo tejido más rico en lípidos del organismo, luego del adiposo. Los fosfolípidos constituyentes de las membranas cerebrales poseen un alto contenido de ácidos grasos poliisaturados de cadena larga (AGPICL) de las familias n-3 y n-6, derivados de los respectivos ácidos grasos esenciales. Las mayores concentraciones de AGPICL en tejido nervioso corresponden al ácido docosahexaenoico (22:6n-3), en membranas de materia gris de corteza cerebral y fotoreceptores de retina. La deficiencia de AGPICL n-3 en recién nacidos, especialmente de pretérmino, modifica la función nerviosa, provocando dificuldades de aprendizaje y alteraciones de la función visual. El período de mayor acumulación de estos lípidos en cerebro es perinatal. Por esta razón, es importante la alimentación adecuada de la embarazada, antes y durante la gestación, y de la mujer que amamanta, que transfieren los AGPICL al feto y recién nacido, respectivamente. En niños de pretérmino, que nacen con menores reservas de AGPICL, estos tienen la calidad de condicionalmente esenciales. La formulación de las preparaciones destinadas a la alimentación de lactantes, especialmente si son prematuros, debe incluir AGPICL n-3 y n-6 en proporciones adecuadas.

Morphological characteristics of the developing human brain during the embryonic period

Many features of the developing nervous system are visible from external observations of intact human embryos. In this study, a photographic atlas from the 4th to the 7th week after ovulation (Carnegie stages 10-18) is provided. The neural folds began to fuse at stage 10, and the rostral and caudal neuropore were closed during stages 11 and 12, respectively. The three primary divisions of the brain were distinguishable before closing of the neural tube. The five secondary brain vesicles were formed during stages 14-15. The development of the cerebellum and cerebrum were first observed at stages 14 and 15, respectively. The mesencephalic flexure was seen at stage 12, and the cervical flexure and pontine flexure at stage 14. After stages 18-19, it became increasingly difficult to identify detailed features of the brain from the surface. Results from this study will help to correlate the characteristic findings of the developing central nervous system of human embryos from stereomicroscopical and light microscopical observations and to locate the exact parts of the developing human brain for other purposes.