Prenatal maternal negative life events associated with child emotional and behavioral problems in the French EDEN cohort.

INTRODUCTION: Prenatal negative life events (NLEs) have been linked to adverse health outcomes in children. However, few studies examine this relationship during late childhood using trajectory analyses. Additionally, the impact of specific NLEs domains on child development remains unclear. This study aims to longitudinally explore the association between NLEs (cumulative score and specific NLEs domains) and child outcomes from birth to late childhood. METHODS: 1135 mother-child pairs from the French EDEN cohort were followed from 24 to 28 weeks of pregnancy up to 11 years of age. Maternal self-reports of prenatal NLEs were collected immediately after birth, then analyzed as a cumulative score and by NLEs domain. Children's emotional and behavioral symptoms were assessed at 4 timepoints through the Strengths and Difficulties Questionnaire. RESULTS: Children of mothers exposed to ≥3 NLEs were more likely to follow trajectories of high levels of peer relationship problems (aOR [95 % CI] = 5.69 [1.74-18.69]), emotional symptoms (aOR [95 % CI] = 3.05 [1.08-8.63]), and conduct problems (aOR [95 %] = 3.53 [1.20-10.42]). Among the domains of NLEs, only events related to housing, finance, and living conditions were significantly associated with high emotional and behavioral difficulties trajectories (aOR [95%CI] = 2.71[1.26-5.81]). LIMITATIONS: Potential attrition bias due to a higher dropout rate for children experiencing early indications of emotional and behavioral difficulties. CONCLUSION: Findings support the relationship between prenatal NLEs and child outcomes, underscoring the importance of assessing prenatal stressors across life domains to identify mothers who might be in need of support.

A Longitudinal, Observational, and Descriptive Study About Benefits of Craniosacral Therapy in Child Neurodevelopment.

INTRODUCTION: Coordination and balance are progressive motor skills that guide physical therapists in recognizing abnormal patterns during childish neurodevelopment. We aim to compare the efficacy of craniosacral therapy (CST) together with balance and coordination therapy (BCT) vs traditional BCT during neurodevelopment. METHODS: Longitudinal, observational, and descriptive study with 111 apparently healthy children divided into 4 groups: craniosacral-balance and coordination therapy placebo (CS-BCTp), craniosacral-balance and coordination therapy (CS-BCT), balance and coordination therapy placebo (BCTp), and balance and coordination therapy (BCT). RESULTS: Significant changes have been observed with the CS-BCT from the fourth session. Balance and coordination therapy is less effective. There are differences in the Battelle Scale at the beginning and after the 7 therapy sessions in the CS-BCT group. CONCLUSIONS: The study shows that CST together with balance and coordination exercises can be a more effective and faster treatment to improve these motor skills, correcting and improving alterations during child neurodevelopment.

Myclobutanil induces neurotoxicity by activating autophagy and apoptosis in zebrafish larvae (Danio rerio).

Myclobutanil (MYC), a typical broad-spectrum triazole fungicide, is often detected in surface water. This study aimed to explore the neurotoxicity of MYC and the underlying mechanisms in zebrafish and in PC12 cells. In this study, zebrafish embryos were exposed to 0, 0.5 and 1 mg/L of MYC from 4 to 96 h post fertilization (hpf) and neurobehavior was evaluated. Our data showed that MYC decreased the survival rate, hatching rate and heart rate, but increased the malformation rate and spontaneous movement. MYC caused abnormal neurobehaviors characterized by decreased swimming distance and movement time. MYC impaired cerebral histopathological morphology and inhibited neurogenesis in HuC:egfp transgenic zebrafish. MYC also reduced the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and downregulated neurodevelopment related genes (gfap, syn2a, gap43 and mbp) in zebrafish and PC12 cells. Besides, MYC activated autophagy through enhanced expression of the LC3-II protein and suppressed expression of the p62 protein and autophagosome formation, subsequently triggering apoptosis by upregulating apoptotic genes (p53, bax, bcl-2 and caspase 3) and the cleaved caspase-3 protein in zebrafish and PC12 cells. These processes were restored by the autophagy inhibitor 3-methyladenine (3-MA) both in vivo and in vitro, indicating that MYC induces neurotoxicity by activating autophagy and apoptosis. Overall, this study revealed the potential autophagy and apoptosis mechanisms of MYC-induced neurotoxicity and provided novel strategies to counteract its toxicity.

TRPM7 in neurodevelopment and therapeutic prospects for neurodegenerative disease.

Neurodevelopment, a complex and highly regulated process, plays a foundational role in shaping the structure and function of the nervous system. The transient receptor potential melastatin 7 (TRPM7), a divalent cation channel with an α-kinase domain, mediates a wide range of cellular functions, including proliferation, migration, cell adhesion, and survival, all of which are essential processes in neurodevelopment. The global knockout of either TRPM7 or TRPM7-kinase is embryonically lethal, highlighting the crucial role of TRPM7 in development in vivo. Subsequent research further revealed that TRPM7 is indeed involved in various key processes throughout neurodevelopment, from maintaining pluripotency during embryogenesis to regulating gastrulation, neural tube closure, axonal outgrowth, synaptic density, and learning and memory. Moreover, a discrepancy in TRPM7 expression and/or function has been associated with neuropathological conditions, including ischemic stroke, Alzheimer's disease, and Parkinson's disease. Understanding the mechanisms of proper neurodevelopment may provide us with the knowledge required to develop therapeutic interventions that can overcome the challenges of regeneration in CNS injuries and neurodegenerative diseases. Considering that ion channels are the third-largest class targeted for drug development, TRPM7's dual roles in development and degeneration emphasize its therapeutic potential. This review provides a comprehensive overview of the current literature on TRPM7 in various aspects of neurodevelopment. It also discusses the links between neurodevelopment and neurodegeneration, and highlights TRPM7 as a potential therapeutic target for neurodegenerative disorders, with a focus on repair and regeneration.

Adolescent alcohol use is associated with differences in the diversity and composition of the oral microbiome.

BACKGROUND: Adolescence is a sensitive stage of oral microbial development that often coincides with the initiation and escalation of alcohol use. Thus, adolescents may be particularly susceptible to alcohol-induced alterations in the oral microbiome, though minimal research has been done in this area. Understanding the connection between the oral microbiome and alcohol use during adolescence is important to understand fully the biological consequences of alcohol use to mitigate potential adverse outcomes. METHODS: Saliva samples were collected from adolescents aged 17-19 who used alcohol heavily (n = 21, 52.4% female) and those who did not use alcohol or any other substances (n = 18, 44.4% female). We utilized 16S rRNA sequencing to examine differences in microbial diversity and composition between the groups. RESULTS: For alpha diversity, evenness was significantly lower in the drinking group than the control group as indicated by Pielou's evenness, Shannon, and Simpson indices. There were no statistically significant findings for beta diversity. Differential abundance analyses revealed higher abundances of Rothia and Corynebacterium in the alcohol-using group using both centered-log-ratio and relative abundance normalization. These genera are known for their high capacity to convert alcohol into acetaldehyde, a toxic metabolite reported to play a role in the neurobiological effects of alcohol. An unclassified Clostridia UCG-014, Streptobacillus, Comamonas, unclassified Lachnospiraceae, and Parvimonas were also identified as significantly different between groups when using only one of the normalization techniques. CONCLUSIONS: This is the first study designed specifically to compare the oral microbiome of adolescents who use alcohol with that of control participants. Our findings reveal distinct alcohol-related differences in microbial composition and taxon abundance, emphasizing the importance of understanding the impact on the oral microbiome of alcohol use during adolescence. Because the oral microbiome is malleable, this study provides foundational work for future prevention and intervention studies.

Variability in Definitions and Criteria of Extrauterine Growth Restriction and Its Association with Neurodevelopmental Outcomes in Preterm Infants: A Narrative Review.

Extrauterine growth restriction (EUGR) has been used in the literature and clinical practice to describe inadequate growth in preterm infants. Significant variability is seen in the criteria for EUGR, with no standard definition reached to date. Moreover, no consensus on the optimal timing for assessment or the ideal growth monitoring tool has been achieved, and an ongoing debate persists on the appropriate terminology to express poor postnatal growth. To ensure an adequate understanding of growth and early intervention in preterm infants at higher risk, it is critical to relate the diagnostic criteria of EUGR to the ability to predict adverse outcomes, such as neurodevelopmental outcomes. This narrative review was conducted to present evidence that evaluates neurodevelopmental outcomes in preterm infants with EUGR, comparing separately the different definitions of this concept by weight (cross-sectional, longitudinal and "true" EUGR). In this article, we highlight the challenges of comparing various published studies on the subject, even when subclassifying by the definition of EUGR, due to the significant variability on the criteria used for each definition and for the evaluation of neurodevelopmental outcomes in different papers. This heterogeneity compromises the obtention of a single firm conclusion on the relation between different definitions of EUGR and adverse neurodevelopmental outcomes.

Biomarkers of Brain Dysfunction in Perinatal Iron Deficiency.

Iron deficiency in the fetal and neonatal period (perinatal iron deficiency) bodes poorly for neurodevelopment. Given its common occurrence and the negative impact on brain development, a screening and treatment strategy that is focused on optimizing brain development in perinatal iron deficiency is necessary. Pediatric societies currently recommend a universal iron supplementation strategy for full-term and preterm infants that does not consider individual variation in body iron status and thus could lead to undertreatment or overtreatment. Moreover, the focus is on hematological normalcy and not optimal brain development. Several serum iron indices and hematological parameters in the perinatal period are associated with a risk of abnormal neurodevelopment, suggesting their potential use as biomarkers for screening and monitoring treatment in infants at risk for perinatal iron deficiency. A biomarker-based screening and treatment strategy that is focused on optimizing brain development will likely improve outcomes in perinatal iron deficiency.

Nutritional Quality Implications: Exploring the Impact of a Fatty Acid-Rich Diet on Central Nervous System Development.

Given the comprehensive examination of the role of fatty acid-rich diets in central nervous system development in children, this study bridges significant gaps in the understanding of dietary effects on neurodevelopment. It delves into the essential functions of fatty acids in neurodevelopment, including their contributions to neuronal membrane formation, neuroinflammatory modulation, neurogenesis, and synaptic plasticity. Despite the acknowledged importance of these nutrients, this review reveals a lack of comprehensive synthesis in current research, particularly regarding the broader spectrum of fatty acids and their optimal levels throughout childhood. By consolidating the existing knowledge and highlighting critical research gaps, such as the effects of fatty acid metabolism on neurodevelopmental disorders and the need for age-specific dietary guidelines, this study sets a foundation for future studies. This underscores the potential of nutritional strategies to significantly influence neurodevelopmental trajectories, advocating an enriched academic and clinical understanding that can inform dietary recommendations and interventions aimed at optimizing neurological health from infancy.

Prenatal organophosphate esters exposure and neurodevelopment trajectory in infancy: Evidence from the Shanghai Maternal-Child Pairs Cohort.

BACKGROUND: Concerns remain about the neurotoxic properties of the ubiquitous organophosphate esters (OPEs), the replacement of the toxicant polybrominated diphenyl ethers. OBJECTIVES: We examined the associations of prenatal exposure to OPEs and their mixtures with early-life neurodevelopment trajectories. METHODS: Totally 1276 mother-child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure the levels of 7 OPEs in cord serum. Ages and Stages Questionnaires was used to examine children's neuropsychological development at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Multiple linear regression and logistic regression model were performed to assess the relationships between OPEs exposure and neurodevelopment and trajectories. Mixtures for widely detected OPEs (n = 4) were investigated using quantile-based g-computation. RESULTS: Tributyl phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and 2-ethylhexyl diphenyl phosphate (EHDPP), had detection rates >50 %. TDCPP had the highest median concentration (1.02 µg/L) in cord serum. EHDPP concentrations were negatively associated with scores in most domains at 12 months of age, with effect values (ß) ranging from -1.89 to -0.57. EHDPP could negatively affect the total ASQ (OR = 1.07, 95 % CI: 1, 1.15) and gross-motor (OR = 1.09, 95 % CI: 1.02, 1.17) trajectory in infancy. Joint exposure to OPEs was associated with decreased scores in the total ASQ, gross-motor, fine-motor and problem-solving domain of 12-month-old infants, with ß ranging from -5.93 to -1.25. In addition, the qgcomp models indicated significant positive associations between the concentrations of OPEs mixtures and risks of the persistently low group of the total ASQ, gross-motor and fine-motor development in early childhood. The impact of OPEs was more pronounced in boys. DISCUSSION: Our findings suggested OPEs, especially EHDPP, had a persistently negative effect on neurodevelopment during the first 2 years.

Microglia pack a toolbox for life.

After decades of being overlooked, a recent wave of studies have explored the roles of microglia in brain health and disease. Microglia perform important physiological functions to set up and maintain proper neural network functions, as well as orchestrate responses to toxic stimuli to limit harm. Many microglial transcriptional programs, extracellular sensing molecules, and functional outputs are seen throughout life. A stark example is the similarity of microglial responses to stressors during neurodevelopment and neurodegeneration. The same themes often match that of other tissue-resident macrophages, presenting an opportunity to apply known concepts as therapeutics develop. We argue that microglial signaling during development and neurologic disease overlap with one another and with other tissue-resident macrophage pathways, in part due to similar sensed stimuli and a conserved sensome of receptors and signaling molecules, akin to a toolkit.

Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

OBJECTIVES: Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth but current evidence on dosing, candidacy, and outcomes are limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. METHODS: This single-centre, open-label, pilot phase 1 safety and feasibility clinical trial included 25 pregnant individuals with a fetal diagnosis of SVP. Participants self-administered continuous supplemental oxygen using medical-grade oxygen concentrators for up to 24 hours per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation by echocardiography and late-gestational cardiovascular magnetic resonance, early outcomes including brain growth and pre-operative brain injury, and 18-month neurodevelopmental outcomes by the Bayley Scales of Infant and Toddler Development 3rd Edition compared to a contemporary fetal SVP cohort that received standard of care (SOC). RESULTS: Among 25 participants, the average maternal age at conception was 35 years, and fetal SVP diagnoses included 16 right ventricle dominant, 8 left ventricle dominant, and 1 indeterminant ventricular morphology. Participants started the trial at approximately 29.3 gestational weeks and took MSO for a median 16.1 hours per day for 63 days, cumulating a median 1029 hours of oxygen intake from enrollment until delivery. The only treatment-associated adverse events were nasal complications that were typically resolved by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio, nor head circumference to abdominal circumference ratio Z-scores over gestation compared to SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over gestation compared to SOC (p=0.02), this was likely due to initial baseline differences in placental resistance. At late-gestational cardiovascular magnetic resonance, MSO was not associated with any significant increase in umbilical vein oxygen saturation, fetal oxygen delivery, or fetal cerebral oxygen delivery. Similarly, we observed no differences in newborn outcomes including brain volume and pre-operative brain injury, nor mortality by 18 months of age, nor neurodevelopmental outcomes at 18 months of age. CONCLUSIONS: This pilot phase 1 clinical trial indicates low-dose maternal supplemental oxygen therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with any significant changes in fetal circulatory physiology or improvements in early neurologic or neurodevelopmental outcomes. This article is protected by copyright. All rights reserved.

[Relationship between gut microbiome and neurodevelopment in early life].

OBJECTIVE: To compare the differences in gut microbiome composition between children with good neurodevelopment and those with delayed neurodevelopment, and to analyze the relationship between gut microbiome and the neurodevelopment status of infants in early life. METHODS: The mothers were included at the Second West China Hospital from November 2020 to April 2021. Their infant stools were collected on day 0 and day 90 after birth, and the follow-up questionnaires at the corresponding time points were completed. Additionally, the Ages and Stages Questionnaires-Third Edition(ASQ-3) were completed by mothers at 12 months of age. The structure and diversity of gut microbiota were examined by 16S rRNA sequencing, and the relationship between gut microbiome and ASQ-3 questionnaire scores in early life was analyzed. RESULTS: According to the ASQ-3 scores, mothers and infants into neurodevelopment good group(G group, n=18) and neurodevelopmental delay group(D group, n=10). Compared with the D group, the relative abundance of the Firmicutes was significantly higher in the G group at day 0(P<0.05), while the level of the Proteobacteria was lower(P<0.05). At day 90 after birth, the relative abundance of the Actinobacteria, Bifidobacteriaceae and Enterococcaceae was significantly higher in the G group(P<0.05). In addition, alpha diversity was not statistically different between the two groups. Spearman's correlation analysis showed that Clostridiaceae of the postnatal day 0 infants was positively correlated with the communication domain score, but negatively associated with gross motor domain score in children at 12 months of age, whereas the relative abundance of Proteobacteria and Enterobacteriaceae of children at postnatal day 90 was negatively associated with communication development, while the relative abundance of Erysipelatoclostridiaceae showed a negative correlation with gross motor domain scores. CONCLUSION: The structure of the gut microbiome in early life between neurodevelopment good and delayed infants, and were associated with the development of communication and gross motor domain in infants at 12 months of age, suggesting that gut microbiome in early life may be related to the level of neurodevelopment in infants.

Motor imagery for paediatric neurorehabilitation: how much do we know? Perspectives from a systematic review.

Background: Motor Imagery (MI) is a cognitive process consisting in mental simulation of body movements without executing physical actions: its clinical use has been investigated prevalently in adults with neurological disorders. Objectives: Review of the best-available evidence on the use and efficacy of MI interventions for neurorehabilitation purposes in common and rare childhood neurological disorders. Methods: systematic literature search conducted according to PRISMA by using the Scopus, PsycArticles, Cinahl, PUBMED, Web of Science (Clarivate), EMBASE, PsychINFO, and COCHRANE databases, with levels of evidence scored by OCEBM and PEDro Scales. Results: Twenty-two original studies were retrieved and included for the analysis; MI was the unique or complementary rehabilitative treatment in 476 individuals (aged 5 to 18 years) with 10 different neurological conditions including, cerebral palsies, stroke, coordination disorders, intellectual disabilities, brain and/or spinal cord injuries, autism, pain syndromes, and hyperactivity. The sample size ranged from single case reports to cohorts and control groups. Treatment lasted 2 days to 6 months with 1 to 24 sessions. MI tasks were conventional, graded or ad-hoc. MI measurement tools included movement assessment batteries, mental chronometry tests, scales, and questionnaires, EEG, and EMG. Overall, the use of MI was stated as effective in 19/22, and uncertain in the remnant studies. Conclusion: MI could be a reliable supportive/add-on (home-based) rehabilitative tool for pediatric neurorehabilitation; its clinical use, in children, is highly dependent on the complexity of MI mechanisms, which are related to the underlying neurodevelopmental disorder.

Comparing Healthcare Needs in Extremely Low Birth Weight Infants With NEC and Spontaneous Intestinal Perforation.

BACKGROUND: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) affect 6-8% of extremely low birth weight (ELBW) infants. SIP has lower mortality than NEC, but with similar short-term morbidity in length of stay, growth failure, and supplemental oxygen requirements. Comparative long-term neurodevelopmental outcomes have not been clarified. METHODS: Data were prospectively collected from 59 North American neonatal units, regarding ELBW infants (401-1000 g or 22-27 weeks gestational age) born between 2011 and 2018 and evaluated again at 16-26 months corrected age. Outcomes were collected from infants with laparotomy-confirmed NEC, laparotomy-confirmed SIP, and those without NEC or SIP. The primary outcome was severe neurodevelopmental disability. Secondary outcomes were weight <10th percentile, medical readmission, post-discharge surgery and medical support at home. Adjusted risk ratios (ARR) were calculated. RESULTS: Of 13,673 ELBW infants, 6391 (47%) were followed including 93 of 232 (40%) with NEC and 100 of 235 (42%) with SIP. There were no statistically significant differences in adjusted risk of any outcomes when directly comparing NEC to SIP (ARR 2.35; 95% CI 0.89, 6.26). However, infants with NEC had greater risk of severe neurodevelopmental disability (ARR 1.43; 1.09-1.86), rehospitalization (ARR 1.46; 1.17-1.82), and post-discharge surgery (ARR 1.82; 1.48-2.23) compared to infants without NEC or SIP. Infants with SIP only had greater risk of post-discharge surgery (ARR 1.64; 1.34-2.00) compared to infants without NEC or SIP. CONCLUSIONS: ELBW infants with NEC had significantly increased risk of severe neurodevelopmental disability and post-discharge healthcare needs, consistent with prior literature. We now know infants with SIP also have increased healthcare needs. LEVELS OF EVIDENCE: Level II.

Decoding the Neurodevelopment and Seizure Puzzle: A Pediatric Case of DYRK1A Gene Mutation and Autosomal Dominant Mental Retardation Type 7.

Autosomal Dominant Mental Retardation Type 7 is a disorder caused by pathogenic variants in the DYRK1A gene. Clinical features associated with this gene mutation include focal dysmorphism, developmental delay, and epilepsy. In this report, we present a case of an 8-year-old boy with a DYRK1A gene mutation, whose clinical manifestations underscore the rarity and clinical challenges of this genetic condition. The patient is a known case of global developmental delay with intractable epilepsy on multiple anti-epileptic medications. Upon examination, the patient showed delayed developmental milestones, hypotonia with brisk deep tendon reflexes, as well as dysmorphic features in the form of microcephaly, deep-set eyes, prominent ears, and a short nose. MRI was done, and findings were suggestive of a DYRK1A gene mutation. The diagnosis was later confirmed by Whole Exome Sequencing (WES). Our report aims to contribute to the growing knowledge about DYRK1A mutations, facilitating a better understanding of the associated clinical features and implications for patient care.

Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review.

BACKGROUND: TRAF7-related cardiac, facial, and digital anomalies with developmental delay (CAFDADD), a multisystemic neurodevelopmental disorder caused by germline missense variants in the TRAF7 gene, exhibits heterogeneous clinical presentations. METHODS: We present a detailed description of 11 new TRAF7-related CAFDADD cases, featuring eight distinct variants, including a novel one. RESULTS: Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects. In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals exhibiting normal development despite early psychomotor delay. Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication methods. Autistic traits, notably rigidity, are observed in the cohort. Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency. Cardiac defects, frequently severe, pose early-life complications. Facial features, including arched eyebrows, contribute to the distinct gestalt. A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germline TRAF7 variants and somatic changes linked to meningiomas. CONCLUSIONS: Our comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations and proposing an evidence-based schedule for clinical management. This study contributes to a better understanding of TRAF7-related CAFDADD, offering insights for improved diagnosis, intervention, and patient care.

Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability.

O-GlcNAcylation is a protein modification that is critical for vertebrate development, catalysed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense mutations in OGT have recently been shown to segregate with a X-linked syndromic form of intellectual disability, OGT-linked Congenital Disorder of Glycosylation (OGT-CDG). Although OGT-CDG suggests a critical role of O-GlcNAcylation in neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and OGT/OGA levels in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlation in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.

Prenatal Progesterone Treatment Modulates Fetal Brain Transcriptome and Impacts Adult Offspring Behavior in Mice.

Maternal exposure to elevated levels of steroid hormones during pregnancy is associated with the development of chronic conditions in offspring that manifest in adulthood. However, the effects of progesterone (P4) administration during early pregnancy on fetal development and subsequent offspring behavior remain poorly understood. In this study, we aimed to investigate the effects of P4 treatment during early pregnancy on the transcript abundance in the fetal brain and assess the behavioral consequences in the offspring during adolescence and adulthood. Using RNA-seq analysis, we examined the impact of P4 treatment on the fetal brain transcriptome in a dosage-dependent manner. Our results revealed differential regulation of genes involved in neurotransmitter transport, synaptic transmission, and transcriptional regulation. Specifically, we observed bidirectional regulation of transcription factors (TFs) by P4 at different doses, highlighting the critical role of these TFs in neurodevelopment. To assess behavioral outcomes, we conducted open field and elevated plus maze tests. Offspring treated with low-dose P4 (LP4) displayed increased exploratory behavior during both adolescence and adulthood. In contrast, the high-dose P4 (HP4) group exhibited impaired exploration and heightened anxiety-like behaviors compared to the control mice. Moreover, in a novel object recognition test, HP4-treated offspring demonstrated impaired object recognition memory during both developmental stages. Additionally, both LP4 and HP4 groups showed reduced social interaction in the three-chamber test. These results suggest that prenatal exposure to P4 exerts a notable influence on the expression of genes associated with neurodevelopment and may induce alterations in behavioral characteristics in progeny, highlighting the need to monitor progesterone levels during pregnancy for long-term impacts on fetal brain development and behavior.

Exploration of the Impact of Dysbiosis in the Gut Microbiota on Microbial Composition in Children's Neurodevelopment.

Objective: To investigate the impact of gut microbiota dysbiosis on neurodevelopment in children.Methods: This study included 338 children aged 0-3 years admitted to our hospital from January to December 2022,The children were divided into a normal neurodevelopment group (169 cases) and a poor neurodevelopment group (169 cases). Basic personal information and clinical data were collected through a detailed questionnaire, and the microbial composition in fecal samples was analyzed using 16S rRNA gene sequencing.Results: Children in the poor neurodevelopment group showed a significant decrease in gut microbiota diversity compared to those in the normal neurodevelopment group (Shannon index, P < 0.05). The abundance of Bifidobacterium and Veillonella genera significantly decreased (P < 0.05), while the abundance of Streptococcus genus increased significantly (P < 0.05).Conclusion: There is an association between gut microbiota dysbiosis and poor neurodevelopment in children. The increased abundance of Streptococcus genus and decreased abundance of Bifidobacterium and Veillonella genera in the gut microbiota may be potential risk factors for poor neurodevelopment in preterm infants. Future research should further explore the potential beneficial effects of gut microbiota modulation on neurodevelopment in children.

Histological characterization and development of mesial surface sulci in the human brain at 13-15 gestational weeks through high-resolution histology.

Cellular-level anatomical data from early fetal brain are sparse yet critical to the understanding of neurodevelopmental disorders. We characterize the organization of the human cerebral cortex between 13 and 15 gestational weeks using high-resolution whole-brain histological data sets complimented with multimodal imaging. We observed the heretofore underrecognized, reproducible presence of infolds on the mesial surface of the cerebral hemispheres. Of note at this stage, when most of the cerebrum is occupied by lateral ventricles and the corpus callosum is incompletely developed, we postulate that these mesial infolds represent the primordial stage of cingulate, callosal, and calcarine sulci, features of mesial cortical development. Our observations are based on the multimodal approach and further include histological three-dimensional reconstruction that highlights the importance of the plane of sectioning. We describe the laminar organization of the developing cortical mantle, including these infolds from the marginal to ventricular zone, with Nissl, hematoxylin and eosin, and glial fibrillary acidic protein (GFAP) immunohistochemistry. Despite the absence of major sulci on the dorsal surface, the boundaries among the orbital, frontal, parietal, and occipital cortex were very well demarcated, primarily by the cytoarchitecture differences in the organization of the subplate (SP) and intermediate zone (IZ) in these locations. The parietal region has the thickest cortical plate (CP), SP, and IZ, whereas the orbital region shows the thinnest CP and reveals an extra cell-sparse layer above the bilaminar SP. The subcortical structures show intensely GFAP-immunolabeled soma, absent in the cerebral mantle. Our findings establish a normative neurodevelopment baseline at the early stage.