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Background: The research was designed to model animals which mimic the exposure to the radiofrequency radiation [RFR] by habitual users of RFR-enabled devices and to observe possible aberrations in behaviours that are attributable to exposures. The research was designed to model cases of continuous, and intermittent exposures in human conditions, using Wistar rats. The primary objective of this study was to study intrauterine and postnatal exposure and study the effects brain structures, functions and behaviours in Wistar rats. Materials and Methods: The experiment started with 42 pregnant rats that were exposed to RFR [4G] to observe the possibilities of RFR-induced teratogenic effects. Thereafter, half of the offspring were sacrificed for their brains to be studied at birth. The other half were exposed to RFR to observe postnatal effects of RFR radiation until puberty. The exposure regimen was the same for the mothers and the offspring in each group. What varied was he duration of exposure per day being 6 hours, 24 hours and 24 hours. Experimental Wistar rats were housed in facilities that enable exposure to specific dose (4G) of radiations during pregnancy (~21 days) of and during post-natal days until day 35, marking approximately the point of puberty. Following the dissection of the rat, brain tissue samples were homogenized in buffered phosphate saline [PBS]. The homogenates were centrifuged, and the supernatant was assayed for each neurotransmitter of interest. The values from each sample were recorded for the sample. The mean values for samples that constituted a group was calculated and statistically analyzed. ELISA biochemical assay kits were used. Results and Conclusion: RFR-exposure caused changes in neurotransmitters and enzyme neurochemistry. Cytochrome C oxidase enzyme and neurotransmitters especially dopamine, gamma-amino butyric acid , glutamine and serotonin and their activities levels were significantly altered especially with prolonged duration in RFR exposure. These findings would altogether suggest that radiofrequency radiation exposure might change brain neurochemistry permanently following exposure either during the intrauterine or the postnatal stage of life. The implications of these changes on later life mental health and neurological attributes will require further investigation

Prenatal opioid exposure (POE) has shown to be a risk factor for adverse long-term cognitive and behavioral outcomes in offspring. However, the neural mechanisms of these outcomes remain poorly understood. While preclinical and human studies suggest that these outcomes may be due to opioid-mediated changes in the fetal and early postnatal brain, other maternal, social, and environmental factors are also shown to play a role. Recent neuroimaging studies reveal brain alterations in children with POE. Early neuroimaging and novel methodology could provide an in vivo mechanistic understanding of opioid mediated alterations in developing brain. However, this is an area of ongoing research. In this review we explore recent imaging developments in POE, with emphasis on the neonatal and infant brain, and highlight some of the challenges of imaging the developing brain in this population. We also highlight evidence from animal models and imaging in older children and youth to understand areas where future research may be targeted in infants with POE.

Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3‐ubiquitin ligase that is critical for typical postnatal brain development. Emerging evidence indicates that UBE3A plays a particularly important role in the nucleus. However, the critical substrates that are controlled by UBE3A remain elusive, which hinders the search for effective treatments. Moreover, given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. Therefore, expectations are very high for approaches that aim to restore UBE3A protein levels. A particular promising strategy is an antisense oligonucleotide approach, which activates the silenced paternal UBE3A gene. When successful, such treatments potentially offer a disease‐modifying therapy for Angelman syndrome and several other neurodevelopmental disorders. What this paper adds Loss of UBE3A affects multiple signalling pathways in the brain.Emerging evidence suggests that UBE3A plays a critical role in the cell nucleus.Trials using antisense oligonucleotides to restore UBE3A levels are continuing., What this paper adds Loss of UBE3A affects multiple signalling pathways in the brain.Emerging evidence suggests that UBE3A plays a critical role in the cell nucleus.Trials using antisense oligonucleotides to restore UBE3A levels are continuing.

Cognitive abilities of the human brain, including language, have expanded dramatically in the course of our recent evolution from nonhuman primates, despite only minor apparent changes at the gene level. The hypothesis we propose for this paradox relies upon fundamental features of human brain connectivity, which contribute to a characteristic anatomical, functional, and computational neural phenotype, offering a parsimonious framework for connectomic changes taking place upon the human-specific evolution of the genome. Many human connectomic features might be accounted for by substantially increased brain size within the global neural architecture of the primate brain, resulting in a larger number of neurons and areas and the sparsification, increased modularity, and laminar differentiation of cortical connections. The combination of these features with the developmental expansion of upper cortical layers, prolonged postnatal brain development, and multiplied nongenetic interactions with the physical, social, and cultural environment gives rise to categorically human-specific cognitive abilities including the recursivity of language. Thus, a small set of genetic regulatory events affecting quantitative gene expression may plausibly account for the origins of human brain connectivity and cognition.

Perineuronal nets (PNNs) represent a highly condensed specialized form of brain extracellular matrix (ECM) enwrapping mostly parvalbumin-positive interneurons in the brain in a mesh-like fashion. PNNs not only regulate the onset and completion of the critical period during postnatal brain development, control cell excitability, and synaptic transmission but are also implicated in several brain disorders including schizophrenia. Holes in the perineuronal nets, harboring the synaptic contacts, along with hole-surrounding ECM barrier can be viewed as PNN compartmentalization units that might determine the properties of synapses and heterosynaptic communication. In this study, we developed a novel open-source script for Fiji (ImageJ) to semi-automatically quantify structural alterations of PNNs such as the number of PNN units, area, mean intensity of PNN marker expression in 2D and 3D, shape parameters of PNN units in the ketamine-treated Sprague-Dawley rat model of schizophrenia using high-resolution confocal microscopic images. We discovered that the mean intensity of ECM within PNN units is inversely correlated with the area and the perimeter of the PNN holes. The intensity, size, and shape of PNN units proved to be three major principal factors to describe their variability. Ketamine-treated rats had more numerous but smaller and less circular PNN units than control rats. These parameters allowed to correctly classify individual PNNs as derived from control or ketamine-treated groups with approximate to 85% reliability. Thus, the proposed multidimensional analysis of PNN units provided a robust and comprehensive morphometric fingerprinting of fine ECM structure abnormalities in the experimental model of schizophrenia.

Insight into illness in schizophrenia (SZ) patients has a major impact on treatment adherence and outcome. Previous studies have linked distinct deviations of brain structure to illness insight, specifically in frontoparietal and subcortical regions. Some of these abnormalities are thought to reflect aberrant cortical development. In this study, we used cross-sectional data to examine associations between illness insight and two cortical surface markers that are known to follow distinct neurodevelopmental trajectories, i.e. cortical gyrification (CG) and thickness (CT). CG and CT was investigated in SZ patients (n = 82) and healthy controls (HC, n = 48) using 3 T structural magnetic resonance imaging. Illness insight in SZ patients was measured using the OSSTI scale, an instrument that provides information on two distinct dimensions of illness insight, i.e. treatment adherence (OSSTI-A) and identification of disease-related symptoms (OSSTI-I). CT and CG were computed using the Computational Anatomy Toolbox (CAT12). Whole-brain and regions-of-interest (ROI)-based analyses were performed. SZ patients showed higher CG in anterior cingulate, superior frontal and temporal gyrus and reduced CG in insular and superior frontal cortex when compared to HC. SZ patients showed decreased CT in pre- and paracentral, occipital, cingulate, frontoparietal and temporal regions. Illness insight in SZ patients was significantly associated with both CG and CT in the left inferior parietal lobule (OSSTI-A) and the right precentral gyrus (CG/OSSTI-A, CT/OSSTI-I). The data support a multi-parametric neuronal model with both pre- and postnatal brain developmental factors having an impact on illness insight in patients with SZ.

Dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) are dynamically regulated before birth and the onset of puberty. Yet, the origins and purpose of increasing DHEA[S] in postnatal development remain elusive. Here, we draw attention to this pre-pubertal surge from the adrenal gland—the adrenarche—and discuss whether this is the result of intra-adrenal gene expression specifically affecting the zona reticularis (ZR), if the ZR is influenced by the hypothalamic-pituitary axis, and the possible role of spino-sympathetic innervation in prompting increased ZR activity. We also discuss whether neural DHEA[S] synthesis is coordinately regulated with the developing adrenal gland. We propose that DHEA[S] is crucial in the brain maturation of humans prior to and during puberty, and suggest that the function of the adrenarche is to modulate, adapt and rewire the pre-adolescent brain for new and ever-changing social challenges. The etiology of DHEA[S] synthesis, neurodevelopment and recently described 11-keto and 11-oxygenated androgens are difficult to investigate in humans owing to: (i) ethical restrictions on mechanistic studies, (ii) the inability to predict which individuals will develop specific mental characteristics, and (iii) the difficulty of conducting retrospective studies based on perinatal complications. We discuss new opportunities for animal studies to overcome these important issues.

Mutations in DYRK1A are a cause of microcephaly, autism spectrum disorder, and intellectual disability; however, the underlying cellular and molecular mechanisms are not well understood.We generated a conditional mouse model using Emx1-cre, including conditional heterozygous and homozygous knockouts, to investigate the necessity of Dyrk1a in the cortex during development. We used unbiased, high-throughput phosphoproteomics to identify dysregulated signaling mechanisms in the developing Dyrk1a mutant cortex as well as classic genetic modifier approaches and pharmacological therapeutic intervention to rescue microcephaly and neuronal undergrowth caused by Dyrk1a mutations.We found that cortical deletion of Dyrk1a in mice causes decreased brain mass and neuronal size, structural hypoconnectivity, and autism-relevant behaviors. Using phosphoproteomic screening, we identified growth-associated signaling cascades dysregulated upon Dyrk1a deletion, including TrkB-BDNF (tyrosine receptor kinase B-brain-derived neurotrophic factor), an important regulator of ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) and mTOR (mammalian target of rapamycin) signaling. Genetic suppression of Pten or pharmacological treatment with IGF-1 (insulin-like growth factor-1), both of which impinge on these signaling cascades, rescued microcephaly and neuronal undergrowth in neonatal mutants.Altogether, these findings identify a previously unknown mechanism through which Dyrk1a mutations disrupt growth factor signaling in the developing brain, thus influencing neuronal growth and connectivity. Our results place DYRK1A as a critical regulator of a biological pathway known to be dysregulated in humans with autism spectrum disorder and intellectual disability. In addition, these data position Dyrk1a within a larger group of autism spectrum disorder/intellectual disability risk genes that impinge on growth-associated signaling cascades to regulate brain size and connectivity, suggesting a point of convergence for multiple autism etiologies.

ImportanceThe ENIGMA clinical high risk for psychosis (CHR) initiative, the largest pooled CHR-neuroimaging sample to date, aims to discover robust neurobiological markers of psychosis risk in a sample with known heterogeneous outcomes.ObjectiveWe investigated baseline structural neuroimaging differences between CHR subjects and healthy controls (HC), and between CHR participants who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). We assessed associations with age by group and conversion status, and similarities between the patterns of effect size maps for psychosis conversion and those found in other large-scale psychosis studies.Design, Setting, and ParticipantsBaseline T1-weighted MRI data were pooled from 31 international sites participating in the ENIGMA CHR Working Group. MRI scans were processed using harmonized protocols and analyzed within a mega- and meta-analysis framework from January-October 2020.Main Outcome(s) and Measure(s)Measures of regional cortical thickness (CT), surface area (SA), and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR, HC) and conversion status (CHR-PS+, CHR-PS-, HC).ResultsThe final dataset consisted of 3,169 participants (CHR=1,792, HC=1,377, age range: 9.5 to 39.8 years, 45% female). Using longitudinal clinical information, we identified CHR-PS+ (N=253) and CHR-PS- (N=1,234). CHR exhibited widespread thinner cortex compared to HC (average d=-0.125, range: -0.09 to -0.17), but not SA or subcortical volume. Thinner cortex in the fusiform, superior temporal, and paracentral regions was associated with psychosis conversion (average d=-0.22). Age showed a stronger negative association with left fusiform and left paracentral CT in HC, compared to CHR-PS+. Regional CT psychosis conversion effect sizes resembled patterns of CT alterations observed in other ENIGMA studies of psychosis.Conclusions and RelevanceWe provide evidence for widespread subtle CT reductions in CHR. The pattern of regions displaying greater CT alterations in CHR-PS+ were similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread CT disruptions coupled with abnormal age associations in CHR may point to disruptions in postnatal brain developmental processes.Key PointsQuestionHow do baseline brain morphometric features relate to later psychosis conversion in individuals at clinical high risk (CHR)?FindingsIn the largest coordinated international analysis to date, reduced baseline cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in CHR, in a manner highly consistent with thinner cortex in established psychosis. Regions that displayed greater cortical thinning in future psychosis converters additionally displayed abnormal associations with age.MeaningCHR status and later transition to psychosis is robustly associated with reduced cortical thickness. Abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in CHR, including pruning and myelination.

Human cerebral cortex shows the dramatic areal expansion and folding during fetal life with the most prominent and dynamic genetic regulation. The position of early sulcal folds appears to be associated with cortical functional areas predetermined from genetic protomap, and specific patterns of sulcal folding have been hypothesized to relate to optimal organization and arrangement of the functional areas and their white matter connections. As primary sulcal folding pattern is prenatally determined and neurodevelopmental disabilities associated with abnormal pattern may have a prenatal origin, it is needed to develop and use in vivo fetal brain magnetic resonance imaging (MRI) analysis techniques to provide a predictive model of postnatal brain development and neurodevelopmental disability risk from early fetal life. Recent advances in fetal MRI analysis allow us to quantify and characterize normal and abnormal sulcal development and detect early-emerging subtle abnormalities in cortical sulcal pattern in several brain developmental disorders.

Aim: To report on prevalence of cerebral palsy (CP), severity rates, and types of brain lesions in children born preterm 2004 to 2010 by gestational age groups.Methods: Data from 12 population-based registries of the Surveillance of Cerebral Palsy in Europe network were used. Children with CP were eligible if they were born preterm (Results: The sample comprised 2,273 children. 25.8% were born from multiple pregnancies. About 2-thirds had a bilateral spastic CP. 43.5% of children born ≤27 weeks had a high impairment index compared to 37.0 and 38.5% in the two other groups. Overall prevalence significantly decreased (incidence rate ratio per year: 0.96 [0.92–1.00[) in children born 32–36 weeks. We showed a decrease until 2009 for children born 28–31 weeks but an increase in 2010 again, and a steady prevalence (incidence rate ratio per year = 0.97 [0.92–1.02] for those born ≤27 weeks. The prevalence of the most severely affected children with CP revealed a similar but not significant trend to the overall prevalence in the corresponding GA groups. Predominant white matter injuries were more frequent in children born Conclusion: Prevalence of CP in preterm born children continues to decrease in Europe excepting the extremely immature children, with the most severely affected children showing a similar trend.

The quantification of cerebrospinal fluid (CSF) in the human brain has shown to play an important role in early postnatal brain development. Extra-axial fluid (EA-CSF), which is characterized by CSF in the subarachnoid space, is a promising marker for the early detection of children at risk for neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD). Yet, non-ventricular CSF quantification, in particular extra-axial CSF quantification, is not supported in the major neuro-imaging software solutions, such as FreeSurfer. Most current structural image analysis packages mask out the extra-axial CSF space in one of the first pre-processing steps. A quantitative protocol was previously developed by our group to objectively measure the volume of total EA-CSF volume using a pipeline workflow implemented in a series of python scripts. While this solution worked for our specific lab, a graphical user interface-based tool is necessary to facilitate the computation of extra-axial CSF volume across a wide array of neuroimaging studies and research labs. This paper presents the development of a novel open-source, cross-platform, user-friendly software tool, called Auto-EACSF, for the automatic computation of such extra-axial CSF volume. Auto-EACSF allows neuroimaging labs to quantify extra-axial CSF in their neuroimaging studies in order to investigate its role in normal and atypical brain development.

Intergenerational effects are described as the genetic, epigenetic, as well as pre- and postnatal environmental influence parents have on their offspring’s behavior, cognition, and brain. During fetal brain development, the primary cortical sulci emerge with a distinctive folding pattern that are under strong genetic influence and show little change of this pattern throughout postnatal brain development. We examined intergenerational transmission of cortical sulcal patterns by comparing primary sulcal patterns between children (N = 16, age 5.5 ± 0.81 years, 8 males) and their biological mothers (N = 15, age 39.72 ± 4.68 years) as well as between children and unrelated adult females. Our graph-based sulcal pattern comparison method detected stronger sulcal pattern similarity for child–mother pairs than child-unrelated pairs, where higher similarity between child–mother pairs was observed mostly for the right lobar regions. Our results also show that child–mother versus child-unrelated pairs differ for daughters and sons with a trend toward significance, particularly for the left hemisphere lobar regions. This is the first study to reveal significant intergenerational transmission of cortical sulcal patterns, and our results have important implications for the study of the heritability of complex behaviors, brain-based disorders, the identification of biomarkers, and targets for interventions.

Artículo editorial, 2 páginas. THIS ARTICLE IS PART OF THE RESEARCH TOPIC Generation of Neurons and Their Integration in Pre-Existing Circuits in the Postnatal Brain: Signalling in Physiological and Regenerative Contexts: https://www.frontiersin.org/research-topics/7853/generation-of-neurons-and-their-integration-in-pre-existing-circuits-in-the-postnatal-brain-signalli#articles, HM laboratory was supported by Spanish MICINN grant (SAF2015-70433-R) and PROMETEO/2018/055 grant from Generalitat Valenciana. Research in RD laboratory was supported by the Champalimaud Foundation. Research in AM laboratory was supported by Spanish MCINN grant (SAF2017-85717-R) and Fundación Alicia Koplowitz (Grant 2018).

Background Defining reliable brain markers for the prediction of abnormal behavioral outcomes remains an urgent but extremely challenging task in neuroscience research. This is particularly important for infant studies given the most dramatic brain and behavioral growth during infancy. Methods In this study, we proposed a novel prediction scheme through abstracting individual newborn's whole‐brain functional connectivity pattern to three outlier measures (Triple O) and tested the hypothesis that neonates identified as “brain outliers” based on Triple O were more likely to develop as IQ outliers at 4 years of age. Without need for training with behavioral data, Triple O represents a novel proof‐of‐concept approach to predict later IQ outcomes based on neonatal brain data. Results Triple O correctly identified 42.1% true IQ outliers among a mixed cohort of 175 newborns with different term, twin, and maternal disorder statuses. Triple O also reached a high level of specificity (96.2%) and overall accuracy (90.3%). Further incorporating a demographic information indicator, the enhanced Triple O+ could further differentiate between high and low 4YR IQ outliers. Validation tests against seven independent reference samples revealed highly consistent results and a minimum sample size of ~50 for robust performance. Conclusions Considering that postnatal brain growth and various environmental factors likely also contribute to 4YR IQ, the fact that Triple O, based purely on neonatal functional connectivity data, could identify >40% of 4YR IQ outliers is striking. Together with the very high level of specificity, each outlier predicted by Triple O represents a meaningful risk but future efforts are needed to explore ways to identify the rest of outliers. Overall, with no need for training, a high level of robustness, and a minimal requirement on sample size, the proposed Triple O approach demonstrates great potential to predict later outlying IQ performances using neonatal functional connectivity data., One of the most desired goals of developmental research is to be able to predict childhood behavioral outcomes based on brain biomarkers as early as possible to facilitate in‐time intervention. However, this problem is notoriously challenging, partly due to the complex nature of brain function and reportedly weak brain–behavioral relationships. In this study, we derived a simple, training‐free prediction scheme to abstract the neonatal whole‐brain functional connectivity pattern to three outlier measures (Triple O) and showed that it could identify over forty percent of 4‐year IQ performance outliers with a high level of robustness against different reference samples. Results in this study represent a first step in this novel direction of brain outlier‐based prediction of later behavioral outcomes.

The most dynamic period of postnatal brain development occurs during adolescence, the period between childhood and adulthood. Neuroimaging studies have observed morphologic and functional changes during adolescence, and it is believed that these changes serve to improve the functions of circuits that underlie decision-making. Direct evidence in support of this hypothesis, however, has been limited because most preclinical decision-making paradigms are not readily translated to humans. Here, we developed a reversal-learning protocol for the rapid assessment of adaptive choice behavior in dynamic environments in rats as young as postnatal day 30. A computational framework was used to elucidate the reinforcement-learning mechanisms that change in adolescence and into adulthood. Using a cross-sectional and longitudinal design, we provide the first evidence that value-based choice behavior in a reversal-learning task improves during adolescence in male and female Long–Evans rats and demonstrate that the increase in reversal performance is due to alterations in value updating for positive outcomes. Furthermore, we report that reversal-learning trajectories in adolescence reliably predicted reversal performance in adulthood. This novel behavioral protocol provides a unique platform for conducting biological and systems-level analyses of the neurodevelopmental mechanisms of decision-making. SIGNIFICANCE STATEMENT The neurodevelopmental adaptations that occur during adolescence are hypothesized to underlie age-related improvements in decision-making, but evidence to support this hypothesis has been limited. Here, we describe a novel behavioral protocol for rapidly assessing adaptive choice behavior in adolescent rats with a reversal-learning paradigm. Using a computational approach, we demonstrate that age-related changes in reversal-learning performance in male and female Long–Evans rats are linked to specific reinforcement-learning mechanisms and are predictive of reversal-learning performance in adulthood. Our behavioral protocol provides a unique platform for elucidating key components of adolescent brain function.

The postnatal brain development is characterized by a substantial gain in weight and size, ascribed to increasing neuronal size and branching, and to massive addition of glial cells. This occurs concomitantly to the shrinkage of VZ and SVZ, considered to be the main germinal zones, thus suggesting the existence of other germinative niches. The aim of this study is to characterize the cortical grey matter proliferating cells during postnatal development, providing their stereological quantification and identifying the nature of their cell lineage. We performed double immunolabeling for the proliferation marker Ki67 and three proteins which identify either astrocytes (S100β) or oligodendrocytes (Olig2 and NG2), in addition to a wider panel of markers apt to validate the former markers or to investigate other cell lineages. We found that proliferating cells increase in number during the first postnatal week until P10 and subsequently decreased until P21. Cell lineage characterization revealed that grey matter proliferating cells are prevalently oligodendrocytes and astrocytes along with endothelial and microglial cells, while no neurons have been detected. Our data showed that astrogliogenesis occurs prevalently during the first 10 days of postnatal development, whereas contrary to the expected peak of oligodendrogenesis at the second postnatal week, we found a permanent pool of proliferating oligodendrocytes enduring from birth until P21. These data support the relevance of glial proliferation within the grey matter and could be a point of departure for further investigations of this complex process.

BACKGROUND AND PURPOSE: The majority of brain growth and development occur in the first 2 years of life. This study investigated these changes by analysis of the brain radiodensity histogram of head CT scans from the clinical population, 0–2 years of age. MATERIALS AND METHODS: One hundred twenty consecutive head CTs with normal findings meeting the inclusion criteria from children from birth to 2 years were retrospectively identified from 3 different CT scan platforms. Histogram analysis was performed on brain-extracted images, and histogram mean, mode, full width at half maximum, skewness, kurtosis, and SD were correlated with subject age. The effects of scan platform were investigated. Normative curves were fitted by polynomial regression analysis. RESULTS: Average total brain volume was 360 cm3 at birth, 948 cm3 at 1 year, and 1072 cm3 at 2 years. Total brain tissue density showed an 11% increase in mean density at 1 year and 19% at 2 years. Brain radiodensity histogram skewness was positive at birth, declining logarithmically in the first 200 days of life. The histogram kurtosis also decreased in the first 200 days to approach a normal distribution. Direct segmentation of CT images showed that changes in brain radiodensity histogram skewness correlated with, and can be explained by, a relative increase in gray matter volume and an increase in gray and white matter tissue density that occurs during this period of brain maturation. CONCLUSIONS: Normative metrics of the brain radiodensity histogram derived from routine clinical head CT images can be used to develop a model of normal brain development.

In the present review, we discuss the very recent findings that the gut microbiota composition can modulate cell-based plasticity in the brain, namely, adult hippocampal neurogenesis, and thereby alter hippocampal dependent behavior. Absence of gut microbiota from birth or antibiotic-induced dysbiosis in adults leads to an aberrant metabolite production and immune functions. Both scenarios compromise a proper postnatal brain development, or brain wiring in adults, including aberrant neurogenesis. This in turn leads to a hippocampal mismanagement of environmental cues and renders the animals to be more susceptible to stress and less cognitively flexible which contribute to general impairments in learning and memory functions and social behavior. Mounting evidence indicates that certain behavior aberrances in germ-free and dysbiotic mice are mediated by changes in neurogenesis. The mechanisms and the relevance of this complex regulation remain to be elucidated by future research.

Adequate sleep is essential for normal brain function, especially during early life developmental stages as postnatal brain maturation occurs during the critical period of childhood and adolescence. Therefore, sleep disturbance and/or deficit during this period can have detrimental consequences. Many epidemiological and clinical studies have linked early life sleep disturbance with occurrence of later life behavioral and cognitive impairments. Role of oxidative stress and inflammation has been implicated in sleep deprivation-related impairments. This review article presents a detailed description of the current state of the literature on the subject.

Human milk oligosaccharides (HMOs) are the first prebiotics humans meet in life. HMOs provide many benefits to infants including impact on gut bacteria, promotion of postnatal brain development, and modulation of the immune system. A complex bidirectional communication pathway called the microbiota-gut-brain axis links gut homeostasis and microbial composition with the central nervous system (CNS). Several mechanisms regulated by the gut microbiota are known to affect this axis. Dynamics in microbiota composition changes the metabolite profile in the gut, including neuroactive biomolecules that influence brain function and health. The gut microbiota also has the potential to affect and interact with the neurologic, immunologic and endocrine pathways of the microbiota-gut-brain axis. In this review, we discuss the potential role of HMOs in microbiota-gut-brain axis and CNS disorders, by describing the role of the gut microbiota in relation to brain health and the importance of dietary interventions in manipulating the microbiota-gut-brain axis.

To elucidate the correlation between pre- and postnatal cerebral Doppler in pregnancies close to term and to explore whether they are associated with perinatal outcome. Prospective study on singleton pregnancies at 36���37 weeks of gestation. The primary outcome was a composite score of perinatal morbidity, while secondary outcomes were adverse intra-partum outcome and abnormal acid���base status. All pregnancies underwent ultrasound assessment of umbilical artery (UA), middle cerebral artery (MCA), uterine arteries (UtAs) pulsatility index (PI), and cerebroplacental ratio (CPR). At birth, neonatal MCA PI was measured 72 h from delivery and correlated with prenatal Doppler, primary and secondary outcomes. Fisher���s test and multivariate logistic regression analysis were used to analyze the data. One hundred and sixty-six fetuses with both pre- and postnatal Doppler assessment of the MCA were included in the study. The risk of composite perinatal morbidity was higher in fetuses (OR: 5.7, 95% CI 2.2���14.6) and newborns (OR: 4.1, 95% CI 1.8���9.6) with fetal MCA PI < 10th centile. Likewise, the incidence of abnormal acid���base status was higher both in fetuses (20 versus 4.2%, p = .026) and newborns (17.1 versus 3.2%, p = .001) with a low MCA PI before and at birth, respectively. At logistic regression analysis, fetal and neonatal MCAPI were independently associated with composite perinatal morbidity and abnormal acid���base status, but not with adverse intra-partum outcome. In small for gestational age (SGA) fetuses, the incidence of composite perinatal morbidity was higher in fetuses and new-borns presenting compared to those not presenting with an MCA PI < 10th centile (61.5 versus 20%, p = .003 and 52.6% versus 7.1%, p = .008, respectively), while such association was lost when considering non-SGA fetuses. A low MCA PI is associated with adverse perinatal outcome in pregnancies at term and tends to persist after birth.

Neurons generated in the postnatal V-SVZ form chainlike aggregates and migrate rapidly within a glial tube for a long distance toward the olfactory bulb. These morphological features are not observed during the embryonic period, suggesting that the chain formation and glial tube have roles specific to the neuronal migration in the postnatal brain. Neuronal migration in the postnatal brain may be affected by changes in the physiological condition of the brain, such as neuronal activity, development, and aging. Furthermore, recent evidence suggests that neuronal migration also depends on nonneural systems such as immune and vascular systems. Further analyses of the spatiotemporal interactions between migrating neurons and other cell types, and identification of the molecules mediating these interactions will be necessary to understand the regulatory mechanisms of neuronal migration in the postnatal brain. Neuronal migration in the postnatal brain appears to be a remarkable strategy for modifying postnatal brain functions, and not just a delivery system of newborn neurons from the germinal zone to their destination. Further studies aimed at clarifying the adaptive potential of migrating neurons in the postnatal brain are needed to establish novel strategies for endogenous neuronal regeneration.

The maturation of the mammalian brain occurs after birth, and this stage of neuronal development is frequently impaired in neurological disorders such as autism and schizophrenia. However, the mechanisms that regulate postnatal brain maturation are poorly defined. By purifying neuronal subpopulations across brain development in mice, we identify a postnatal switch in the transcriptional regulatory circuits that operates in the maturing mammalian brain. We show that this developmental transition includes the formation of hundreds of cell type-specific neuronal enhancers in the postnatal period that may in part be modulated by neuronal activity. Once selected, these enhancers are active throughout adulthood, suggesting that their formation in early life shapes both neuronal identity and regulates mature brain function.

Summary The translation initiation repressor 4E-BP2 is deamidated in the brain on asparagines N99/N102 during early postnatal brain development. This post-translational modification enhances 4E-BP2 association with Raptor, a central component of mTORC1 and alters the kinetics of excitatory synaptic transmission. We show that 4E-BP2 deamidation is neuron specific, occurs in the human brain, and changes 4E-BP2 subcellular localization, but not its disordered structure state. We demonstrate that deamidated 4E-BP2 is ubiquitinated more and degrades faster than the unmodified protein. We find that enhanced deamidated 4E-BP2 degradation is dependent on Raptor binding, concomitant with increased association with a Raptor-CUL4B E3 ubiquitin ligase complex. Deamidated 4E-BP2 stability is promoted by inhibiting mTORC1 or glutamate receptors. We further demonstrate that deamidated 4E-BP2 regulates the translation of a distinct pool of mRNAs linked to cerebral development, mitochondria, and NF-κB activity, and thus may be crucial for postnatal brain development in neurodevelopmental disorders, such as ASD., Graphical Abstract, Highlights • Deamidated 4E-BP2 occurs in neurons and is susceptible to ubiquitination/degradation • mTORC1 or glutamate receptor inhibition stabilizes deamidated 4E-BP2 • A Raptor-CUL4B ubiquitin ligase complex binds to deamidated 4E-BP2 • Deamidated 4E-BP2 regulates postnatal brain translation and NF-κB activity, Kouloulia et al. demonstrate that, during early postnatal brain development, deamidation of the translation initiation factor 4E-BP2 renders it susceptible to ubiquitination and proteasomal degradation via enhanced binding to the Raptor-CUL4B complex. mTORC1 or glutamate receptor inhibition stabilizes deamidated 4E-BP2. Moreover, deamidated 4E-BP2 regulates the translation of specific mRNAs and NF-κB activity.

Neonatal intensive care practices have resulted in marked improvements in the survival of premature infants; however, they remain at significant risk for adverse neurodevelopmental outcomes. The impact of current nutritional practices on brain development following early extra-uterine exposure in premature infants is not well known. We performed a systematic review to investigate nutritional effects on postnatal brain development in healthy term and prematurely born infants utilizing advanced magnetic resonance imaging tools. Systematic screen yielded 595 studies for appraisal. Of these, 22 total studies were selected for inclusion in the review, with findings summarized in a qualitative, descriptive fashion. Fat and energy intake are associated with improved brain volume and development in premature infants. While breast milk intake and long-chain polyunsaturated fatty acid supplementation has been proven beneficial in term infants, the impact in preterm infants is less well understood.

Mature mammalian brains consist of variety of neuronal and non-neuronal cell types, which are progressively generated from embryonic neural progenitors through the embryonic and postnatal periods. However, it remains unknown whether all embryonic progenitors equivalently contribute to multiple cell types, or individual neural progenitors have variable potentials to generate specific cell types in a stochastic manner. Here, we performed population-level tracing of mouse embryonic neural progenitors by using Tol2-mediated genome integration vectors. We identified that neural progenitors in early embryonic stages predominantly contribute to cortical or subcortical neurons than astrocytes, ependymal cells, and neuroblasts in the postnatal brain. Notably, neurons and astrocytes were cumulatively labeled by the increase of total labeled cells, suggesting constant neurogenic and gliogenic potentials of individual neural progenitors. On the contrary, numbers of labeled ependymal cell are more fluctuated, implicating intrinsic variability of progenitor potentials for ependymal cell generation. Differential progenitor potentials that contribute to neurons, astrocytes, and ependymal cells were also detected in the developing avian pallium. Our data suggest evolutionary conservations of coherent and variable potentials of neural progenitors that generate multiple cell types in the developing amniote brain.

Background: Critical periods (CP) in brain development are characterized by heightened neural plasticity in the relevant brain regions. They are associated with changes in gene expression cascades, in particular with altered expression of genes involved in plasticity regulation, such as immediate early genes. Here we examine the expression of the immediate early genes c-Fos and Egr1 at different stages of mouse visual cortex (VC) development. Methods: Mice 11, 25, and 50 days of age were maintained under standard light-dark conditions, deprived of light for 5 days, or deprived of light for 5 days and then exposed to light for 90 min. Their brains were analyzed at PND16 (before the onset of the CP), PND30 (during the CP) and PND55 (after the CP) to determine the changes in the number of cells expressing c-Fos and Egr1 in the binocular primary visual and primary somatosensory cortices. Results: We found highly specific induction of c-Fos expression in the primary VC in response to light. We also observed transient cross-modal activation of c-Fos in the barrel field of the primary somatosensory cortex in response to light before and during the CP; such activation disappeared after the CP. Expression of Egr1 was not induced by light in the VC before the CP, but was evident during and after the CP, although the induction was much less pronounced than that of c-Fos. Conclusions: Dynamic changes in c-Fos and Egr1 expression may reflect their contribution to the VC plasticity during the CPs of postnatal brain development.

Neurodevelopment As the brain develops, neurons build new connections that are refined by pruning. Gour et al. used electron microscopy to build a high-resolution study of mouse postnatal brain development. The survey reveals the details of how circuits are built to incorporate inhibitory neurons in the somatosensory cortex. Science , this issue p. [eabb4534][1] [1]: /lookup/doi/10.1126/science.abb4534

Although the Zika virus (ZIKV) typically causes mild or no symptoms in adults, during the 2015−2016 outbreak, ZIKV infection in pregnancy resulted in a spectrum of diseases in infants, including birth defects and neurodevelopmental disorders identified in childhood. While intense clinical and basic science research has focused on the neurodevelopmental outcomes of prenatal ZIKV infection, less is known about the consequences of infection during early life. Considering the neurotropism of ZIKV and the rapidly-developing postnatal brain, it is important to understand how infection during infancy may disrupt neurodevelopment. This paper reviews the current knowledge regarding early postnatal ZIKV infection. Emerging clinical evidence supports the hypothesis that ZIKV infection during infancy can result in negative neurologic consequences. However, clinical data regarding postnatal ZIKV infection in children are limited; as such, animal models play an important role in understanding the potential complications of ZIKV infection related to the vulnerable developing brain. Preclinical data provide insight into the potential behavioral, cognitive, and motor domains that clinical studies should examine in pediatric populations exposed to ZIKV during infancy.

Sensory experience remodels neural circuits in the early postnatal brain through mechanisms that remain to be elucidated. Applying a new method of ultrastructural analysis to the retinogeniculate circuit, we find that visual experience alters the number and structure of synapses between the retina and the thalamus. These changes require the vision-dependent transcription of the receptor Fn14 in thalamic relay neurons and the induction of its ligand TWEAK in microglia. Fn14 functions to increase the number of bulbous spine-associated synapses at retinogeniculate connections likely contributing to the strengthening of the circuit that occurs in response to visual experience. However, at retinogeniculate connections nearby TWEAK-expressing microglia, TWEAK signals via Fn14 to restrict the number of bulbous spines on relay neurons, leading to the elimination of a subset of connections. Thus, TWEAK and Fn14 represent an intercellular signaling axis through which microglia shape retinogeniculate connectivity in response to sensory experience.

Postnatal brain circuit assembly is driven by temporally regulated intrinsic and cell-extrinsic cues that organize neurogenesis, migration, and axo-dendritic specification in post-mitotic neurons. While cell polarity is an intrinsic organizer of morphogenic events, environmental cues in the germinal zone (GZ) instructing neuron polarization and their coupling during postnatal development are unclear. We report that oxygen tension, which rises at birth, and the von Hippel-Lindau (VHL)-hypoxia-inducible factor 1α (Hif1α) pathway regulate polarization and maturation of post-mitotic cerebellar granule neurons (CGNs). At early postnatal stages with low GZ vascularization, Hif1α restrains CGN-progenitor cell-cycle exit. Unexpectedly, cell-intrinsic VHL-Hif1α pathway activation also delays the timing of CGN differentiation, germinal zone exit, and migration initiation through transcriptional repression of the partitioning-defective (Pard) complex. As vascularization proceeds, these inhibitory mechanisms are downregulated, implicating increasing oxygen tension as a critical switch for neuronal polarization and cerebellar GZ exit.