Low-grade glioma of the temporal lobe and tumor-related epilepsy in children.

PURPOSE: Low-grade glioma is the most common brain tumor among children and adolescents. When these tumors arise in the temporal lobe, patients frequently present with seizures that are poorly controlled with antiepileptic drugs. Here we summarize the clinical features, pathophysiology, preoperative evaluation, surgical treatment, and outcomes of pediatric patients with low-grade gliomas in the temporal lobe. METHODS: We reviewed the literature on pediatric low-grade gliomas in the temporal lobe, focusing on cohort studies and systematic reviews that described surgical treatment strategies and reported both oncologic and epilepsy outcomes. RESULTS: The differential diagnoses of pediatric low-grade gliomas in the temporal lobe include ganglioglioma, dysembryoplastic neuroepithelial tumor, desmoplastic infantile ganglioglioma, papillary glioneuronal tumor, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, angiocentric glioma, and polymorphous low-grade neuroepithelial tumor of the young. There is no consensus on the optimal surgical approach for these tumors: lesionectomy alone, or extended lesionectomy with anterior temporal lobectomy, with or without removal of mesial temporal structures. Gross total resection and shorter preoperative duration of epilepsy are strongly associated with favorable seizure outcomes, defined as Engel Class I or Class II, approaching 90% in most series. The risk of surgical complications ranges from 4 to 17%, outweighing the lifetime risks of medically refractory epilepsy. CONCLUSION: Pediatric patients with temporal low-grade glioma and tumor-related epilepsy are best managed by a multidisciplinary epilepsy surgery team. Early and appropriate surgery leads to prolonged survival and a greater likelihood of seizure freedom, improving their overall quality of life.

Growth charts of brain morphometry for preschool children.

Brain development from 1 to 6 years of age anchors a wide range of functional capabilities and carries early signs of neurodevelopmental disorders. However, quantitative models for depicting brain morphology changes and making individualized inferences are lacking, preventing the identification of early brain atypicality during this period. With a sample size of 285, we characterized the age dependence of the cortical thickness and subcortical volume in neurologically normal children and constructed quantitative growth charts of all brain regions for preschool children. While the cortical thickness of most brain regions decreased with age, the entorhinal and parahippocampal regions displayed an inverted-U shape of age dependence. Compared to the cortical thickness, the normalized volume of subcortical regions exhibited more divergent trends, with some regions increasing, some decreasing, and some displaying inverted-U-shaped trends. The growth curve models for all brain regions demonstrated utilities in identifying brain atypicality. The percentile measures derived from the growth curves facilitate the identification of children with developmental speech and language disorders with an accuracy of 0.875 (area under the receiver operating characteristic curve: 0.943). Our results fill the knowledge gap in brain morphometrics in a critical development period and provide an avenue for individualized brain developmental status evaluation with demonstrated sensitivity. The brain growth charts are shared with the public (http://phi-group.top/resources.html).

Harmonized-Multinational qEEG norms (HarMNqEEG).

This paper extends frequency domain quantitative electroencephalography (qEEG) methods pursuing higher sensitivity to detect Brain Developmental Disorders. Prior qEEG work lacked integration of cross-spectral information omitting important functional connectivity descriptors. Lack of geographical diversity precluded accounting for site-specific variance, increasing qEEG nuisance variance. We ameliorate these weaknesses. (i) Create lifespan Riemannian multinational qEEG norms for cross-spectral tensors. These norms result from the HarMNqEEG project fostered by the Global Brain Consortium. We calculate the norms with data from 9 countries, 12 devices, and 14 studies, including 1564 subjects. Instead of raw data, only anonymized metadata and EEG cross-spectral tensors were shared. After visual and automatic quality control, developmental equations for the mean and standard deviation of qEEG traditional and Riemannian DPs were calculated using additive mixed-effects models. We demonstrate qEEG "batch effects" and provide methods to calculate harmonized z-scores. (ii) We also show that harmonized Riemannian norms produce z-scores with increased diagnostic accuracy predicting brain dysfunction produced by malnutrition in the first year of life and detecting COVID induced brain dysfunction. (iii) We offer open code and data to calculate different individual z-scores from the HarMNqEEG dataset. These results contribute to developing bias-free, low-cost neuroimaging technologies applicable in various health settings.

Postnatal Ethanol Exposure Activates HDAC-Mediated Histone Deacetylation, Impairs Synaptic Plasticity Gene Expression and Behavior in Mice.

BACKGROUND: Alcohol consumption during pregnancy is widespread and contributes to pediatric neurological defects, including hippocampal and neocortex dysfunction, causing cognitive deficits termed fetal alcohol spectrum disorders. However, the critical mechanisms underlying these brain abnormalities remain poorly described. METHODS: Using a postnatal ethanol exposure (PEE) animal model and pharmacological, epigenetic, synaptic plasticity-related and behavioral approaches, we discovered a novel persistent epigenetic mechanism of neurodegeneration in neonatal hippocampus and neocortex brain regions and of cognitive decline in adult animals. RESULTS: PEE, which activates caspase-3 (CC3, a neurodegeneration marker), enhanced histone deacetylase (HDAC1-HDAC3) levels and reduced histone 3 (H3) and 4 (H4) acetylation (ac) in mature neurons. PEE repressed the expression of several synaptic plasticity genes, such as brain-derived neurotrophic factor, C-Fos, early growth response 1 (Egr1), and activity-regulated cytoskeleton-associated protein (Arc). Detailed studies on Egr1 and Arc expression revealed HDAC enrichment at their promoter regions. HDAC inhibition with trichostatin A (TSA) before PEE rescued H3ac/H4ac levels and prevented CC3 formation. Antagonism/null mutation of cannabinoid receptor type-1 (CB1R) before PEE to inhibit CC3 production prevented Egr1 and Arc loss via epigenetic events. TSA administration before PEE prevented postnatal ethanol-induced loss of Egr1 and Arc expression and neurobehavioral defects in adult mice via epigenetic remodeling. In adult mice, 3-day TSA administration attenuated PEE-induced behavioral defects. CONCLUSIONS: These findings demonstrate that CB1R/HDAC-mediated epigenetic remodeling disrupts gene expression and is a critical step in fetal alcohol spectrum disorder-associated cognitive decline but is reversed by restoration of histone acetylation in the brain.

Neural progenitors derived from Tuberous Sclerosis Complex patients exhibit attenuated PI3K/AKT signaling and delayed neuronal differentiation.

Tuberous Sclerosis Complex (TSC) is a disease caused by autosomal dominant mutations in the TSC1 or TSC2 genes, and is characterized by tumor susceptibility, brain lesions, seizures and behavioral impairments. The TSC1 and TSC2 genes encode proteins forming a complex (TSC), which is a major regulator and suppressor of mammalian target of rapamycin complex 1 (mTORC1), a signaling complex that promotes cell growth and proliferation. TSC1/2 loss of heterozygosity (LOH) and the subsequent complete loss of TSC regulatory activity in null cells causes mTORC1 dysregulation and TSC-associated brain lesions or other tissue tumors. However, it is not clear whether TSC1/2 heterozygous brain cells are abnormal and contribute to TSC neuropathology. To investigate this issue, we generated induced pluripotent stem cells (iPSCs) from TSC patients and unaffected controls, and utilized these to obtain neural progenitor cells (NPCs) and differentiated neurons in vitro. These patient-derived TSC2 heterozygous NPCs were delayed in their ability to differentiate into neurons. Patient-derived progenitor cells also exhibited a modest activation of mTORC1 signaling downstream of TSC, and a marked attenuation of upstream PI3K/AKT signaling. We further show that pharmacologic PI3K or AKT inhibition, but not mTORC1 inhibition, causes a neuronal differentiation delay, mimicking the patient phenotype. Together these data suggest that heterozygous TSC2 mutations disrupt neuronal development, potentially contributing to the disease neuropathology, and that this defect may result from dysregulated PI3K/AKT signaling in neural progenitor cells.

Genetic deletion of Rnd3 results in aqueductal stenosis leading to hydrocephalus through up-regulation of Notch signaling.

Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation through the Rho kinase-dependent signaling pathway. We report a role of Rnd3 in the pathogenesis of hydrocephalus disorder. Mice with Rnd3 genetic deletion developed severe obstructive hydrocephalus with enlargement of the lateral and third ventricles, but not of the fourth ventricles. The cerebral aqueducts in Rnd3-null mice were partially or completely blocked by the overgrowth of ependymal epithelia. We examined the molecular mechanism contributing to this Rnd3-deficiency-mediated hydrocephalus and found that Rnd3 is a regulator of Notch signaling. Rnd3 deficiency, through either gene deletion or siRNA knockdown, resulted in a decrease in Notch intracellular domain (NICD) protein degradation. However, there was no correlated change in mRNA change, which in turn led to an increase in NICD protein levels. Immunoprecipitation analysis demonstrated that Rnd3 and NICD physically interacted, and that down-regulation of Rnd3 attenuated NICD protein ubiquitination. This eventually enhanced Notch signaling activity and promoted aberrant growth of aqueduct ependymal cells, resulting in aqueduct stenosis and the development of congenital hydrocephalus. Inhibition of Notch activity rescued the hydrocephalus disorder in the mutant animals.

The Developmental Brain Disorders Database (DBDB): a curated neurogenetics knowledge base with clinical and research applications.

The number of single genes associated with neurodevelopmental disorders has increased dramatically over the past decade. The identification of causative genes for these disorders is important to clinical outcome as it allows for accurate assessment of prognosis, genetic counseling, delineation of natural history, inclusion in clinical trials, and in some cases determines therapy. Clinicians face the challenge of correctly identifying neurodevelopmental phenotypes, recognizing syndromes, and prioritizing the best candidate genes for testing. However, there is no central repository of definitions for many phenotypes, leading to errors of diagnosis. Additionally, there is no system of levels of evidence linking genes to phenotypes, making it difficult for clinicians to know which genes are most strongly associated with a given condition. We have developed the Developmental Brain Disorders Database (DBDB: https://www.dbdb.urmc.rochester.edu/home), a publicly available, online-curated repository of genes, phenotypes, and syndromes associated with neurodevelopmental disorders. DBDB contains the first referenced ontology of developmental brain phenotypes, and uses a novel system of levels of evidence for gene-phenotype associations. It is intended to assist clinicians in arriving at the correct diagnosis, select the most appropriate genetic test for that phenotype, and improve the care of patients with developmental brain disorders. For researchers interested in the discovery of novel genes for developmental brain disorders, DBDB provides a well-curated source of important genes against which research sequencing results can be compared. Finally, DBDB allows novel observations about the landscape of the neurogenetics knowledge base.

Gómez-López-hernández syndrome versus rhombencephalosynapsis spectrum: a rare co-occurrence with bipartite parietal bone.

Rhombencephalosynapsis (RES) is a rare hindbrain malformation that could occur in isolation or as a part of a syndrome for example, Gómez-López-Hernández syndrome (GLH) or VACTERL-H. We identified male patient with severe RES. Ventriculomegaly, agenesis of septum pellucidum, very thin corpus callosum with interhemispheric cyst were additional neuroimaging findings. He had brachyturricephaly, midface retrusion, low-set posteriorly rotated ears and bilateral parietal well circumscribed areas of alopecia. No corneal anesthesia was observed; thus, demonstrating many of the diagnostic criteria of GLH. Interestingly, he additionally had bilateral bipartite parietal bone (BPB) that is an extremely rare anomaly of the parietal sutures. This is the first co-occurrence of this rare anomaly with GLH. We believe the presence of this unique finding could represent an important clue for understanding the pathogenesis of this malformation.

Spatiotemporal Mapping and Molecular Basis of Whole-brain Circuit Maturation.

Brain development is highly dynamic and asynchronous, marked by the sequential maturation of functional circuits across the brain. The timing and mechanisms driving circuit maturation remain elusive due to an inability to identify and map maturing neuronal populations. Here we create DevATLAS (Developmental Activation Timing-based Longitudinal Acquisition System) to overcome this obstacle. We develop whole-brain mapping methods to construct the first longitudinal, spatiotemporal map of circuit maturation in early postnatal mouse brains. Moreover, we uncover dramatic impairments within the deep cortical layers in a neurodevelopmental disorders (NDDs) model, demonstrating the utility of this resource to pinpoint when and where circuit maturation is disrupted. Using DevATLAS, we reveal that early experiences accelerate the development of hippocampus-dependent learning by increasing the synaptically mature granule cell population in the dentate gyrus. Finally, DevATLAS enables the discovery of molecular mechanisms driving activity-dependent circuit maturation.

Assessment of autonomic symptom scales in patients with neurodevelopmental diagnoses using electronic health record data.

Background: Sleep disturbances, gastrointestinal problems, and atypical heart rate are commonly observed in patients with autism spectrum disorder (ASD) and may relate to underlying function of the autonomic nervous system (ANS). The overall objective of the current study was to quantitatively characterize features of ANS function using symptom scales and available electronic health record (EHR) data in a clinically and genetically characterized pediatric cohort. Methods: We assessed features of ANS function via chart review of patient records adapted from items drawn from a clinical research questionnaire of autonomic symptoms. This procedure coded for the presence and/or absence of targeted symptoms and was completed in 3 groups of patients, including patients with a clinical neurodevelopmental diagnosis and identified genetic etiology (NPD, n=244), those with an ASD diagnosis with no known genetic cause (ASD, n=159), and age and sex matched controls (MC, n=213). Symptoms were assessed across four main categories: (1) Mood, Behavior, and Emotion; (2) Secretomotor, Sensory Integration; (3) Urinary, Gastrointestinal, and Digestion; and (4) Circulation, Thermoregulation, Circadian function, and Sleep/Wake cycles. Results: Chart review scores indicate an increased rate of autonomic symptoms across all four sections in our NPD group as compared to scores with ASD and/or MC. Additionally, we note several significant relationships between individual differences in autonomic symptoms and quantitative ASD traits. Conclusion: These results highlight EHR review as a potentially useful method for quantifying variance in symptoms adapted from a questionnaire or survey. Further, using this method indicates that autonomic features are more prevalent in children with genetic disorders conferring risk for ASD and other neurodevelopmental diagnoses.

Higher scores on autonomic symptom scales in pediatric patients with neurodevelopmental disorders of known genetic etiology.

INTRODUCTION: Features of underlying autonomic dysfunction, including sleep disturbances, gastrointestinal problems, and atypical heart rate, have been reported in neurodevelopmental conditions, including autism spectrum disorder (ASD). The current cross-sectional, between-groups study aimed to quantify symptoms of autonomic dysfunction in a neurodevelopmental pediatric cohort characterized by clinical diagnoses as well as genetic etiology. METHOD: The Pediatric Autonomic Symptom Scales (PASS) questionnaire was used to assess autonomic features across a group of patients with clinical neurodevelopmental diagnoses (NPD; N = 90) and genetic etiologies. Patients were subdivided based on either having a clinical ASD diagnosis (NPD-ASD; n = 37) or other non-ASD neurodevelopmental diagnoses, such as intellectual disability without ASD, speech and language disorders, and/or attention deficit hyperactivity disorder (NPD-OTHER; n = 53). Analyses focused on characterizing differences between the NPD group compared to previously published reference samples, as well as differences between the two NPD subgroups (NPD-ASD and NPD-OTHER). RESULTS: Our results indicate higher PASS scores in our NPD cohort relative to children with and without ASD from a previously published cohort. However, we did not identify significant group differences between our NPD-ASD and NPD-OTHER subgroups. Furthermore, we find a significant relationship between quantitative ASD traits and symptoms of autonomic function. CONCLUSION: This work demonstrates the utility of capturing quantitative estimates of autonomic trait dimensions that may be significantly linked with psychosocial impairments and other core clinical features of ASD.

1H-MR Spectroscopy of the Early Developmental Brain, Neonatal Encephalopathies, and Neurometabolic Disorders.

MRI interpretations of the pediatric brain are often challenging for general radiologists and clinicians because MR signals and morphology are continuously changing in the developing brain. Furthermore, the developing brain reacts differently to injuries, resulting in imaging characteristics that differ from those of the mature brain. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method for assessing neurological abnormalities at the microscopic level and measures in vivo brain metabolites using a clinical MR machine. In MR examinations of the pediatric brain, 1H-MRS demonstrates its powerful diagnostic capability when MRI is insufficient for diagnostic features. MRI and 1H-MRS may be complementary tools for diagnosing and monitoring diseases. However, there is currently no consensus on how to include 1H-MRS in clinical MR examinations. An overview of the clinical implementation of 1H-MRS for the assessment of early pediatric developmental brains as well as the diagnosis, prognostification, and disease monitoring of various non-neoplastic brain disorders, including neonatal encephalopathies and neurometabolic/neurodegenerative diseases, was provided herein. Qualitative and quantitative 1H-MRS is a powerful non-invasive tool for accessing various brain metabolites to confirm age appropriate peaks and detect abnormal peaks or deficient or reduced peaks, which may facilitate the identification of metabolic and neurodegenerative disorders as well as damage associated with hypoxic-ischemic encephalopathy (HIE). Moreover, 1H-MRS has potential as a biomarker for monitoring therapeutic efficacy in metabolic diseases and neonatal HIE. It also provides insights into the pathophysiologies of various disorders, which may facilitate the use of novel therapeutic approaches. Therefore, 1H-MRS needs to be included more frequently in routine clinical MR examinations of pediatric patients with neurological disorders.

Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats.

Administration of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) is believed to be an effective method for treating neurodevelopmental disorders. In this study, we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism. We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy. Rat offspring were intranasally administered hUC-MSCs on postnatal day 14. We found that polypyrimidine tract-binding protein-1 (PTBP-1) participated in the regulation of lipopolysaccharide-induced maternal immune activation, which led to neonatal hypoxic/ischemic brain injury. Intranasal delivery of hUC-MSCs inhibited PTBP-1 expression, alleviated neonatal brain injury-related inflammation, and regulated the number and function of glial fibrillary acidic protein-positive astrocytes, thereby promoting plastic regeneration of neurons and improving brain function. These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.

Developmental patterns of CBF and BOLD responses to visual stimulus.

To investigate the developmental changes of cerebral blood flow (CBF) and hemodynamic responses to changing neural activity, we used the arterial spin label (ASL) technique to measure resting CBF and simultaneous CBF / blood-oxygen-level dependent (BOLD) signal changes during visual stimulation in 97 typically developing children and young adults (age 13.35 [6.02, 25.25] (median [min, max]) years old at the first time point). The longitudinal study protocol included three MRIs (2.7 ± 0.06 obtained), one year apart, for each participant. Mixed-effect linear and non-linear statistical models were used to analyze age effects on CBF and BOLD signals. Resting CBF decreased exponentially with age (p = 0.0001) throughout the brain, and developmental trajectories differed across brain lobes. The absolute CBF increase in visual cortex during stimulation was constant over the age range, but the fractional CBF change increased with age (p = 0.0001) and the fractional BOLD signal increased with age (p = 0.0001) correspondingly. These findings suggest that the apparent neural hemodynamic coupling in visual cortex does not change after age six years, but age-related BOLD signal changes continue through adolescence primarily due to the changes with age in resting CBF.

Building the brain from scratch: Engineering region-specific brain organoids from human stem cells to study neural development and disease.

Human brain development is an intricate process that involves precisely timed coordination of cell proliferation, fate specification, neuronal differentiation, migration, and integration of diverse cell types. Understanding of these fundamental processes, however, has been largely constrained by limited access to fetal brain tissue and the inability to prospectively study neurodevelopment in humans at the molecular, cellular and system levels. Although non-human model organisms have provided important insights into mechanisms underlying brain development, these systems do not fully recapitulate many human-specific features that often relate to disease. To address these challenges, human brain organoids, self-assembled three-dimensional neural aggregates, have been engineered from human pluripotent stem cells to model the architecture and cellular diversity of the developing human brain. Recent advancements in neural induction and regional patterning using small molecules and growth factors have yielded protocols for generating brain organoids that recapitulate the structure and neuronal composition of distinct brain regions. Here, we first provide an overview of early mammalian brain development with an emphasis on molecular cues that guide region specification. We then focus on recent efforts in generating human brain organoids that model the development of specific brain regions and highlight endeavors to enhance the cellular complexity to better mimic the in vivo developing human brain. We also provide examples of how organoid models have enhanced our understanding of human neurological diseases and conclude by discussing limitations of brain organoids with our perspectives on future advancements to maximize their potential.

The molecular landscape of neural differentiation in the developing Drosophila brain revealed by targeted scRNA-seq and multi-informatic analysis.

The Drosophila type II neuroblast lineages present an attractive model to investigate the neurogenesis and differentiation process as they adapt to a process similar to that in the human outer subventricular zone. We perform targeted single-cell mRNA sequencing in third instar larval brains to study this process of the type II NB lineage. Combining prior knowledge, in silico analyses, and in situ validation, our multi-informatic investigation describes the molecular landscape from a single developmental snapshot. 17 markers are identified to differentiate distinct maturation stages. 30 markers are identified to specify the stem cell origin and/or cell division numbers of INPs, and at least 12 neuronal subtypes are identified. To foster future discoveries, we provide annotated tables of pairwise gene-gene correlation in single cells and MiCV, a web tool for interactively analyzing scRNA-seq datasets. Taken together, these resources advance our understanding of the neural differentiation process at the molecular level.

Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer's Disease.

Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer's disease (AD)-type ß-amyloid (Aß) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.

Acrobatic exercise recovers object recognition memory impairment in hypoxic-ischemic rats.

Neonatal hypoxia-ischemia (HI) can lead to cognitive impairments and motor dysfunction. Acrobatic exercises (AE) were proposing as therapeutic option to manage HI motor deficits, however, the cognitive effects after this treatment are still poorly understood. Therefore, we evaluated the effects of AE protocol on memory impairments and brain plasticity markers after Rice-Vannucci HI rodent model. Wistar rats on the 7th postnatal day (PND) were submitted to HI model and after weaning (PND22) were trained for 5 weeks with AE protocol, then subsequently submitted to cognitive tests. Our results showed recovery in novel object recognition (NOR) memory, but not, spatial Morris Water Maze (WM) memory after AE treatment in HI rats. BDNF and synaptophysin neuroplasticity markers indicate plastic alterations in the hippocampus and striatum, with maintenance of synaptophysin despite the reduction of total volume tissue, besides, hippocampal HI-induced ipsilateral BDNF increased, and striatum contralateral BDNF decreased were noted. Nevertheless, the exercise promoted functional recovery and seems to be a promising strategy for HI treatment, however, future studies identifying neuroplastic pathway for this improvement are needed.

The importance of non-coding RNAs in environmental stress-related developmental brain disorders: A systematic review of evidence associated with exposure to alcohol, anesthetic drugs, nicotine, and viral infections.

Brain development is a dynamic and lengthy process that includes cell proliferation, migration, neurogenesis, gliogenesis, synaptogenesis, and pruning. Disruption of any of these developmental events can result in long-term outcomes ranging from brain structural changes, to cognitive and behavioral abnormality, with the mechanisms largely unknown. Emerging evidence suggests non-coding RNAs (ncRNAs) as pivotal molecules that participate in normal brain development and neurodevelopmental disorders. NcRNAs such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are transcribed from the genome but not translated into proteins. Many ncRNAs have been implicated as tuners of cell fate. In this review, we started with an introduction of the current knowledge of lncRNAs and miRNAs, and their potential roles in brain development in health and disorders. We then reviewed and discussed the evidence of ncRNA involvement in abnormal brain development resulted from alcohol, anesthetic drugs, nicotine, and viral infections. The complex connections among these ncRNAs were also discussed, along with potential overlapping ncRNA mechanisms, possible pharmacological targets for therapeutic/neuroprotective interventions, and potential biomarkers for brain developmental disorders.

Intrauterine growth restriction compromises cerebellar development by affecting radial migration of granule cells via the JamC/Pard3a molecular pathway.

Intrauterine growth restriction (IUGR) affects ~10% of human pregnancies, results in infants born small for gestational age (SGA), and is associated with motor and cognitive deficits. Human studies suggest that some deficits in SGA patients originate in the cerebellum, a major motor-coordination and cognitive center, but the underlying mechanisms remain unknown. To identify the cerebellar developmental program affected by IUGR, we analyzed the pig as a translational animal model in which some fetuses spontaneously develop IUGR due to early-onset chronic placental insufficiency. Similar to humans, SGA pigs revealed small cerebella, which contained fewer mature granule cells (GCs) in the internal granule cell layer (IGL). Surprisingly, newborn SGA pigs had increased proliferation of GC precursors in the external granule cell layer (EGL), which was associated with an increased density of Purkinje cells, known to non-autonomously promote the proliferation of GCs. However, the GCs of SGA pigs did not properly initiate exit from the EGL to IGL, which was associated with a decreased density of guiding Bergmann glial fibers, reduced expression of pro-migratory genes Pard3a, JamC and Sema6a, and increased apoptosis. While proliferation spontaneously normalized during postnatal development, accumulation of pre-migratory GCs and apoptosis in the EGL were long-lasting consequences of IUGR. Using organotypic cerebellar slice cultures, we showed that normalizing expression of Pard3a and JamC, which operate in the same molecular pathway in GCs, was sufficient to rescue both migratory and, at a later time point, apoptotic defects of IUGR. Thus, a decreased exit of GCs from the EGL, due to disrupted Pard3a/JamC radial migration initiation pathway, is a major mechanism of IUGR-related cerebellar pathology.