RESUMO
Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in newborn pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.
Drinking excessive amounts of alcohol during pregnancy can cause foetal alcohol spectrum disorder and other conditions in children that affect their physical and mental development. Many countries advise women who are pregnant or trying to conceive to avoid drinking alcohol entirely. However, surveys of large groups of women in Western countries indicate that most women continue drinking low to moderate amounts of alcohol until they discover they are pregnant and then stop consuming alcohol for the rest of their pregnancy. It remains unclear how this common drinking pattern affects the foetus. The instructions needed to build and maintain a human body are stored within molecules of DNA. Some regions of DNA called genes contain the instructions to make proteins, which perform many tasks in the body. Other so-called 'non-coding' regions do not code for any proteins but instead have roles in regulating gene activity. One way cells control which genes are switched on or off is adding or removing tags known as methyl groups to certain locations on DNA. Previous studies indicate that alcohol may affect how children develop by changing the patterns of methyl tags on DNA. To investigate the effect of moderate drinking during the early stages of pregnancy, Bestry et al. exposed pregnant mice to alcohol and examined how this affected the patterns of methyl tags on DNA in their offspring. The experiments found moderate levels of alcohol were sufficient to alter the patterns of methyl tags in the brains and livers of the newborn mice. Most of the changes were observed in non-coding regions of DNA, suggesting alcohol may affect how large groups of genes are regulated. Fewer changes in the patterns of methyl tags were found in mice whose mothers had diets rich in two essential nutrients known as folate and choline. Further experiments found that some of the affected mouse genes were similar to genes linked to foetal alcohol spectrum disorder and other related conditions in humans. These findings highlight the potential risks of consuming even moderate levels of alcohol during pregnancy and suggest that a maternal diet rich in folate and choline may help mitigate some of the harmful effects on the developing foetus.
Assuntos
Metilação de DNA , Efeitos Tardios da Exposição Pré-Natal , Animais , Metilação de DNA/efeitos dos fármacos , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Camundongos , Humanos , Dieta , Masculino , Etanol/efeitos adversos , Etanol/toxicidade , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/metabolismo , Transtornos do Espectro Alcoólico Fetal/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/embriologiaRESUMO
INTRODUCTION: Evolutionary theory suggests that the ancestors of all placental animals were nocturnal. Visual perceptive function of mammalian brain has evolved extensively, but nearly 70 % of today's mammals are still nocturnal. While placental influence on brain development is known, if placenta plays a role in the visual perceptive function of mammalian brain remains untested. The present study aims to test this hypothesis. METHODS: In this study, single-nuclei RNA sequencing was performed to identify genes expressed in the pig placenta and fetal brain, and then compared with the orthologous genes expressed in the placenta and fetal brain cells of mouse. Differential gene expression analysis was performed to identify placental genes regulated differentially between nocturnal and diurnal animals. Phylogenetic modeling was performed to test correlated evolution between placenta type, and the nocturnal or diurnal activity among different mammals. RESULTS: The results showed that genes differentially regulated in the fetal brain were related to visual perception whereas the placental genes were related to the nocturnal or diurnal activity in placental animals. Phylogenetic modeling of these genes in thirty-four diverse mammalian species showed evidence for evolutionary link between placenta and the nocturnal/diurnal activity in animals. DISCUSSION: The findings of this study suggest that the placenta plays a role in the evolution of visual perceptive function of brain to shape the nocturnal or diurnal activity of placental animals.
Assuntos
Encéfalo , Ritmo Circadiano , Placenta , Animais , Feminino , Placenta/metabolismo , Placenta/fisiologia , Gravidez , Encéfalo/fisiologia , Encéfalo/metabolismo , Encéfalo/embriologia , Suínos , Ritmo Circadiano/fisiologia , Ritmo Circadiano/genética , Camundongos , Mamíferos/fisiologia , Filogenia , Evolução BiológicaRESUMO
The ellipsoid body (EB) of the insect brain performs pivotal functions in controlling navigation. Input and output of the EB is provided by multiple classes of R-neurons (now referred to as ER-neurons) and columnar neurons which interact with each other in a stereotypical and spatially highly ordered manner. The developmental mechanisms that control the connectivity and topography of EB neurons are largely unknown. One indispensable prerequisite to unravel these mechanisms is to document in detail the sequence of events that shape EB neurons during their development. In this study, we analyzed the development of the Drosophila EB. In addition to globally following the ER-neuron and columnar neuron (sub)classes in the spatial context of their changing environment we performed a single cell analysis using the multi-color flip out (MCFO) system to analyze the developmental trajectory of ER-neurons at different pupal stages, young adults (4d) and aged adults (â¼60d). We show that the EB develops as a merger of two distinct elements, a posterior and anterior EB primordium (prEBp and prEBa, respectively. ER-neurons belonging to different subclasses form growth cones and filopodia that associate with the prEBp and prEBa in a pattern that, from early pupal stages onward, foreshadows their mature structure. Filopodia of all ER-subclasses are initially much longer than the dendritic and terminal axonal branches they give rise to, and are pruned back during late pupal stages. Interestingly, extraneous branches, particularly significant in the dendritic domain, are a hallmark of ER-neuron structure in aged brains. Aging is also associated with a decline in synaptic connectivity from columnar neurons, as well as upregulation of presynaptic protein (Brp) in ER-neurons. Our findings advance the EB (and ER-neurons) as a favorable system to visualize and quantify the development and age-related decline of a complex neuronal circuitry.
Assuntos
Envelhecimento , Neurônios , Animais , Neurônios/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Encéfalo/metabolismo , Encéfalo/embriologia , Drosophila melanogaster/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Pseudópodes/metabolismo , Pupa/metabolismo , Pupa/crescimento & desenvolvimento , Drosophila/metabolismo , Cones de Crescimento/metabolismoRESUMO
BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females. METHODS: We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum. RESULTS: We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males', but in the last trimester of pregnancy, male components were more related to each other than female's. CONCLUSIONS: This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development.
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RNA Mensageiro , Caracteres Sexuais , Feminino , Masculino , Animais , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Gravidez , Encéfalo/metabolismo , Encéfalo/embriologia , Sistema Hipotálamo-Hipofisário/metabolismo , Feto/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Desenvolvimento FetalRESUMO
Brain development involves a sequence of structural changes from early stages of the embryo until several months after birth. Currently, ultrasound is the established technique for screening due to its ability to acquire dynamic images in real-time without radiation and to its cost-efficiency. However, identifying abnormalities remains challenging due to the difficulty in interpreting foetal brain images. In this work we present a set of 104 2D foetal brain ultrasound images acquired during the 20th week of gestation that have been co-registered to a common space from a rough skull segmentation. The images are provided both on the original space and template space centred on the ellipses of all the subjects. Furthermore, the images have been annotated to highlight landmark points from structures of interest to analyse brain development. Both the final atlas template with probabilistic maps and the original images can be used to develop new segmentation techniques, test registration approaches for foetal brain ultrasound, extend our work to longitudinal datasets and to detect anomalies in new images.
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Encéfalo , Ultrassonografia Pré-Natal , Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Humanos , Feminino , Gravidez , Feto/diagnóstico por imagem , BenchmarkingRESUMO
Microglia, the crucial immune cells inhabiting the central nervous system (CNS), perform a range of vital functions, encompassing immune defense and neuronal regulation. Microglia subsets with diverse functions and distinct developmental regulations have been identified recently. It is generally accepted that all microglia originate from hematopoiesis and depend on the myeloid transcription factor PU.1. However, a recent study reported the existence of mrc1+ microglia in zebrafish embryos, which are seemingly independent of Pu.1 and reliant on lymphatic vessels, sparking great interest in the possibility of lymphatic-originated microglia. To address this, we took advantage of a pu.1 knock-in zebrafish allele for a detailed investigation. Our results conclusively showed that almost all zebrafish embryonic microglia (~95% on average) express pu.1. Further, lineage tracing and mutant analysis revealed that these microglia neither emerged from nor depended on lymphatic vessels. In essence, our study refutes the presence of pu.1-independent but lymphatic-dependent microglia.
Assuntos
Encéfalo , Vasos Linfáticos , Microglia , Proteínas Proto-Oncogênicas , Transativadores , Peixe-Zebra , Animais , Microglia/metabolismo , Peixe-Zebra/embriologia , Transativadores/metabolismo , Transativadores/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Encéfalo/metabolismo , Encéfalo/embriologia , Vasos Linfáticos/metabolismo , Vasos Linfáticos/citologia , Vasos Linfáticos/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Embrião não Mamífero/metabolismoRESUMO
The use of time-lapse live imaging enables us to track the dynamic changes in neurites during their formation. Ex vivo live imaging with acute brain slices provides a more physiological environment than cultured cells. To accomplish this, a certain method of labeling is necessary to visualize and identify neurite morphology. To understand the dynamics of neurite structure at early stages of neurite formation, we describe in this chapter ex vivo live imaging using a confocal microscope at P0 in combination with in utero electroporation (IUE).
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Encéfalo , Eletroporação , Neuritos , Animais , Eletroporação/métodos , Neuritos/metabolismo , Encéfalo/citologia , Encéfalo/embriologia , Encéfalo/diagnóstico por imagem , Camundongos , Feminino , Microscopia Confocal/métodos , Imagem com Lapso de Tempo/métodos , Gravidez , NeurogêneseRESUMO
It is well known that the human cortex is expanded compared with other mammalian species, but the molecular mechanisms underpinning the evolution of human corticogenesis are not well understood. A new paper in Development takes a novel computational approach to screen for genetic changes that could have played an important role in human brain evolution. To learn more about the story behind the paper, we caught up with first author Juan Moriano and corresponding author Cedric Boeckx, a Research Professor at Catalan Institute for Research and Advanced Studies (ICREA).
Assuntos
Evolução Biológica , Humanos , Animais , História do Século XXI , Córtex Cerebral/embriologia , História do Século XX , Encéfalo/embriologia , Encéfalo/metabolismoRESUMO
Pre-clinical trials have demonstrated the neuroprotective effects of transplanted human neural stem cells (hNSCs) during the post-ischemic phase. However, the exact neuroprotective mechanism remains unclear. Tunneling nanotubes (TNTs) are long plasma membrane bridges that physically connect distant cells, enabling the intercellular transfer of mitochondria and contributing to post-ischemic repair processes. Whether hNSCs communicate through TNTs and their role in post-ischemic neuroprotection remains unknown. In this study, non-immortalized hNSC lines derived from fetal human brain tissues were examined to explore these possibilities and assess the post-ischemic neuroprotection potential of these hNSCs. Using Tau-STED super-resolution confocal microscopy, live cell time-lapse fluorescence microscopy, electron microscopy, and direct or non-contact homotypic co-cultures, we demonstrated that hNSCs generate nestin-positive TNTs in both 3D neurospheres and 2D cultures, through which they transfer functional mitochondria. Co-culturing hNSCs with differentiated SH-SY5Y (dSH-SY5Y) revealed heterotypic TNTs allowing mitochondrial transfer from hNSCs to dSH-SY5Y. To investigate the role of heterotypic TNTs in post-ischemic neuroprotection, dSH-SY5Y were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (OGD/R) with or without hNSCs in direct or non-contact co-cultures. Compared to normoxia, OGD/R dSH-SY5Y became apoptotic with impaired electrical activity. When OGD/R dSH-SY5Y were co-cultured in direct contact with hNSCs, heterotypic TNTs enabled the transfer of functional mitochondria from hNSCs to OGD/R dSH-SY5Y, rescuing them from apoptosis and restoring the bioelectrical profile toward normoxic dSH-SY5Y. This complete neuroprotection did not occur in the non-contact co-culture. In summary, our data reveal the presence of a functional TNTs network containing nestin within hNSCs, demonstrate the involvement of TNTs in post-ischemic neuroprotection mediated by hNSCs, and highlight the strong efficacy of our hNSC lines in post-ischemic neuroprotection. Human neural stem cells (hNSCs) communicate with each other and rescue ischemic neurons through nestin-positive tunneling nanotubes (TNTs). A Functional mitochondria are exchanged via TNTs between hNSCs. B hNSCs transfer functional mitochondria to ischemic neurons through TNTs, rescuing neurons from ischemia/reperfusion ROS-dependent apoptosis.
Assuntos
Comunicação Celular , Técnicas de Cocultura , Mitocôndrias , Células-Tronco Neurais , Neurônios , Humanos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Neurônios/metabolismo , Mitocôndrias/metabolismo , Encéfalo/metabolismo , Encéfalo/embriologia , Diferenciação Celular , Nanotubos/química , Feto , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Estruturas da Membrana CelularRESUMO
Fetal brain MRI is becoming an increasingly relevant complement to neurosonography for perinatal diagnosis, allowing fundamental insights into fetal brain development throughout gestation. However, uncontrolled fetal motion and heterogeneity in acquisition protocols lead to data of variable quality, potentially biasing the outcome of subsequent studies. We present FetMRQC, an open-source machine-learning framework for automated image quality assessment and quality control that is robust to domain shifts induced by the heterogeneity of clinical data. FetMRQC extracts an ensemble of quality metrics from unprocessed anatomical MRI and combines them to predict experts' ratings using random forests. We validate our framework on a pioneeringly large and diverse dataset of more than 1600 manually rated fetal brain T2-weighted images from four clinical centers and 13 different scanners. Our study shows that FetMRQC's predictions generalize well to unseen data while being interpretable. FetMRQC is a step towards more robust fetal brain neuroimaging, which has the potential to shed new insights on the developing human brain.
Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Diagnóstico Pré-Natal , Controle de Qualidade , Humanos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Diagnóstico Pré-Natal/métodos , Feminino , Gravidez , Aprendizado de MáquinaRESUMO
The study conducted retrospective analysis design, aiming to explore the use of Microvascular Imaging Technique (MVFI) to assess fetal cerebral microcirculation and analyze the relationship between Microvascular Index (MVI) and fetal growth and development. 100 pregnant women who met the criteria for fetal growth restriction (FGR) provided in the Expert Consensus on Fetal Growth Restriction (2019 Edition) and underwent routine prenatal examinations at the Obstetrics and Gynecology Department of Peking University Third Hospital from January 2021 to June 2023 were selected as the study subjects. A normal fetus with a fetal weight less than 10 % can be classified as FGR, Pregnant women with fetal umbilical artery (UA) systolic and diastolic (S/D) values ≥3 were included in the observation group, while 200 pregnant women with normal fetuses were selected as the control group during the same period. The fetuses' change in both groups were measured using color Doppler ultrasound, including bi-parietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). The cerebral microcirculation of the fetuses in both groups was evaluated using MVFI, and the MVI values were compared. The clinical characteristics of FGR fetuses with umbilical artery S/D ratio ≥ 3 were summarized, and the correlation between fetal cerebral microvascular status and fetal growth and development was analyzed using Pearson correlation analysis. The outcomes told that the BPD, HC, AC, and FL values of the fetuses in the control group were lower the other's value (P < 0.05), and the MVI and peak systolic velocity of the middle cerebral artery (MCA-PSV) values were also lower in the control group (P < 0.05). Pearson correlation analysis revealed a positive correlation between fetal growth and development and MVI and MCA-PSV values in FGR fetuses. In conclusion, MVFI can monitor and quantitatively analyze fetal intracranial microcirculation, visualize slow blood flow in microvascular structures, and this study provides preliminary evidence of the close relationship between fetal cerebral microcirculation and intrauterine growth and development.
Assuntos
Desenvolvimento Fetal , Retardo do Crescimento Fetal , Microcirculação , Ultrassonografia Pré-Natal , Humanos , Feminino , Gravidez , Ultrassonografia Pré-Natal/métodos , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/fisiopatologia , Desenvolvimento Fetal/fisiologia , Estudos Retrospectivos , Adulto , Microcirculação/fisiologia , Circulação Cerebrovascular/fisiologia , Microvasos/diagnóstico por imagem , Microvasos/embriologia , Artérias Umbilicais/diagnóstico por imagem , Ultrassonografia Doppler em Cores , Encéfalo/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Encéfalo/embriologiaRESUMO
A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.
Assuntos
Neoplasias Encefálicas , Encéfalo , Malformações Vasculares do Sistema Nervoso Central , Células Endoteliais , Feto , RNA-Seq , Análise da Expressão Gênica de Célula Única , Feminino , Humanos , Masculino , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/embriologia , Encéfalo/metabolismo , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Comunicação Celular , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/citologia , Feto/irrigação sanguínea , Feto/citologia , Feto/embriologia , Malformações Vasculares do Sistema Nervoso Central/patologia , Antígenos HLA-D/metabolismo , Adulto , SaúdeRESUMO
Diffusion-weighted Magnetic Resonance Imaging (dMRI) is increasingly used to study the fetal brain in utero. An important computation enabled by dMRI is streamline tractography, which has unique applications such as tract-specific analysis of the brain white matter and structural connectivity assessment. However, due to the low fetal dMRI data quality and the challenging nature of tractography, existing methods tend to produce highly inaccurate results. They generate many false streamlines while failing to reconstruct the streamlines that constitute the major white matter tracts. In this paper, we advocate for anatomically constrained tractography based on an accurate segmentation of the fetal brain tissue directly in the dMRI space. We develop a deep learning method to compute the segmentation automatically. Experiments on independent test data show that this method can accurately segment the fetal brain tissue and drastically improve the tractography results. It enables the reconstruction of highly curved tracts such as optic radiations. Importantly, our method infers the tissue segmentation and streamline propagation direction from a diffusion tensor fit to the dMRI data, making it applicable to routine fetal dMRI scans. The proposed method can facilitate the study of fetal brain white matter tracts with dMRI.
Assuntos
Encéfalo , Imagem de Tensor de Difusão , Feto , Substância Branca , Humanos , Imagem de Tensor de Difusão/métodos , Encéfalo/embriologia , Encéfalo/diagnóstico por imagem , Encéfalo/anatomia & histologia , Substância Branca/diagnóstico por imagem , Substância Branca/embriologia , Substância Branca/anatomia & histologia , Feto/diagnóstico por imagem , Feto/anatomia & histologia , Feminino , Aprendizado Profundo , Gravidez , Processamento de Imagem Assistida por Computador/métodos , Imagem de Difusão por Ressonância Magnética/métodosRESUMO
We inquire into the role of Turing's biological thought in the development of his concept of intelligent machinery. We trace the possible relations between his proto-connectionist notion of 'organising' machines in Turing (1948) on the one hand and his mathematical theory of morphogenesis in developmental biology (1952) on the other. These works were concerned with distinct fields of inquiry and followed distinct paradigms of biological theory, respectively postulating analogues of Darwinian selection in learning and mathematical laws of form in organic pattern formation. Still, these strands of Turing's work are related, first, in terms of being amenable in principle to his (1936) computational method of modelling. Second, they are connected by Turing's scattered speculations about the possible bearing of learning processes on the anatomy of the brain. We argue that these two theories form an unequal couple that, from different angles and in partial fashion, point towards cognition as a biological and embodied phenomenon while, for reasons inherent to Turing's computational approach to modelling, not being capable of directly addressing it as such. We explore ways in which these two distinct-but-related theories could be more explicitly and systematically connected, using von Neumann's contemporaneous and related work on Cellular Automata and more recent biomimetic approaches as a foil. We conclude that the nature of 'initiative' and the mode of material realisation are the key issues that decide on the possibility of intelligent machinery in Turing.
Assuntos
Biologia do Desenvolvimento , Biologia do Desenvolvimento/história , História do Século XX , Morfogênese , Seleção Genética , Inteligência , Modelos Biológicos , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Encéfalo/embriologia , Aprendizagem , Evolução BiológicaRESUMO
Pressure exerted by fluid contained within a lumen plays a crucial role in the growth, morphogenesis, and patterning of epithelial organs. Accurate modulation of lumen pressure in the developing embryo requires sensitive and robust methods that can detect and vary pressure in the range of tens to hundreds of Pascals (Pa). Here we describe a simple, cost-effective protocol for setting up a pressure modulation apparatus combining a high-sensitivity pressure sensor and a water column whose height can be finely tuned. We demonstrate lumen pressure control using the developing brain of early chicken embryos.
Assuntos
Pressão , Animais , Embrião de Galinha , Encéfalo/embriologia , Encéfalo/fisiologiaRESUMO
Small non-coding RNAs (sncRNAs) make up ~1% of the transcriptome; nevertheless, they play significant roles in regulating cellular processes. Given the complexity of the central nervous system, sncRNAs likely hold particular importance in the human brain. In this study, we provide sncRNA transcriptomic profiles in a range of adult and prenatal brain regions, with a focus on piRNAs, due to their underexplored expression in somatic cells and tissue-specific nature. Using the WIND workflow, which combines two detection methods, we found 1333 (731 miRNAs, 249 piRNAs, 285 snoRNAs, and 68 other sncRNAs) and 1445 unique sncRNAs (770 miRNAs, 307 piRNAs, 289 snoRNAs, and 79 other sncRNAs) in developing and adult brains, respectively. Significant variations were found upon comparison of fetal and adult brain groups, with 82 miRNAs, 17 piRNAs, and 70 snoRNAs enriched in fetal brains and 22 miRNAs, 11 piRNAs in adult brains. This dataset represents a valuable resource for exploring the sncRNA roles in brain function, their involvement in neurological diseases, and the molecular mechanisms behind brain region interactions.
Assuntos
Encéfalo , Feto , Perfilação da Expressão Gênica , Pequeno RNA não Traduzido , Humanos , Encéfalo/metabolismo , Encéfalo/embriologia , Feto/metabolismo , Pequeno RNA não Traduzido/genética , Transcriptoma , Adulto , MicroRNAs/genéticaRESUMO
BACKGROUND: The significant role of embryonic cerebrospinal fluid (eCSF) in the initial stages of brain development has been thoroughly studied. This fluid contains crucial molecules for proper brain development such as members of the Wnt and FGF families, apolipoproteins, and retinol binding protein. Nevertheless, the source of these molecules remains uncertain since they are present before the formation of the choroid plexus, which is conventionally known as the primary producer of cerebrospinal fluid. The subcommissural organ (SCO) is a highly conserved gland located in the diencephalon and is one of the earliest differentiating brain structures. The SCO secretes molecules into the eCSF, prior to the differentiation of the choroid plexus, playing a pivotal role in the homeostasis and dynamics of this fluid. One of the key molecules secreted by the SCO is SCO-spondin, a protein involved in maintenance of the normal ventricle size, straight spinal axis, neurogenesis, and axonal guidance. Furthermore, SCO secretes transthyretin and basic fibroblast growth factor 2, while other identified molecules in the eCSF could potentially be secreted by the SCO. Additionally, various transcription factors have been identified in the SCO. However, the precise mechanisms involved in the early SCO development are not fully understood. RESULTS: To uncover key molecular players and signaling pathways involved in the role of the SCO during brain development, we conducted a transcriptomic analysis comparing the embryonic chick SCO at HH23 and HH30 stages (4 and 7 days respectively). Additionally, a public transcriptomic data from HH30 entire chick brain was used to compare expression levels between SCO and whole brain transcriptome. These analyses revealed that, at both stages, the SCO differentially expresses several members of bone morphogenic proteins, Wnt and fibroblast growth factors families, diverse proteins involved in axonal guidance, neurogenic and differentiative molecules, cell receptors and transcription factors. The secretory pathway is particularly upregulated at stage HH30 while the proliferative pathway is increased at stage HH23. CONCLUSION: The results suggest that the SCO has the capacity to secrete several morphogenic molecules to the eCSF prior to the development of other structures, such as the choroid plexus.
Assuntos
Encéfalo , Perfilação da Expressão Gênica , Órgão Subcomissural , Animais , Encéfalo/metabolismo , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Órgão Subcomissural/metabolismo , Órgão Subcomissural/embriologia , Embrião de Galinha , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
Hormonal imbalance during pregnancy is a risk factor for neuropsychiatric impairment in the offspring. It has been suggested that hypothyroidism leads to dysfunction of cortical GABAergic interneurons and inhibitory system development that in turn underlies impairment of the central nervous system. Here we investigated how gestational hypothyroidism affected offspring GABAergic system development as well as redox regulation parameters, because of previous links identified between the two. Experimental Gestational Hypothyroidism (EGH) was induced in CD-1 mice with 0.02% methimazole (MMI) in drinking water from embryonic day 9 (E9) until tissue collection at embryonic day 14 (E14) or E18. We examined GABAergic cell distribution and inhibitory system development gene expression as well as redox relevant gene expression and direct measures across all embryos regardless of sex. Intrauterine restriction of maternal thyroid hormones significantly impacted both of these outcomes in brain, as well as altering redox regulation in the placenta. GAD67+ neuronal migration was reduced, accompanied by a disruption in gene expression influencing GABAergic cell migration and cortical inhibitory neural system development. EGH also altered embryonic brain gene expression of Gpx1, Nfe2l2, Cat levels in the dorsal E14 brains. Additionally, EGH resulted in elevated TBARS, Gpx1 and Nfe2l2 in the ventral E18 brains. Furthermore, EGH downregulated placental Gpx1 gene expression at E14 and increased protein oxidation at E18. These findings support the hypothesis that sufficient maternal thyroid hormone supply to the fetus influences central nervous system development, including processes of GABAergic system development and redox equilibrium.
Assuntos
Encéfalo , Neurônios GABAérgicos , Glutationa Peroxidase GPX1 , Glutationa Peroxidase , Hipotireoidismo , Estresse Oxidativo , Animais , Feminino , Gravidez , Hipotireoidismo/metabolismo , Camundongos , Encéfalo/metabolismo , Encéfalo/embriologia , Neurônios GABAérgicos/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/genética , Metimazol , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Movimento Celular , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Masculino , Placenta/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Activation of the maternal immune system during gestation has been associated with an increased risk for neurodevelopmental disorders in the offspring, particularly schizophrenia and autism spectrum disorder. Microglia, the tissue-resident macrophages of the central nervous system, are implicated as potential mediators of this increased risk. Early in development, microglia start populating the embryonic central nervous system and in addition to their traditional role as immune responders under homeostatic conditions, microglia are also intricately involved in various early neurodevelopmental processes. The timing of immune activation may interfere with microglia functioning during early neurodevelopment, potentially leading to long-term consequences in postnatal life. In this review we will discuss the involvement of microglia in brain development during the prenatal and early postnatal stages of life, while also examining the effects of maternal immune activation on microglia and neurodevelopmental processes. Additionally, we discuss recent single cell RNA-sequencing studies focusing on microglia during prenatal development, and hypothesize how early life microglial priming, potentially through epigenetic reprogramming, may be related to neurodevelopmental disorders.
Assuntos
Microglia , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Microglia/imunologia , Microglia/metabolismo , Humanos , Gravidez , Animais , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Feminino , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/embriologia , Epigênese Genética , Suscetibilidade a DoençasRESUMO
Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal radiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal radiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)-nitroxide radiation mitigator JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total-body irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time-and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed a significant reduction of mitochondrial function in the fetal brain after 3 Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. One day after TBI (E14.5) maternal administration of JP4-039, which passes through the placenta, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. Treatment also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. JP4-039 administration following irradiation resulted in increased survival of pups. These findings indicate that JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure.