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1.
Am J Psychiatry ; 177(9): 811-817, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32867523

RESUMO

Causal pathways to disruptive behavior disorders, even within the same diagnostic category, are varied. Both equifinality and multifinality pose considerable challenges to uncovering underlying mechanisms and understanding varied developmental trajectories associated with disruptive behavior disorders. Uncovering genetic causes requires improved granularity in how we operationalize presentation and developmental trajectories associated with disruptive behavior disorders. If we want to integrate the study of genetic, environmental, and neurocognitive factors within a longitudinal framework, we need to improve measurement. Furthermore, brain changes associated with disruptive behavior disorders should not simply be understood as outcomes of genetic and environmental influences, but also as factors that reciprocally influence future social environments over time in ways that are important in contributing to risk and resilience. Advancing the field with regard to these challenges will result in more truly integrated investigation of disruptive behavior disorders, which holds the promise of improving our ability to develop more effective preventive and intervention approaches.


Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo , Encéfalo , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/etiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/prevenção & controle , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Interação Gene-Ambiente , Humanos , Comportamento Problema/psicologia , Psicologia do Desenvolvimento/métodos , Psicologia do Desenvolvimento/tendências , Psicopatologia , Fatores de Risco , Meio Social
2.
Nat Commun ; 11(1): 4523, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908125

RESUMO

Thousands of functional magnetic resonance imaging (fMRI) studies have provided important insight into the human brain. However, only a handful of these studies tested infants while they were awake, because of the significant and unique methodological challenges involved. We report our efforts to address these challenges, with the goal of creating methods for awake infant fMRI that can reveal the inner workings of the developing, preverbal mind. We use these methods to collect and analyze two fMRI datasets obtained from infants during cognitive tasks, released publicly with this paper. In these datasets, we explore and evaluate data quantity and quality, task-evoked activity, and preprocessing decisions. We disseminate these methods by sharing two software packages that integrate infant-friendly cognitive tasks and eye-gaze monitoring with fMRI acquisition and analysis. These resources make fMRI a feasible and accessible technique for cognitive neuroscience in awake and behaving human infants.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Desenvolvimento Infantil/fisiologia , Imagem por Ressonância Magnética/métodos , Vigília/fisiologia , Técnicas de Observação do Comportamento , Encéfalo/crescimento & desenvolvimento , Pré-Escolar , Cognição/fisiologia , Estudos de Coortes , Estudos de Viabilidade , Feminino , Humanos , Lactente , Masculino
3.
Pediatrics ; 146(Suppl 1): S18-S24, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32737228

RESUMO

With a few notable exceptions, adolescents do not possess the legal authority to provide consent for or refuse medical interventions. However, in some situations, the question arises regarding whether a mature minor should be permitted to make a life-altering medical decision that would be challenged if made by the minor's parent. In this article, I explore what we currently know about the adolescent brain and how that knowledge should frame our understanding of adolescent decision-making. The prevailing approach to determining when adolescents should have their decisions respected in the medical and legal context, an approach that is focused on establishing capacity under a traditional informed consent model, will be reviewed and critiqued. I will suggest that the traditional model is insufficient and explore the implications for the adolescent role in health care decision-making.


Assuntos
Desenvolvimento do Adolescente , Encéfalo/crescimento & desenvolvimento , Tomada de Decisão Clínica , Doença de Hodgkin/tratamento farmacológico , Consentimento Livre e Esclarecido/psicologia , Recusa do Paciente ao Tratamento/psicologia , Adolescente , Comportamento do Adolescente/psicologia , Fatores Etários , Feminino , Humanos , Consentimento Livre e Esclarecido/legislação & jurisprudência , Competência Mental/legislação & jurisprudência , Competência Mental/psicologia , Mães , Patient Self-Determination Act , Autonomia Pessoal , Recusa do Paciente ao Tratamento/legislação & jurisprudência , Estados Unidos
4.
Chem Biol Interact ; 329: 109217, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32750324

RESUMO

Developing brain is very sensitive to the influence of environmental factors during gestation and the neonatal period. The aim of the study is to assess cobalt and iron accumulation in the brain as well as changes in the expression of iron-regulatory proteins transferrin receptor 1, hepcidin, and ferroportin in suckling mice. Perinatal exposure to cobalt chloride increased significantly cobalt content in brain tissue homogenates of 18-day-old (d18) and 25-day-old (d25) mice inducing alterations in brain iron homeostasis. Higher degree of transferrin receptor 1 expression was demonstrated in cobalt chloride-exposed mice with no substantial changes between d18 and d25 mice. A weak ferroportin expression was found in 18-day-old control and cobalt-treated mouse brain. Cobalt exposure of d25 mice resulted in increased ferroportin expression in brain compared to the untreated age-matched control group. Hepcidin level in cobalt-exposed groups was decreased in d18 mice and slightly increased in d25 mice. The obtained data contribute for the better understanding of metal toxicity impact on iron homeostasis in the developing brain with further possible implications in neurodegeneration.


Assuntos
Encéfalo/metabolismo , Cobalto/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Reguladoras do Ferro/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobalto/metabolismo , Feminino , Hepcidinas/genética , Hepcidinas/metabolismo , Ferro/metabolismo , Proteínas Reguladoras do Ferro/genética , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo
5.
Gene ; 758: 144975, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32707302

RESUMO

Dip2C is highly expressed in brain and many other tissues but its biological functions are still not clear. Genes regulated by Dip2C in brain have never been studied. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems, adaptive immune systems of bacteria and archaea, have been recently developed and broadly used in genome editing. Here, we describe targeted gene deletions of Dip2c gene in mice via CRISPR/Cas9 system and study of brain transcriptome under Dip2C regulation. The CRISPR/Cas9 system effectively generated targeted deletions of Dip2c by pronuclei injection of plasmids that express Cas9 protein and two sgRNAs. We achieved targeted large fragment deletion with efficiencies at 14.3% (1/7), 66.7% (2/3) and 20% (1/5) respectively in 3 independent experiments, averaging 26.7%. The large deletion DNA segments are 160.4 kb (Dip2CΔ160kb), spanning from end of exon 4 to mid of exon 38. A mouse with two base pair deletion was generated from a single sgRNA targeting in exon 4 (Dip2cΔ2bp) by non-homologous end joining (NHEJ). Loss of gene expression for Dip2c mRNA was confirmed by quantitative real-time PCR (qPCR). Dip2C-regulated genes and pathways in brain were investigated through RNAseq of Dip2cΔ2bp. In total, 838 genes were found differentially regulated, with 252 up and 586 down. Gene ontology (GO) analysis indicated that DEGs in brain are enriched in neurological functions including 'memory', 'neuropeptide signaling pathway', and 'response to amphetamine' while KEGG analysis shows that 'neuroactive ligand-receptor interaction pathway' is the most significantly enriched. DEGs Grid2ip, Grin2a, Grin2c, Grm4, Gabbr2, Gabra5, Gabre, Gabrq, Gabra6 and Gabrr2 are among the highly regulated genes by Dip2C. Results confirm Dip2C may play important roles in brain development and function.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Proteínas de Neoplasias/genética , Transcriptoma/genética , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Feminino , Deleção de Genes , Edição de Genes/métodos , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , RNA Guia/genética
6.
Nat Commun ; 11(1): 3791, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728089

RESUMO

Brain organoids are promising tools for disease modeling and drug development. For proper neuronal network formation excitatory and inhibitory neurons as well as glia need to co-develop. Here, we report the directed self-organization of human induced pluripotent stem cells in a collagen hydrogel towards a highly interconnected neuronal network at a macroscale tissue format. Bioengineered Neuronal Organoids (BENOs) comprise interconnected excitatory and inhibitory neurons with supportive astrocytes and oligodendrocytes. Giant depolarizing potential (GDP)-like events observed in early BENO cultures mimic early network activity of the fetal brain. The observed GABA polarity switch and reduced GDPs in >40 day BENO indicate progressive neuronal network maturation. BENOs demonstrate expedited complex network burst development after two months and evidence for long-term potentiation. The similarity of structural and functional properties to the fetal brain may allow for the application of BENOs in studies of neuronal plasticity and modeling of disease.


Assuntos
Encéfalo/citologia , Neurogênese , Plasticidade Neuronal/fisiologia , Organoides/fisiologia , Engenharia Tecidual/métodos , Potenciais de Ação/fisiologia , Encéfalo/crescimento & desenvolvimento , Técnicas de Cultura de Células , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurônios/fisiologia , Ácido gama-Aminobutírico/metabolismo
7.
Pediatrics ; 146(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32661188

RESUMO

Cannabinoids, the psychoactive compounds in marijuana, are one of the most commonly used substances in the United States. In this review, we summarize the impact of marijuana on child and adolescent health and discuss the implications of marijuana use for pediatric practice. We review the changing epidemiology of cannabis use and provide an update on medical use, routes of administration, synthetic marijuana and other novel products, the effect of cannabis on the developing brain, other health and social consequences of use, and issues related to marijuana legalization.


Assuntos
Cannabis , Uso da Maconha , Adolescente , Comportamento do Adolescente/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Canabinoides/efeitos adversos , Canabinoides/síntese química , Canabinoides/farmacologia , Cannabis/efeitos adversos , Cannabis/química , Cannabis/envenenamento , Criança , Comportamento Infantil/efeitos dos fármacos , Interações Medicamentosas , Endocanabinoides/fisiologia , Feminino , Feto/efeitos dos fármacos , Humanos , Drogas Ilícitas/efeitos adversos , Masculino , Abuso de Maconha/epidemiologia , Abuso de Maconha/terapia , Uso da Maconha/efeitos adversos , Uso da Maconha/epidemiologia , Uso da Maconha/legislação & jurisprudência , Uso da Maconha/psicologia , Meios de Comunicação de Massa , Maconha Medicinal/efeitos adversos , Maconha Medicinal/uso terapêutico , Leite Humano/química , Transtornos Neurocognitivos/induzido quimicamente , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores de Canabinoides/efeitos dos fármacos , Receptores de Canabinoides/fisiologia , Uso de Tabaco/epidemiologia
8.
PLoS One ; 15(7): e0235311, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628734

RESUMO

OBJECTIVE: This study aimed to define the prevalence and predictors of non-right-handedness and its link to long-term neurodevelopmental outcome and early neuroimaging in a cohort of children born extremely preterm (<28 weeks gestation). METHODS: 179 children born extremely preterm admitted to the Neonatal Intensive Care Unit of our tertiary centre from 2006-2013 were included in a prospective longitudinal cohort study. Collected data included perinatal data, demographic characteristics, neurodevelopmental outcome measured by the Bayley Scales of Infant and Toddler Development at 2 years and the Movement Assessment Battery for Children at 5 years, and handedness measured at school age (4-8 years). Magnetic resonance imaging performed at term-equivalent age was used to study overt brain injury. Diffusion tensor imaging scans were analysed using tract-based spatial statistics to assess white matter microstructure in relation to handedness and neurodevelopmental outcome. RESULTS: The prevalence of non-right-handedness in our cohort was 22.9%, compared to 12% in the general population. Weaker fine motor skills at 2 years and paternal non-right-handedness were significantly associated with non-right-handedness. Both overt brain injury and fractional anisotropy of white matter structures on diffusion tensor images were not related to handedness. Fractional anisotropy measurements showed significant associations with neurodevelopmental outcome. CONCLUSIONS: Our data show that non-right-handedness in children born extremely preterm occurs almost twice as frequently as in the general population. In the studied population, non-right-handedness is associated with weaker fine motor skills and paternal non-right-handedness, but not with overt brain injury or microstructural brain development on early magnetic resonance imaging.


Assuntos
Encéfalo/crescimento & desenvolvimento , Desenvolvimento Infantil/fisiologia , Imagem de Tensor de Difusão/estatística & dados numéricos , Lateralidade Funcional/fisiologia , Lactente Extremamente Prematuro/crescimento & desenvolvimento , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Estudos Prospectivos
9.
J Thorac Cardiovasc Surg ; 160(2): e55-e66, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689704

RESUMO

OBJECTIVES: This study aims to evaluate the protective effects of progesterone on white matter injury and brain immaturity in neonatal rats with chronic hypoxia. METHODS: Three-day old Sprague-Dawley rats were randomly divided into 3 groups: (1) control (n = 48), rats were exposed to normoxia (fraction of inspired oxygen: 21% ± 0%); (2) chronic hypoxia (n = 48), rats were exposed to hypoxia (fraction of inspired oxygen: 10.5% ± 1.0%); and (3) progesterone (n = 48), rats were exposed to hypoxia and administrated with progesterone (8 mg/kg/d). Hematoxylin-eosin staining, immunohistochemistry, real-time quantitative polymerase chain reaction, and Western blot analyses were compared on postnatal day 14 in different groups. Motor skill and coordination abilities of rats were assessed via rotation experiments. RESULTS: Increased brain weights (P < .05), narrowed ventricular sizes (P < .01), and rotarod experiment scores (P < .01) were better in the progesterone group than in the chronic hypoxia group. The number of mature oligodendrocytes and myelin basic protein expression increased in the progesterone group compared with the chronic hypoxia group (P < .01). The polarization of M1 microglia cells in the corpus callosum of chronic hypoxia-induced hypomyelination rats was significantly increased, whereas there were fewer M2 microglia cells. Conversely, progesterone therapy had an opposite effect and caused an increase in M2 microglia polarization versus a reduction in M1 microglia cells. CONCLUSIONS: Progesterone could prevent white matter injury and improve brain maturation in a neonatal hypoxic rat model; this may be associated with inducing a switch from M1 to M2 in microglia.


Assuntos
Encéfalo/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Leucoencefalopatias/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Substância Branca/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Plasticidade Celular/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Feminino , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/fisiopatologia , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos Sprague-Dawley , Substância Branca/metabolismo , Substância Branca/patologia , Substância Branca/fisiopatologia
11.
BMC Evol Biol ; 20(1): 72, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576137

RESUMO

BACKGROUND: The remarkable abilities of the human brain are distinctive features that set us apart from other animals. However, our understanding of how the brain has changed in the human lineage remains incomplete, but is essential for understanding cognition, behavior, and brain disorders in humans. Here, we compared the expression trajectory in brain development between humans and rhesus macaques (Macaca mulatta) to explore their divergent transcriptome profiles. RESULTS: Results showed that brain development could be divided into two stages, with a demarcation date in a range between 25 and 26 postconception weeks (PCW) for humans and 17-23PCWfor rhesus macaques, rather than birth time that have been widely used as a uniform demarcation time of neurodevelopment across species. Dynamic network biomarker (DNB) analysis revealed that the two demarcation dates were transition phases during brain development, after which the brain transcriptome profiles underwent critical transitions characterized by highly fluctuating DNB molecules. We also found that changes between early and later brain developmental stages (as defined by the demarcation points) were substantially greater in the human brain than in the macaque brain. To explore the molecular mechanism underlying prolonged timing during early human brain development, we carried out expression heterochrony tests. Results demonstrated that compared to macaques, more heterochronic genes exhibited neoteny during early human brain development, consistent with the delayed demarcation time in the human lineage, and proving that neoteny in human brain development could be traced to the prenatal period. We further constructed transcriptional networks to explore the profile of early human brain development and identified the hub gene RBFOX1 as playing an important role in regulating early brain development. We also found RBFOX1 evolved rapidly in its non-coding regions, indicating that this gene played an important role in human brain evolution. Our findings provide evidence that RBFOX1 is a likely key hub gene in early human brain development and evolution. CONCLUSIONS: By comparing gene expression profiles between humans and macaques, we found divergent expression trajectories between the two species, which deepens our understanding of the evolution of the human brain.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Animais , Redes Reguladoras de Genes , Humanos , Macaca mulatta/genética , Macaca mulatta/crescimento & desenvolvimento , Especificidade da Espécie , Transcriptoma
12.
J Psychiatr Res ; 128: 1-4, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32474140

RESUMO

Prenatal COVID-19 infection is anticipated by the U.S. Centers for Disease Control to affect fetal development similarly to other common respiratory coronaviruses through effects of the maternal inflammatory response on the fetus and placenta. Plasma choline levels were measured at 16 weeks gestation in 43 mothers who had contracted common respiratory viruses during the first 6-16 weeks of pregnancy and 53 mothers who had not. When their infants reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), which assesses their infants' level of activity (Surgency), their fearfulness and sadness (Negativity), and their ability to maintain attention and bond to their parents and caretakers (Regulation). Infants of mothers who had contracted a moderately severe respiratory virus infection and had higher gestational choline serum levels (≥7.5 mM consistent with U.S. Food and Drug Administration dietary recommendations) had significantly increased development of their ability to maintain attention and to bond with their parents (Regulation), compared to infants whose mothers had contracted an infection but had lower choline levels (<7.5 mM). For infants of mothers with choline levels ≥7.5 µM, there was no effect of viral infection on infant IBQ-R Regulation, compared to infants of mothers who were not infected. Higher choline levels obtained through diet or supplements may protect fetal development and support infant early behavioral development even if the mother contracts a viral infection in early gestation when the brain is first being formed.


Assuntos
Betacoronavirus/patogenicidade , Encéfalo , Desenvolvimento Infantil , Colina , Desenvolvimento Fetal , Comportamento do Lactente , Complicações Infecciosas na Gravidez , Adulto , Atenção , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Desenvolvimento Infantil/efeitos dos fármacos , Desenvolvimento Infantil/fisiologia , Colina/administração & dosagem , Colina/sangue , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Suplementos Nutricionais , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Desenvolvimento Fetal/fisiologia , Idade Gestacional , Humanos , Lactente , Comportamento do Lactente/fisiologia , Comportamento do Lactente/psicologia , Masculino , Nootrópicos/administração & dosagem , Nootrópicos/sangue , Apego ao Objeto , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/virologia , Cuidado Pré-Natal/métodos
13.
Am J Hum Genet ; 106(6): 830-845, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32442410

RESUMO

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Craniossinostoses/genética , Transtornos do Neurodesenvolvimento/genética , Osteocondroma/genética , Fatores de Transcrição SOXD/genética , Transporte Ativo do Núcleo Celular , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Criança , Pré-Escolar , Simulação por Computador , Feminino , Variação Estrutural do Genoma/genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/diagnóstico , RNA-Seq , Fatores de Transcrição SOXD/química , Fatores de Transcrição SOXD/metabolismo , Síndrome , Transcrição Genética , Transcriptoma , Translocação Genética/genética
14.
Proc Natl Acad Sci U S A ; 117(22): 12411-12418, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430323

RESUMO

Genetic factors and socioeconomic status (SES) inequalities play a large role in educational attainment, and both have been associated with variations in brain structure and cognition. However, genetics and SES are correlated, and no prior study has assessed their neural associations independently. Here we used a polygenic score for educational attainment (EduYears-PGS), as well as SES, in a longitudinal study of 551 adolescents to tease apart genetic and environmental associations with brain development and cognition. Subjects received a structural MRI scan at ages 14 and 19. At both time points, they performed three working memory (WM) tasks. SES and EduYears-PGS were correlated (r = 0.27) and had both common and independent associations with brain structure and cognition. Specifically, lower SES was related to less total cortical surface area and lower WM. EduYears-PGS was also related to total cortical surface area, but in addition had a regional association with surface area in the right parietal lobe, a region related to nonverbal cognitive functions, including mathematics, spatial cognition, and WM. SES, but not EduYears-PGS, was related to a change in total cortical surface area from age 14 to 19. This study demonstrates a regional association of EduYears-PGS and the independent prediction of SES with cognitive function and brain development. It suggests that the SES inequalities, in particular parental education, are related to global aspects of cortical development, and exert a persistent influence on brain development during adolescence.


Assuntos
Encéfalo/crescimento & desenvolvimento , Cognição , Escolaridade , Sucesso Acadêmico , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Memória de Curto Prazo , Herança Multifatorial , Classe Social , Adulto Jovem
15.
Dev Cogn Neurosci ; 42: 100773, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32452463

RESUMO

Adolescence is characterized by rapid brain development in white matter (WM) that is attributed in part to surges in gonadal hormones. To date, however, there have been few longitudinal investigations relating changes in gonadal hormones and WM development in adolescents. We acquired diffusion-weighted MRI to estimate mean fractional anisotropy (FA) from 10 WM tracts and salivary testosterone from 51 females and 29 males (ages 9-14 years) who were matched on pubertal stage and followed, on average, for 2 years. We tested whether interactions between sex and changes in testosterone levels significantly explained changes in FA. We found positive associations between changes in testosterone and changes in FA within the corpus callosum, cingulum cingulate, and corticospinal tract in females (all ps<0.05, corrected) and non-significant associations in males. We also collected salivary estradiol from females and found that increases in estradiol were associated with increases in FA in the left uncinate fasciculus (p = 0.04, uncorrected); however, this effect was no longer significant after accounting for changes in testosterone. Our findings indicate there are sex differences in how changes in testosterone relate to changes in WM microstructure of tracts that support impulse control and emotion regulation across the pubertal transition.


Assuntos
Encéfalo/crescimento & desenvolvimento , Hormônios Gonadais/metabolismo , Substância Branca/crescimento & desenvolvimento , Adolescente , Criança , Feminino , Humanos , Masculino , Caracteres Sexuais
16.
Adv Exp Med Biol ; 1195: 237-247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468482

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA molecules of about 20-22 nucleotides. After their posttranscriptional maturation, miRNAs are loaded into the ribonucleoprotein complex RISC and modulate gene expression by binding to the 3' untranslated region of their target mRNAs through base-pairing, which in turn triggers mRNA degradation or translational inhibition. There is mounting evidence that miRNAs regulate various biological processes, including cell proliferation, differentiation, and apoptosis. Several studies have shown that miRNAs play an important role in neurogenesis and brain development.This review discusses recent progress on understanding the implication of precisely regulated miRNA expression in normal brain development and function. In addition, it reports known cases of dysregulation of miRNA expression and function implicated in the pathogenesis of neurodevelopmental disorders, craniofacial dysmorphic syndromes, neurodegenerative diseases, and psychiatric disorders. Current knowledge regarding the role of miRNAs in the brain in conjunction with the complex interplay between genetic and epigenetic factors are discussed.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Humanos , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , MicroRNAs/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurogênese/genética
17.
Proc Natl Acad Sci U S A ; 117(22): 12419-12427, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32409600

RESUMO

The expanding behavioral repertoire of the developing brain during childhood and adolescence is shaped by complex brain-environment interactions and flavored by unique life experiences. The transition into young adulthood offers opportunities for adaptation and growth but also increased susceptibility to environmental perturbations, such as the characteristics of social relationships, family environment, quality of schools and activities, financial security, urbanization and pollution, drugs, cultural practices, and values, that all act in concert with our genetic architecture and biology. Our multivariate brain-behavior mapping in 7,577 children aged 9 to 11 y across 585 brain imaging phenotypes and 617 cognitive, behavioral, psychosocial, and socioeconomic measures revealed three population modes of brain covariation, which were robust as assessed by cross-validation and permutation testing, taking into account siblings and twins, identified using genetic data. The first mode revealed traces of perinatal complications, including preterm and twin birth, eclampsia and toxemia, shorter period of breastfeeding, and lower cognitive scores, with higher cortical thickness and lower cortical areas and volumes. The second mode reflected a pattern of sociocognitive stratification, linking lower cognitive ability and socioeconomic status to lower cortical thickness, area, and volumes. The third mode captured a pattern related to urbanicity, with particulate matter pollution (PM25) inversely related to home value, walkability, and population density, associated with diffusion properties of white matter tracts. These results underscore the importance of a multidimensional and interdisciplinary understanding, integrating social, psychological, and biological sciences, to map the constituents of healthy development and to identify factors that may precede maladjustment and mental illness.


Assuntos
Encéfalo/fisiologia , Cognição , Comportamento , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Criança , Saúde da Criança/economia , Feminino , Humanos , Recém-Nascido , Masculino , Fatores Socioeconômicos
18.
PLoS Biol ; 18(5): e3000721, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32463838

RESUMO

Dietary nutrients provide macromolecules necessary for organism growth and development. In response to animal feeding, evolutionarily conserved growth signaling pathways are activated, leading to increased rates of cell proliferation and tissue growth. It remains unclear how different cell types within developing tissues coordinate growth in response to dietary nutrients and whether coordinated growth of different cell types is necessary for proper tissue function. Here, we report that Drosophila neural stem cells, known as neuroblasts, reactivate from developmental quiescence in a dietary-nutrient-dependent manner. Neuroblast reactivation in the brain requires nonautonomous activation of phosphoinositide 3-kinase (PI3-kinase) signaling from cortex glia and tracheal processes, both of which are closely associated with neuroblasts. Furthermore, PI3-kinase activation in neuroblasts is required nonautonomously for glial membrane expansion and robust neuroblast-glial contact. Finally, PI3-kinase is required cell autonomously for nutrient-dependent growth of neuroblasts, glia, and trachea. Of the 7 Drosophila insulin-like peptides (Dilps), we find that Dilp-2 is required for PI3-kinase activation and growth coordination between neuroblasts and glia in the brain. Dilp-2 induces brain cortex glia to initiate membrane growth and make first contact with quiescent neuroblasts. After contact, neuroblasts increase in size and reenter S-phase. Once reactivated from quiescence, neuroblasts promote growth of cortex glia, which, in turn, form a selective membrane barrier around neuroblasts and their newborn progeny. Our results highlight the importance of bidirectional growth signaling between neural stem cells and surrounding cell types in the brain in response to nutrition and demonstrate how coordinated growth among different cell types drives tissue morphogenesis and function.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/crescimento & desenvolvimento , Células-Tronco Neurais/fisiologia , Neuroglia/fisiologia , Neuropeptídeos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Drosophila/enzimologia , Ingestão de Alimentos , Ativação Enzimática , Larva/crescimento & desenvolvimento , Morfogênese , Transdução de Sinais , Nicho de Células-Tronco
19.
Int. j. morphol ; 38(2): 259-264, abr. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1056432

RESUMO

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.


Assuntos
Humanos , Medula Espinal/metabolismo , Encéfalo/crescimento & desenvolvimento , Desenvolvimento Embrionário , Fator de Transcrição PAX7/metabolismo , Fator de Transcrição PAX6/metabolismo , Medula Espinal/embriologia , Encéfalo/embriologia , Imuno-Histoquímica
20.
Artigo em Inglês | MEDLINE | ID: mdl-32320288

RESUMO

Plasticity within the neuronal networks of the brain underlies the ability to learn and retain new information. The initial discovery of synaptic plasticity occurred by measuring synaptic strength in vivo, applying external stimulation and observing an increase in synaptic strength termed long-term potentiation (LTP). Many of the molecular pathways involved in LTP and other forms of synaptic plasticity were subsequently uncovered in vitro. Over the last few decades, technological advances in recording and imaging in live animals have seen many of these molecular mechanisms confirmed in vivo, including structural changes both pre- and postsynaptically, changes in synaptic strength, and changes in neuronal excitability. A well-studied aspect of neuronal plasticity is the capacity of the brain to adapt to its environment, gained by comparing the brains of deprived and experienced animals in vivo, and in direct response to sensory stimuli. Multiple in vivo studies have also strongly linked plastic changes to memory by interfering with the expression of plasticity and by manipulating memory engrams. Plasticity in vivo also occurs in the absence of any form of external stimulation, i.e., during spontaneous network activity occurring with brain development. However, there is still much to learn about how plasticity is induced during natural learning and how this is altered in neurological disorders.


Assuntos
Encéfalo/metabolismo , Sinapses Elétricas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Transmissão Sináptica , Animais , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Sinapses Elétricas/patologia , Aprendizagem , Potenciação de Longa Duração , Modelos Neurológicos , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Neurônios/patologia , Potenciais Sinápticos
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