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The present study aimed to clarify the development of motor unit (MU) firing properties and the association between those neural properties and force steadiness (FS)/neurological tests in 6- to 12-year-old children. Fifty-eight school-aged children performed maximal voluntary knee extension contraction, a submaximal FS test at 10% of maximal voluntary knee extension contraction, knee extension reaction time to light stimulus test, and single-leg standing test, and data from 38 children who passed the criteria were subject to analysis. During the FS test, high-density surface electromyography was recorded from the vastus lateralis muscle to identify individual MU firing activity. FS was improved with an increase in age (r = −.540, P <.001). The MU firing rate (MUFR) was significantly decreased with an increase in age (r = −.343, P =.035). MUFR variability was not associated with age. Although there was no significant correlation between FS and MUFR, FS was significantly correlated with MUFR variability even after adjustment for the effect of age (r =.551, P =.002). Neither the reaction time nor the single-leg standing test was correlated with any MU firing properties. These findings suggest that MUFR variability makes an important contribution to precise force control in children but does not naturally develop with age. [ABSTRACT FROM AUTHOR]

This systematic review synthesized current literature regarding the effect of physical activity (PA) interventions on brain structure (BS) and brain function (BF) in healthy children. This review followed the Preferred Reporting Items for Systematic Reviews protocols and used the Rayyan web for data extraction. Eleven experimental studies were included. Specifically, six studies conducted chronic PA interventions, and the others applied acute PA interventions. Evidence from five articles (45.45%) confirmed that PA interventions had beneficial effects on brain structure and function in healthy children, including enhancing brain activation and microstructural plasticity. These articles shared a study protocol and were conducted in school settings, indicating homogeneity. Due to the technical complexity and limitations involved, there are few studies on brain health and development. Future research is necessary to validate and evaluate the effectiveness of PA interventions on brain structure and function in healthy children. [ABSTRACT FROM AUTHOR]

Milk fat globule membrane (MFGM) is a complex trilayer structure present in mammalian milk and is mainly composed of phospholipids and proteins (>90%). Many studies revealed MFGM has positive effects on the immune system, brain development, and cognitive function of infants. Probiotics are live microorganisms that have been found to improve mental health and insulin sensitivity, regulate immunity, and prevent allergies. Probiotics are unstable and prone to degradation by environmental, processing, and storage conditions. In this review, the processes used for encapsulation of probiotics particularly the potential of MFGM and its constituents as encapsulating materials for probiotics are described. This study analyzes the importance of MFGM in encapsulating bioactive substances and emphasizes the interaction with probiotics and the gut as well as its resistance to adverse environmental factors in the digestive system when used as a probiotic embedding material. MFGM can enhance the gastric acid resistance and bile resistance of probiotics, mainly manifested in the survival rate of probiotics. Due to the role of digestion, MFGM-coated probiotics can be released in the intestine, and due to the biocompatibility of the membrane, it can promote the binding of probiotics to intestinal epithelial cells, and promote the colonization of some probiotics in the intestine. [ABSTRACT FROM AUTHOR]

N‐methyl‐D‐aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re‐entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage‐dependent Mg2+ inhibition. Voltage‐dependent Mg2+ block is a unique feature of NMDAR biology whereby channel activation requires both ligand binding and postsynaptic membrane depolarization. Thus, loss of NMDAR Mg2+ block will have a profound impact on synaptic function and plasticity. Here, we choose 11 missense variants within the GRIN1, GRIN2A, and GRIN2B genes that alter residues located in the M2 loop and significantly reduce Mg2+ inhibition. Each variant was evaluated for tolerance to genetic variation using the 3‐dimensional structure and assessed for functional rescue pharmacology via electrophysiological recordings. Three FDA‐approved NMDAR drugs—memantine, dextromethorphan, and ketamine—were chosen based on their ability to bind near the M2 re‐entrant loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage‐dependent Mg2+ block. These results provide insight of structural determinants of FDA‐approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescue pharmacology. [ABSTRACT FROM AUTHOR]

The fish escape response is a high-energy, stress-induced reaction displayed when encountering environmental hazards. Reducing the escape response during the aquaculture has important economic value and ecological safety significance. This study takes the common strain black carp (Cyprinus carpio var. baisenensis), which is known for its low-escape response, as the main research object. Through a simulated flood experiment, the common strain black carps were divided into the low-escape (BL) group and the high-escape (BH) group. Multi-omics techniques (transcriptome sequencing, LS-MS/MS detection, and 16 s sequencing) were used to analyze the differences in brain gene transcription levels, liver metabolites, and intestinal microbiota composition between the two groups. In addition, in order to reduce false positives generated by transcriptome experiments, Jian carps (Cyprinus carpio var. Jian) were also grouped into the low-escape (JL) group and the high-escape (JH) group and subjected to transcriptome analysis. According to the differentially expressed genes (DEGs) analysis, 18 DEGs were obtained from both the common strain black carp and Jian carp. Except for the MAP6 gene, which was significantly highly expressed, the remaining 17 genes showed significantly low expression in the BL group, which were almost related to signal transduction, and brain tissue and neuronal development. The results of KEGG signaling pathway annotation, KOG functional annotation, and topGO enrichment analysis showed that there were significant differences in signal transduction between the BL and BH groups, especially in the gamma aminobutyric acid (GABA) signaling pathway. The detection of liver metabolites showed that there were differences in tryptophan metabolism between the BL and BH groups of the common strain black carp, with higher tryptophan content in the liver of the BL group fish. This study suggests that the brain activity and development of low-escape fish may be lower than those of high-escape fish. Meanwhile, differences in the brain's GABA signaling pathway and the liver's tryptophan metabolism may also affect fish's escape response. This study accumulates experimental foundation of fish escape response and provides a new insight into breeding low-escape fish and developing novel strategies to reduce escape responses during aquaculture. [ABSTRACT FROM AUTHOR]

Primitive reflexes (PRs) are involuntary motor responses present at birth, typically replaced by voluntary motor control during development. If PRs remain active beyond infancy, they can impair motor and cognitive abilities. This study investigated the correlation between active PRs and Tactical (TaS) and Technical Skills (TeS) in professional football matches. Fifty-eight male football players (17.5 ± 1.4 years) from a French academy were assessed for PR activity, categorized into inactive or active PR groups. Assessed PRs included asymmetrical tonic neck reflex (ATNR), symmetrical tonic neck reflex (STNR), tonic labyrinthine reflex (TLR), and Moro reflex (MR). Analysis of twenty matches showed players with active PRs had significantly lower success rates in TaS and TeS, including 15.5% and 31.8% lower pass success in imbalance and finishing zones (p < 0.01). Players with active PRs also performed worse in defensive actions and duels (p < 0.01). The findings highlight that active PRs hinder football performance, especially in challenging match situations like duels and crowded zones. This suggests the need for training programs to address PR effects and enhance player performance. Further research should refine methods for integrating these RPs. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF) is a very rarely reported disease. The disease is due to microdeletions in the PURA gene on chromosome 5q31. It is one of the rare causes of central hypotonia in neonates causing parental concern and anxiety. We report one such rarely diagnosed case of NEDRIHF-PURA (purine-richelement-binding protein A) syndrome. [ABSTRACT FROM AUTHOR]

Myelination is essential for the proper conduction of impulses across neuronal networks. Mature, myelinating glia differentiate from progenitor cells through distinct stages that correspond to oligodendrocyte-specific gene expression markers. Reverse transcription quantiatative PCR (RT-qPCR) is a common technique used to quantify gene expression across cell development; however, a lack of standardization and transparency in methodology may lead to irreproducible data. Here, we have designed and validated RT-qPCR assays for oligodendrocyte genes and reference genes in the developing C57BL6/J mouse brain that align with the MIQE guidelines, including quality controls for primer specificity, temperature dependence, and efficiency. A panel of eight commonly used reference genes was ranked using a series of reference gene stability methods that consistently identified Gapdh, Sdha, Hmbs, Hprt1, and Pgk1 as the top candidates for normalization across brain regions. In the cerebrum, myelin genes peaked in expression at postnatal day 21, which corresponds to the peak of developmental myelination. The gene expression patterns from the brain homogenate were in agreement with previously reported RNA-seq and microarray profiles from oligodendrocyte lineage cells. The validated RT-qPCR assays begin to build a framework for future investigation into the molecular mechanisms that regulate myelination in mouse models of brain development, aging, and disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Prior studies have not examined blood lead levels (BLL) in the preterm population relative to their developmental and behavioral outcomes. METHODS: Neonatal demographic and clinical characteristics and results on scales of intelligence, development, and behavior were compared between children born ≤32 weeks gestation (n=354) with detected lead levels in childhood of ≥5 μg/dL (n=37, 10%) and <5 μg/dL (n=317, 90%). RESULTS: The 10% rate of BLL ≥5 μg/dL for this cohort was higher than rates previously reported for the general population, and was associated with low SES. Preterm infants with a lead level of ≥5 μg/dL were twice as likely to score in the borderline to clinical range for sleep problems on the Childhood Behavioral Checklist. CONCLUSIONS: Robust screening and follow-up may protect against negative developmental outcomes in the setting of elevated lead levels. The association of higher lead levels with poor sleep supports continued lead screening efforts and appropriate support services for preterm children. [ABSTRACT FROM AUTHOR]

Objective: To investigate midbrain growth, including corpus callusum (CC), cerebellar vermis (CV) and cortical development in late fetal growth restriction (FGR) depending on uterine artery (UtA) Pulsatility Index (PI) values. Methods: This was a prospective study including singleton fetuses with late FGR characterized by abnormal cerebral placental ratio (CPR). According to UtA PI values, the FGR fetuses were subdivided into normal ≤95th centile) and abnormal (>95th centile). Neurosonography was performed at 33–44 weeks of gestations to assess CC and CV lengths and the depth of Sylvian fissure (SF), parieto-occipital (POF) and calcarine fissures (CF). Neurosonographic variables were normalized for fetal head circumference size. Results: The study cohort included 60 fetuses with late FGR, 39 with normal UtA PI and 21 with abnormal PI values. The latter group showed significant differences in CC (median (interquartile range) normal 35.9 (28.49–45.53) vs abnormal UtA PI 25.31(19.76–35.13) mm; p < 0.0022), CV (normal 25.78 (18.19–29.35) abnormal UtA PI 17.03 (14.07–24.16)mm; p = 0.0067); SF (normal 10.58 (8.99–11.97)vs abnormal UtA PI 7.44 (6.23–8.46) mm; p < 0.0001), POF (normal 6.85 (6.35–8.14) vs abnormal UtA PI 4.82 (3.46–7.75) mm; p < = 0.0184) and CF (normal 04.157 (2.85–5.41) vs abnormal UtA PI 2.33 (2.49–4.01)); p < 0.0382). Conclusions: Late onset FGR fetuses with abnormal UtA PI showed shorter CC and CV length and delayed cortical development compared to those with normal uterine PI. These findings support the existence of a link between abnormal brain development and changes in utero placental circulation. [ABSTRACT FROM AUTHOR]

The recognition that there is an innate immune system of the brain, referred to as the neuroimmune system, that preforms many functions comparable to that of the peripheral immune system is a relatively new concept and much is yet to be learned. The main cellular components of the neuroimmune system are the glial cells of the brain, primarily microglia and astrocytes. These cell types preform many functions through secretion of signaling factors initially known as immune factors but referred to as neuroimmune factors when produced by cells of the brain. The immune functions of glial cells play critical roles in the healthy brain to maintain homeostasis that is essential for normal brain function, to establish cytoarchitecture of the brain during development, and, in pathological conditions, to minimize the detrimental effects of disease and injury and promote repair of brain structure and function. However, dysregulation of this system can occur resulting in actions that exacerbate or perpetuate the detrimental effects of disease or injury. The neuroimmune system extends throughout all brain regions, but attention to the cerebellar system has lagged that of other brain regions and information is limited on this topic. This article is meant to provide a brief introduction to the cellular and molecular components of the brain immune system, its functions, and what is known about its role in the cerebellum. The majority of this information comes from studies of animal models and pathological conditions, where upregulation of the system facilitates investigation of its actions. [ABSTRACT FROM AUTHOR]

Several neurodevelopmental disorders are associated with a higher prevalence of atypical laterality (e.g., left‐handedness). Both genetic and non‐genetic factors play a role in this association, yet the underlying neurobiological mechanisms are largely unclear. Recent studies have found that stress, mediated by the hypothalamic–pituitary–adrenal (HPA) axis, could be linked to laterality development. These findings provide an opportunity to explore new theoretical perspectives on the association between atypical laterality and neurodevelopmental disorders. This article aims to provide a theoretical framework demonstrating how perinatal adversities could disrupt the typical developmental trajectories of both laterality and neurodevelopment, potentially impacting both the HPA axis and the vestibular system. Additionally, we argue that the relationship between atypical laterality and neurodevelopmental disorders cannot be understood by simply linking genetic and non‐genetic factors to a diagnosis, but the developmental trajectories must be considered. Based on these ideas, several perspectives for future research are proposed. Atypical laterality (e.g., left‐handedness) is more prevalent in neurodevelopmental disorders. However, the nature of this relationship is unclear. This article aims to provide a comprehensive theoretical framework, adopting a developmental perspective, that demonstrates how perinatal adversities could explain the association between atypical laterality and neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Cranial vault remodelling for craniosynostosis aims to increase intracranial volume to facilitate brain growth, avoid the development of raised intracranial pressure and address cosmesis. The extent of vault expansion is predominantly limited by scalp closure and reconstruction technique. Virtual surgical planning tools have been developed to predict post-operative changes and guide expansion. We present a validation study of a novel 'Dura-based Automated Vault Expansion-Remodeling' (DAVE-R) model to guide pre-operative planning for fronto-orbital advancement and remodelling (FOAR). Methods: Patients with trigonocephaly who underwent FOAR with pre- and post-operative imaging from 2018 to 2020 were identified from a prospectively maintained database. Post-operative scans, normative atlas and whole brain parcellation were registered to the pre-operative images to quantify the change in intracranial volume and morphology (utilising measurement of fronto-orbital advancement and bifrontozygomatic distance) compared to that predicted by the DAVE-R model. Results: Ten patients were included. The DAVE-R model predicted bifrontozygomatic distances of 92.0 + / − 5.14 mm (mean + /SD), which closely matched the post-operative results of 92.7 + / − 6.02 mm (mean + / − SD); (t(d.f. 9) = -0.306, p = 0.77). The fronto-orbital advancement predicted by the DAVE-R method was 11.5 + / − 1.96 mm (mean + / − SD) which was significantly greater than 8.6 + / − 2.94 mm (mean ± SD); (t(d.f. 9) = 3.137, p = 0.01) achieved post-operatively. Conclusions: We demonstrate that the DAVE-R model provides an objective means of extracting realistic surgical goals in patients undergoing FOAR for trigonocephaly that closely correlates with post-operative outcomes. The normative dural model warrants further study and validation for other forms of craniosynostosis correction. [ABSTRACT FROM AUTHOR]

Context In 2020, 13.6 million children under 5 years suffered from severe acute malnutrition (SAM)/wasting. Standard ready-to-use therapeutic foods (RUTFs) improve polyunsaturated fatty acid (PUFA) status but contain suboptimal amounts of omega-3 (n-3) PUFAs with unbalanced n-6-to-n-3 PUFA ratios. Objectives The aim was to compare the effects of RUTFs with different essential fatty acid contents on PUFA status, neurodevelopmental, and clinical outcomes (mortality, comorbidities, and recovery) of children with severe wasting. Data Sources Twelve databases, trial repositories, and article references with no publication limitations. Data Extraction Ten studies from randomized, quasi, and cluster-randomized controlled trials providing RUTFs as home treatment to children 6–59 months with SAM/wasting were included. Data Analysis Plasma phospholipid eicosapentaenoic acid content was higher in children receiving RUTF with altered essential fatty acid contents compared with standard RUTF (0.20 [0.15–0.25], P < 0.00001). Docosahexaenoic acid (DHA) status only improved in children receiving RUTF with added fish oil (0.33 [0.15–0.50], P = 0.0003). The Malawi Developmental Assessment tool (MDAT) global development and problem-solving assessment scores were higher in global assessment and gross motor domains in children receiving added fish oil compared with standard formulation (0.19 [0.0–0.38] and 0.29 [0.03–0.55], respectively). Children receiving high-oleic-acid RUTF (lowering the n-6:n-3 PUFA ratio of the RUTF) with or without fish oil had significantly higher scores in social domains compared with those receiving the standard formulation (0.16 [0.00–0.31] and 0.24 [0.09–0.40]). Significantly higher mortality risk was found in children receiving a standard formulation compared with RUTF with a lower n-6:n-3 PUFA ratio (0.79 [0.67–0.94], P = 0.008). Conclusion Although lowering n-6:n-3 PUFA ratios did not increase plasma DHA, it improved specific neurodevelopmental scores and mortality due to lower linoleic acid (high-oleic-acid peanuts), higher alpha-linolenic acid (altered oil), or both. Additional preformed n-3 long-chain PUFAs (fish oil) with RUTF improved the children's DHA status, neurodevelopmental outcomes, and weight-for-height z score. More research is needed regarding cost, availability, stability, acceptability, and the appropriate amount of n-3 long-chain PUFAs required in RUTFs for the best clinical outcomes. Systematic Review Registration PROSPERO registration no. CRD42022303694. [ABSTRACT FROM AUTHOR]

Pax‐6 emerges as a critical transcription factor that guides the fate of stem cells towards neural lineages. Its expression influences the differentiation of neural progenitors into diverse neuronal subtypes, glial cells, and other neural cell types. Pax‐6 operates with other regulatory factors to ensure the precise patterning and organization of the developing nervous system. The intricate interplay between Pax‐6 and other signaling pathways, transcription factors, and epigenetic modifiers underpins the complicated balance between stem cell maintenance, proliferation, and differentiation in neuroectodermal and ocular contexts. Dysfunction of Pax‐6 can lead to a spectrum of developmental anomalies, underscoring its importance in these processes. This review highlights the essential role of Pax‐6 expression in neuroectodermal and ocular stem cells, shedding light on its significance in orchestrating the intricate journey from stem cell fate determination to the emergence of diverse neural and ocular cell types. The comprehensive understanding of Pax‐6 function gained from a developmental biology perspective offers valuable insights into normal development and potential therapeutic avenues for neuroectodermal and ocular disorders. [ABSTRACT FROM AUTHOR]

Background: Semaphorins are axonal guidance molecules involved in neural development and contribute to the regulation of various phases of the immune response. This study aimed to investigate the plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and the regulatory T (Treg) cell-related cytokine interleukin-10 (IL-10), as well as the gene expression levels of forkhead box P3 (FoxP3), Semaphorin-3A (Sema-3A), Neuropilin-1 (Nrp-1), Semaphorin-4A (Sema-4A), and Plexin-D1 (Plxn-D1), in the peripheral blood of newly diagnosed rheumatoid arthritis (RA) patients treated with conventional disease-modifying antirheumatic drugs (DMARDs) for 6 months compared with healthy controls. Methods: Peripheral blood samples were obtained from 40 newly diagnosed RA patients (before and after treatment) and 40 age- and sex-matched healthy subjects. The plasma concentrations of IL-6 and IL-10 were quantified via enzyme-linked immunosorbent assay (ELISA), and the mRNA expression levels of FoxP3, Sema-3A, Nrp-1, Sema-4A, and Plxn-D1 were assessed via quantitative real-time PCR. Results: Compared with those in the controls, the plasma IL-6 levels in the RA patients (both pre- and post-treatment) were significantly greater (P < 0.001). Compared with the pre-treatment levels, the plasma IL-6 levels decreased significantly after DMARD therapy (P < 0.05). Moreover, plasma IL-10 levels were significantly greater in post-treatment RA patients than in controls (P < 0.05). The gene expression of FoxP3, Sema-3A, and Nrp-1 was significantly lower in pre-treated RA patients than in controls (P < 0.001). Compared with that in pre-treatment RA patients, the gene expression of FoxP3, Sema-3A, and Nrp-1 in DMARDs-treated RA patients was strongly increased (P < 0.05, P < 0.01, and P < 0.01, respectively). There was a positive correlation between Sema-3A gene expression and the gene expression of FoxP3 (r = 0.292, P < 0.01) and Nrp-1 (r = 0.569, P < 0.0001). Conclusion: Conventional DMARDs therapy effectively reduces disease activity and inflammation in newly diagnosed RA patients by increasing FoxP3, Sema-3A, and Nrp-1 gene expression. [ABSTRACT FROM AUTHOR]

This study was designed to test the effects of Attention Deficit Hyperactivity Disorder (ADHD) and Developmental Co-ordination Disorder (DCD) on depression levels and investigate the mediating role of executive function (EF) in adults. Adults with ADHD, DCD, and ADHD + DCD (N = 139) completed self-report measures of ADHD, DCD, depression, and EF. There were distinct profiles of EF across diagnostic groups, and higher depression symptoms in adults with ADHD + DCD than DCD alone. All EF domains were predicted by ADHD symptoms, and several by DCD symptoms. ADHD and DCD symptoms, and most EF domains, predicted depression symptoms. Overall EF difficulties fully mediated the relationships between ADHD/DCD and depression symptoms. Several specific EF domains relating to behavioural regulation and metacognition also showed full/partial mediating effects. The mediating role of EF difficulties between these neurodevelopmental conditions and depression symptoms has implications for their understanding and treatment, suggesting that targeting EF may be important for preventing co-occurring depression. [ABSTRACT FROM AUTHOR]

Enterovirus (EV) and parechovirus (HPeV) are common viruses in the neonatal period, with similar seasonality and symptomatology. They also are the main causes of aseptic meningitis in newborns and children under 1 year of age. We compared the clinical signs, laboratory data, brain, and neurodevelopmental outcome of 10 infants with HPeV and 8 with EV meningitis. In patients with EV meningitis, serum C-reactive protein (CRP) values were significantly higher than those of patients with HPeV infection. Procalcitonin values were low in both groups. White blood cell (WBC) and lymphocyte values were significantly higher in EV patients. None of the infants had a brain lesion on cerebral ultrasound neither negative neurological outcome. Based solely on symptoms, it is not possible to distinguish HPeV from EV infection. C-reactive protein, WBC, and lymphocyte values might allow the physician to assume EV infection. The gold standard test for diagnosis remains real-time polymerase chain reaction on cerebral spinal fluid. [ABSTRACT FROM AUTHOR]

To say teachers and other school staff are overworked and underpaid is an understatement. Teachers play the role of counselors, mentors, comforters, disciplinarians, security, and educators to large groups of children, sometimes up to 20 or more in a single class. It is also an understatement to say that teachers want their classrooms to run smoothly, with minimal emotional or behavioral challenges to disrupt an already busy school day. When students act out, it can be easy to see the child as the behavior and judge them accordingly without considering the function or root cause of that behavior. [ABSTRACT FROM AUTHOR]

Background: Gliomas are highly lethal malignancies that develop in the central nervous system. The primary treatment for gliomas involves surgical resection followed by chemoradiotherapy. However, due to the infiltrative growth nature of gliomas, surgical resection is often incomplete. Moreover, the efficacy of chemotherapeutic drugs is constrained by their ability to cross the blood–brain barrier, and the currently utilized agents can lose effectiveness, particularly with prolonged administration. Lentinan, an active compound in Lentinula edodes, exhibits various pharmacological activities. Purpose: This study aims to investigate the anti-tumor effects of lentinan on glioma U251 cells. Materials and Methods: Cell proliferation assays, cell fluorescence staining, scratch healing experiments, and transwell chamber experiments were conducted to assess the anti-tumor activity of lentinan on U251 cells. Additionally, quantitative real-time polymerase chain reaction (qPCR) and Western blot experiments were performed to validate the anti-tumor mechanism of lentinan. Results: The findings revealed that lentinan significantly suppressed the proliferation of U251 cells, induced robust apoptosis, and decreased the cells' migration and invasion capabilities. Furthermore, lentinan notably influenced the gene and protein expression of p53, Bcl-2, Cyto-c, Bax, Caspases, and MMP-9 in U251 cells. Conclusion: These findings suggest that lentinan may inhibit glioma cells by activating P53 and caspase-related apoptosis pathways. [ABSTRACT FROM AUTHOR]

Background: While accumulating research has tested the hypothesis that screen time causes psychiatric symptoms in children, less attention has been paid to the hypothesis that children with psychiatric symptoms change their patterns of screen time and digital media use. We aimed to test whether children with psychiatric symptoms subsequently change their patterns of screen time and digital media use. Methods: N = 9,066 children primarily aged 9–10 in the Adolescent Brain Cognitive Development Study at baseline and 1-year later. Psychiatric symptoms included internalizing, attention, and externalizing symptoms. Screen time was measured as ordinally defined weekday and weekend time on social and nonsocial [e.g., YouTube] digital media). Models assessed psychiatric symptoms as predictors of screen time, and screen time as predictors of psychiatric symptoms, controlled for baseline measures of each, sex, age, race/ethnicity, and income. Results: Children with psychiatric symptoms spent more time on non-social media one year later compared with peers. Considering total psychiatric problems, clinical levels of problems predicted higher levels of weekday (OR = 1.22, 95% CI 1.22–1.23) and weekend (OR = 1.10, 95% CI 1.09–1.11) nonsocial screen time. For nearly all analyses of psychiatric symptoms predicting screen time, associations were highest for a non-social screen time outcome rather than a social screen time outcome (Highest OR = 1.65, 95% CI 1.63–1.67, clinical rule breaking predicting weekday nonsocial screen time). Comparable magnitude associations were observed for social and nonsocial media use predicting future psychiatric symptoms, suggesting bidirectionality. Conclusion: Children with psychiatric symptoms have different subsequent media use patterns, including higher rates of subsequent nonsocial engagement. Ensuring that ongoing data collection and analysis efforts attend to temporality and transitions in the relation between media use and psychiatric symptoms will accelerate progress in the field. [ABSTRACT FROM AUTHOR]

Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca2+/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury. [ABSTRACT FROM AUTHOR]

Social isolation not only increases the risk of mortality in later life but also causes depressive symptoms, cognitive and physical disabilities. Although RNA m6A modifications are suggested to play key roles in brain development, neuronal signaling and neurological disorders, both the roles of m6A and the enzymes that regulate RNA m6A modification in social isolation induced abnormal behavior is unknown. The present study aims to explore the possible epitranscriptomic role of RNA m6A modifications and its enzymes in social isolation induced impaired behavior. 3–4 weeks mice experiencing 8 weeks social isolation stress (SI) were used in the present study. We quantified m6A levels in brain regions related to mood and cognitive behavior. And the expression of hippocampal m6A enzymes was also determined. The role of hippocampal m6A and its enzymes in SI induced abnormal behavior was further verified by the virus tool. SI led to not only depressive and anxiety-like behaviors but also cognitive impairment, with corresponding decreases in hippocampal m6A and METTL14. Hippocampal over-expression METTL14 with lentivirus not only rescued these behaviors but also enhanced the hippocampal m6A level. Hippocampal over-expression METTL14 resulted in increased synaptic related genes. We provide the first evidence that post-weaning social isolation reduces hippocampal m6A level and causes altered expression of m6A enzyme in mice. Importantly, hippocampal METTL14 over-expression alleviated the SI-induced depression/anxiety-like and impaired cognitive behaviors and enhanced m6A level and synaptic related genes expression. • Social isolation (SI) causes abnormal behaviors such as depression-like behavior in mice. • SI leads to decreased hippocampal m6A and METTL14 level. • Hippocampal METTL14 over-expression enhances m6A level and alleviates the SI-induced abnormal behaviors. [ABSTRACT FROM AUTHOR]

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Although it is known that prenatal maternal stress (PNMS) has a negative influence on nervous system development in offspring, there is no conclusive evidence clarifying its impact on early neurogenesis during development. In this study, we established a chick embryo model to investigate how PNMS affects early neurogenesis by mimicking an intrauterine environment with elevated dexamethasone levels. The results showed that dexamethasone-mimicked PNMS significantly suppressed the development of gastrula embryos and increased the risks of neural tube defects and cranial deformity. Using immunofluorescence staining and Western blots to evaluate the expression levels of pHIS3 and PCNA/Sox2, we found that PNMS significantly inhibited the proliferation of neural progenitor cells and that the downregulation of TGF-β signaling pathway might be responsible for the inhibition. Furthermore, immunofluorescence staining and Western blots manifested that PNMS could suppress the differentiation of neural progenitor cells to neuronal lineages, but promote them to transform into neuroglial cells, which might be due to the restriction of expressions of key genes (BMP4, SHH, Wnt3a, Slug, and Msx1) related to neural differentiation. In summary, our data reveal that PNMS dramatically impacts the earliest stages of neural development, thereby greatly increasing the risk of physical and mental health problems in childhood or adulthood. [ABSTRACT FROM AUTHOR]

Background The efficacy of parent training for neurodevelopmental disorders has been demonstrated in numerous studies. This study conducted a needs assessment of Japanese parents regarding parent training for neurodevelopmental disorders. Methods Responses from 806 parents of children with neurodevelopmental disorders, as well as those with suspected but undiagnosed neurodevelopmental disorders, who had not yet received parent training were analyzed. The survey examined overall trends in the conditions for implementing parent training, methods of grouping, fees, methods of follow-up, facilitator expertise, and effects of parent training. Additionally, differences based on neurodevelopmental diagnosis, parental employment status, household income, parental educational background, and child age were also analyzed. Results The results showed that parents preferred the program to be offered "once per week," "five sessions per program," "lasting 60 minutes each," "on weekends" and "in the morning," and "at a location within 30 minutes of travel to the venue." However, parents' expectations for parent training varied according to parental employment, household income, parental education, and child age. The only difference in diagnostic status was the preferred institution of attendance. Conclusion To expand the parent training programs within communities and increase the number of participants, it is necessary to analyze the expectations of prospective participants. The results of this survey suggest that PT providers should consider the conditions for implementing parent training, cost, and facilitator expertise to meet the participants expectations. [ABSTRACT FROM AUTHOR]

The nervous system contains complex circuits comprising thousands of cell types and trillions of connections. Here, we discuss how the field of “developmental systems neuroscience” combines the molecular and genetic perspectives of developmental neuroscience with the (typically adult-focused) functional perspective of systems neuroscience. This combination of approaches is critical to understanding how a handful of cells eventually produce the wide range of behaviors necessary for survival. Functional circuit development typically lags behind neural connectivity, leading to intermediate stages of neural activity that are either not seen in adults or, if present, are considered pathophysiological. Developmental systems neuroscience examines these intermediate stages of neural activity, mapping out the critical phases and inflection points of neural circuit function to understand how neural activity and behavior emerge across development. Beyond understanding typical development, this approach provides invaluable insight into the pathophysiology of neurodevelopmental disorders by identifying when and how functional development diverges between health and disease. We argue that developmental systems neuroscience will identify important periods of neural development, reveal novel therapeutic windows for treatment, and set the stage to answer fundamental questions about the brain in health and disease. [ABSTRACT FROM AUTHOR]

Background and purpose: Neurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development. Experimental Approach: The maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons. Key results: In VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE2/PTGER-2/IDO-1 and abolished these alterations. Conclusion: Taprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development. [ABSTRACT FROM AUTHOR]

Fetal Alcohol Spectrum Disorder (FASD) encompasses the deleterious consequences of Prenatal Alcohol Exposure (PAE), including developmental delay, microcephaly, dysmorphologies, and cognitive and behavioral issues. The dose and timing of alcohol exposure, maternal and environmental factors, and genetics all impact FASD outcomes, but differential susceptibility and resiliency to PAE remains poorly understood. In this study, we examined the differential effects of PAE during early mouse development on brain growth and gene expression. Brains were weighed and collected either 24 hours or five days after treatment. We then performed transcriptomics to determine whether offspring differentially affected by PAE, by brain weight, also differ in gene expression, despite having the same genetic background, alcohol exposure, and maternal factors. We found within litter variation in brain weights after PAE, and classified offspring as having normal, middle, and low-weight brains relative to saline-treated controls. The normal-weight brains showed no significant differences in gene expression, suggesting these offspring were both phenotypically and transcriptionally unaffected by PAE. While both middle- and low-weight brains showed changes in gene expression, the middle-weight brains showed the most robust transcriptome differences. Twenty-four hours after PAE, we saw an upregulation of cell cycle and apoptosis in affected offspring, whereas at roughly a week later, we saw a downregulation of metabolic processes. Overall, these findings highlight variability in response to PAE and demonstrate the molecular processes involved in offspring phenotypically affected by alcohol. [ABSTRACT FROM AUTHOR]

The human neocortex has a huge surface area with unique cytoarchitectonics, most of which is concealed in sulci. Some cytoarchitectonic fields are associated with macroscopic landmarks. In particular, the primary visual field 17 is associated with the calcarine sulcus. During the prenatal development of the human brain, neocortical gyri and sulci undergo changes and modifications after primary formation. To explore the morphogenetic processes in visual fields during the formation of the primary (provisional) and secondary (permanent) sulci, the occipital lobe of the human fetal brain was studied using immunohistochemical methods. The distribution of various glial and neuronal markers (S-100, β-III-tubulin, NeuN, reelin) in the calcarine sulcus and parietooccipital sulcus was compared. The heterogeneity in the formation of primary and secondary visual fields was demonstrated. The study revealed that the development of the primary visual field 17, linked with the calcarine sulcus, preceded the development of a shared anlage of fields 18 and 19 linked with the parietooccipital sulcus. The functional differentiation of the primary visual field begins during the period of thalamic afferent ingrowth. This process coincides with the temporal smoothing of the calcarine sulcus, indicating a simultaneous progression of functional specialization and structural modifications. At the late fetal period, cortical plate of gyri and sulci banks showed higher NeuN-labeling than inside the sulcus in the same cytoarchitectonic field. [ABSTRACT FROM AUTHOR]

Multiple lines of evidence indicate that altered dopamine signaling may be involved in neuropsychiatric disorders and common behavioral traits. Here we critically review evidence collected during the past 40-plus years supporting the role of dopamine dysfunction in attention deficit hyperactivity disorder (ADHD). We recapitulate the basic components of dopaminergic signaling in the central nervous system, focusing on core enzymes, transporters and receptors involved in monoaminergic functions, particularly in striatal and cortical regions. We summarize key human brain imaging and genetic studies reporting associations between dopaminergic neurotransmission and behavioral traits, with an emphasis on ADHD. We also consider ADHD in the context of animal models and single gene, metabolic, and neurological disorders with established dysfunction of the dopaminergic system. Examining the evidence in this way leads us to conclude that there is evidence for the involvement of dopamine but limited evidence for a hypo-dopaminergic state per se as a key component of ADHD. We propose a path forward to increase our understanding of dopamine signaling in human behavioral traits and disorders that should particularly focus on its role in clinical subgroups, during brain development and how it interacts with other neurotransmitter systems. [ABSTRACT FROM AUTHOR]

Introduction: Glucose Transporter 1-Deficiency Syndrome (GLUT1-DS) is a rare genetic disorder caused by mutations in the gene encoding for GLUT1 and characterized by impaired glucose uptake in the brain. This leads to brain hypometabolism and the development of symptoms that include epilepsy, motor dysfunctions and cognitive impairment. The development of patient-specific in vitro models is a valuable tool for understanding the pathophysiology of rare genetic disorders and testing new therapeutic interventions. Methods: In this study, we generated brain organoids from induced pluripotent stem cells (iPSCs) derived either from a GLUT1-DS patient or a healthy individual. The functional organoids were analyzed for cellular composition, maturity, and electrophysiological activity using a custom-made microelectrode array (MEA) platform, which allowed for the detection of spikes, burst patterns, and epileptiform discharges. Results: Immunostaining revealed a similar distribution of neurons and astrocytes in both healthy and GLUT1-DS brain organoids, though GLUT1-DS brain organoids exhibited reduced cellular density and smaller overall size. Electrophysiological recordings demonstrated functional spike profiles in both organoid types. Notably, our study demonstrates that brain organoids derived from a GLUT1-DS patient exhibit distinct epileptiform activity and heightened sensitivity to glucose deprivation, reflecting key features of the disorder. Discussion: These findings validate the use of brain organoids as a model for studying GLUT1-DS and highlight their potential for testing novel therapeutic strategies aimed at improving glucose metabolism and managing epilepsy in patients. [ABSTRACT FROM AUTHOR]

Background: The spatial layout of large-scale functional brain networks exhibits considerable inter-individual variability, especially in the association cortex. Research has demonstrated a link between early socioeconomic status (SES) and variations in both brain structure and function, which are further associated with cognitive and mental health outcomes. However, the extent to which SES is associated with individual differences in personalized functional network topography during childhood remains largely unexplored. Methods: We used a machine learning approach—spatially regularized non-negative matrix factorization (NMF)—to delineate 17 personalized functional networks in children aged 9–10 years, utilizing high-quality functional MRI data from 6001 participants in the Adolescent Brain Cognitive Development study. Partial least square regression approach with repeated random twofold cross-validation was used to evaluate the association between the multivariate pattern of functional network topography and three SES factors, including family income-to-needs ratio, parental education, and neighborhood disadvantage. Results: We found that individual variations in personalized functional network topography aligned with the hierarchical sensorimotor-association axis across the cortex. Furthermore, we observed that functional network topography significantly predicted the three SES factors from unseen individuals. The associations between functional topography and SES factors were also hierarchically organized along the sensorimotor-association cortical axis, exhibiting stronger positive associations in the higher-order association cortex. Additionally, we have made the personalized functional networks publicly accessible. Conclusions: These results offer insights into how SES influences neurodevelopment through personalized functional neuroanatomy in childhood, highlighting the cortex-wide, hierarchically organized plasticity of the functional networks in response to diverse SES backgrounds. [ABSTRACT FROM AUTHOR]

Structural and functional connectomes undergo rapid changes during the third trimester and the first month of postnatal life. Despite progress, our understanding of the developmental trajectories of the connectome in the perinatal period remains incomplete. Brain age prediction uses machine learning to estimate the brain's maturity relative to normative data. The difference between the individual's predicted and chronological age—or brain age gap (BAG)—represents the deviation from these normative trajectories. Here, we assess brain age prediction and BAGs using structural and functional connectomes for infants in the first month of life. We use resting-state fMRI and DTI data from 611 infants (174 preterm; 437 term) from the Developing Human Connectome Project (dHCP) and connectome-based predictive modeling to predict postmenstrual age (PMA). Structural and functional connectomes accurately predict PMA for term and preterm infants. Predicted ages from each modality are correlated. At the network level, nearly all canonical brain networks—even putatively later developing ones—generate accurate PMA prediction. Additionally, BAGs are associated with perinatal exposures and toddler behavioral outcomes. Overall, our results underscore the importance of normative modeling and deviations from these models during the perinatal period. Here, the authors show that altered brain development of infants after birth, driven by perinatal exposures, influences long-term cognitive outcomes. [ABSTRACT FROM AUTHOR]

Background: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer's disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expression, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD. Methods: We used SH-CDKL5-KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects. Results: We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 KO mice, resulting in limited behavioral benefit. Conclusions: At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro. [ABSTRACT FROM AUTHOR]

AbstractThis research aims to address designing an experiment to evaluate the impact of a developed posture correction system. Also, the correct posture learning habits of users can be estimated with an artificial neural network (ANN) structure that predicts the poor posture count (PPC) in the last session of the experiment using the information received from the users and the developed system. The developed system aims to collect data from different individuals about their sitting posture information. An ANN analysis tool is developed to predict the individuals’ habits of learning the correct posture. This setup is based on a flex sensor and has the capability of collecting posture information data and warning the user when the posture is not correct. A three-session experiment was conducted on 12 healthy participants to investigate his/her posture habits. The data was analyzed to determine the average PPC value. It was observed that PPC decreased by 56.27% from session one to session three, and the average improvement evaluation (IE) value after each session was found to be positive. In addition to experimental analysis, the collected posture data was used to train and validate an ANN architecture capable of predicting PPC values. The developed device is effective in improving posture habits and has the potential to predict PPC values with the ANN architecture. [ABSTRACT FROM AUTHOR]

• During pregnancy, mother and child induce reciprocal neurobiological changes. • Communication between mother and fetus is constant, and effects persist long-term. • After childbirth, the mother and child undergo an adaptive transitional phase. • "Limbo" states allow for an easier transition to subsequent phases of development. From the start of pregnancy, mother and child induce reciprocal neurobiological changes in the brain that will prove critical for neurodevelopment and survival of both. Molecular communication between mother and fetus is constantly active and persists even after the fetus starts to synthesize its hormones in late gestation. Intriguingly, some mother and fetus exchange cells remain in the other's brain and body with long-lasting effects and memories that do not follow the laws of classical genetics but involve complex epigenetic mechanisms. After childbirth, mother and child go through a transitional phase, a sort of limbo in which both will have a peculiar functioning profile, which is adaptive for contingencies but also renders them vulnerable. The interplay between these two "limbo" states allows for an easier transition to the subsequent phases of development. In this review, we will trace mother's and child's path from pregnancy to the months following birth and, in particular, unravel i) the key features of pregnancy and brain development and the reciprocal influences; ii) how a transitory pattern of functioning characterize mother and child, moving them toward more flexible and evolved forms; and iii) how mother and fetus act during childbirth to promote neuroprotection, pain reduction, and neurophysiological changes. Therefore, this review covers a wide range of topics, integrating neuroanatomical, neurological, biochemical, neurophysiological, and psychological studies in a meaningful way, trying to integrate them in a holistic view of the mother–child interface that is usually neglected. [ABSTRACT FROM AUTHOR]

The primary cilium, a single microtubule-based organelle protruding from the cell surface and critical for neural development, also functions in adult neurons. While some dorsal root ganglion neurons elaborate a primary cilium, whether it is expressed by and functional in nociceptors is unknown. Recent studies have shown the role of Hedgehog, whose canonical signaling is primary cilium dependent, in nociceptor sensitization. We establish the presence of primary cilia in soma of rat nociceptors, where they contribute to mechanical threshold, prostaglandin E2 (PGE2)-induced hyperalgesia, and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of siRNA targeting Ift88, a primary cilium-specific intraflagellar transport (IFT) protein required for ciliary integrity, resulted in attenuation of Ift88 mRNA and nociceptor primary cilia. Attenuation of primary cilia was associated with an increase in mechanical nociceptive threshold in vivo and decrease in nociceptor excitability in vitro, abrogation of hyperalgesia, and nociceptor sensitization induced by both a prototypical pronociceptive inflammatory mediator PGE2 and paclitaxel CIPN, in a sex-specific fashion. siRNA targeting Ift52, another IFT protein, and knockdown of NompB, the Drosophila Ift88 ortholog, also abrogated CIPN and reduced baseline mechanosensitivity, respectively, providing independent confirmation for primary cilia control of nociceptor function. Hedgehog-induced hyperalgesia is attenuated by Ift88 siRNA, supporting the role for primary cilia in Hedgehog-induced hyperalgesia. Attenuation of CIPN by cyclopamine (intradermal and intraganglion), which inhibits Hedgehog signaling, supports the role of Hedgehog in CIPN. Our findings support the role of the nociceptor primary cilium in control of mechanical nociceptive threshold and inflammatory and neuropathic pain, the latter Hedgehog-dependent. [ABSTRACT FROM AUTHOR]

The morphogen FGF8 establishes graded positional cues imparting regional cellular responses via modulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to investigate the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity, leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic regions, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors and the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development. [ABSTRACT FROM AUTHOR]

Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in pre-motor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their downstream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of principles of neural development. [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) and Huntington’s Disease (HD) are distinct neurodevelopmental and neurodegenerative disorders, respectively, characterized by significant genetic and molecular alterations. ASD primarily affects early childhood and is associated with genetic mutations impacting brain development, while HD, an autosomal dominant disorder, leads to progressive neurodegeneration due to mutations in the HTT gene. Despite their differences, both disorders share common genetic pathways and molecular mechanisms. This study aims to explore the genetic and molecular connections between ASD and HD through a comprehensive analysis of differentially expressed genes (DEGs) and protein–protein interaction (PPI) networks to uncover shared pathways and potential overlapping mechanisms. Transcriptomic data were acquired from the NCBI-GEO database, specifically GSE180185 for ASD and GSE1751 for HD. DEGs were identified using thresholds of log2 fold change (FC) > 1 and an adjusted p-value < 0.05. Common DEGs between the two disorders were determined and analyzed using Cytoscape’s STRING app to construct a PPI network with a confidence level of 0.7. Functional enrichment was conducted through KEGG and Gene Ontology (GO) analyses. Key regulatory modules and hubs were identified using CytoNCA and MCODE plugins. The ASD dataset revealed 565 DEGs, with 206 upregulated and 347 downregulated, while the HD dataset had 1091 DEGs, with 743 upregulated and 202 downregulated. Twelve genes were common to both conditions, including 4 upregulated and 8 downregulated. The PPI network comprised 62 nodes and 215 edges, with significant pathways including ascorbate metabolism and steroid hormone biosynthesis. Notably, Module 3, containing 12 nodes, was linked to EGFR tyrosine kinase resistance and apoptosis. This study identifies shared genetic and molecular pathways between ASD and HD, highlighting common regulatory mechanisms and potential targets for further research. The use of transcriptomic data and PPI network analysis reveals significant overlaps in the molecular mechanisms underlying these disorders. Further experimental validation and expanded dataset analyses could elucidate specific interactions and enhance our understanding of the shared pathways. Investigating these common mechanisms may also provide insights into potential therapeutic approaches for both ASD and HD. [ABSTRACT FROM AUTHOR]

Understanding the sequence and timing of brain functional network development at the beginning of human life is critically important from both normative and clinical perspectives. Yet, we presently lack rigorous examination of the longitudinal emergence of human brain functional networks over the birth transition. Leveraging a large, longitudinal perinatal functional magnetic resonance imaging (fMRI) data set, this study models developmental trajectories of brain functional networks spanning 25 to 55 weeks of post-conceptual gestational age (GA). The final sample includes 126 fetal scans (GA = 31.36 ± 3.83 weeks) and 58 infant scans (GA = 48.17 ± 3.73 weeks) from 140 unique subjects. In this study, we document the developmental changes of resting-state functional connectivity (RSFC) over the birth transition, evident at both network and graph levels. We observe that growth patterns are regionally specific, with some areas showing minimal RSFC changes, while others exhibit a dramatic increase at birth. Examples with birth-triggered dramatic change include RSFC within the subcortical network, within the superior frontal network, within the occipital-cerebellum joint network, as well as the cross-hemisphere RSFC between the bilateral sensorimotor networks and between the bilateral temporal network. Our graph analysis further emphasized the subcortical network as the only region of the brain exhibiting a significant increase in local efficiency around birth, while a concomitant gradual increase was found in global efficiency in sensorimotor and parietal-frontal regions throughout the fetal to neonatal period. This work unveils fundamental aspects of early brain development and lays the foundation for future work on the influence of environmental factors on this process. How do the functional networks in the brain change at the beginning of human life? This longitudinal perinatal fMRI study of 140 babies reveals regionally specific changes in neural connectivity at the birth transition, with some areas showing minimal variation while others show increases in connectivity at birth. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive. Methods: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells. Results: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth. Conclusions: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma. [ABSTRACT FROM AUTHOR]

Introduction: For many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy. However, many antiretroviral drugs are approved for widespread use following clinical testing only in non-pregnant populations and there may be limited information on potential teratogenicity until pregnancy outcomes are evaluated. The integrase strand transfer inhibitor dolutegravir (DTG) is a frontline antiretroviral drug that is effective in viral suppression of HIV but was previously reported to be associated with a slight increase in the risk for neural tube defects in one study, although this has not been replicated in other cohorts. Methods: To directly investigate the potential impact of DTG on human cortical neurogenesis, we measured the effects of daily drug exposure on the early stages of corticogenesis in a human iPSC-based forebrain organoid model. We quantified organoid size and structure and analyzed gene and protein expression to evaluate the impact of several doses of DTG on organoid development. Results: We observed deficits in organoid structure and impaired neurogenesis in DTG-treated organoids compared to vehicle-treated control organoids after 20 or 40 days in culture. Our highest dose of DTG (10 μM) resulted in significantly smaller organoids with a reduced density of neural rosette structures compared to vehicle-treated controls. Mechanistically, RNA-sequencing and immunohistological analysis suggests dysregulated amino acid transport and activation of the integrated stress response in the DTG-treated organoids, and functionally, a small molecule integrated stress response inhibitor (ISRIB) could partially rescue increased expression of proteins related to cell cycle regulation. Discussion: Together, these results illustrate the potential for human iPSC-based strategies to reveal biological processes during neurogenesis that may be affected by therapeutic drugs and provide complementary data in relevant human cell types to augment preclinical investigations of drug safety during pregnancy. [ABSTRACT FROM AUTHOR]

Adolescence is a pivotal stage during development when one's personality, emotion, and behavioral traits are shaped to a great extent, and the underlying neural circuits undergo substantial developmental organizations. Dramatic and dynamic changes occur in sleep architecture throughout the postnatal developmental course. Insufficient sleep and disruption of sleep/wake coherence are prevalent among the adolescents worldwide, and even so in young patients with neuropsychiatric conditions. Although accumulating evidence has suggested a tight association between sleep disruption and depression/anxiety, the causal relationship remains largely unclear. More importantly, most of these studies focused on adult subjects, and little is known about the role of sleep during the development of mood and behavior. Here we review recent studies investigating the acute and chronic effects of adolescent sleep disruption on depression and anxiety both in humans and rodent models with focuses on the assessment methodology and age. By discussing the findings and unsolved problems, we hope to achieve a better understanding of the relationship between sleep and mental health in adolescents and provide insights for future research. [ABSTRACT FROM AUTHOR]

It has been recognized that subtle, cosmetically insignificant anomalies tend to occur cumulatively in diseases with neurodevelopmental origin. These visible signs of morphogenesis errors are called minor physical anomalies (MPAs), serving as sensitive external markers of abnormal neurodevelopment. After the introduction of the Waldrop Scale, the studies conducted on MPAs in diseases with neurodevelopmental origin gave conflicting results. It has been debated that this discrepancy can be – at least partly – attributed to the use of the Waldrop Scale. Understanding the need of a comprehensive scale of MPAs that also differentiates according to the time of development, Hungarian pediatrician professor of University of Pécs, Károly Méhes developed a scale with 57 items, the only scale differentiating minor malformations from phenogenetic variants. With the use of the Méhes Scale, our research group has been investigating the role of abnormal neurodevelopment in different neuropsychiatric and neurologic disorders since 1997. 25 years into our research, in this review we summarize the results of our 18 research articles on MPAs in different diseases. We have found an increased number of MPAs, especially in the head and mouth region, in patients with schizophrenia, bipolar disorder, Tourette syndrome, autism and many epilepsy syndromes, fortifying the role of abnormal neurodevelopment in these diseases. Moreover, an increased number of MPAs was detected among the first-degree relatives of patients with schizophrenia and bipolar I disorder, supporting the hypothesis about MPAs being endophenotypic trait markers. [ABSTRACT FROM AUTHOR]

Cephalopods have dominated the oceans for hundreds of millions of years and are unquestionably at the peak of molluscan evolution. The development of the large brain and a well-sophisticated sensory system contributed significantly to its success. Therefore, it is considered the best example of convergent evolution and attracted the attention of scientists from various disciplines of biology. The aim of the present study is to construct a reference transcriptome in the Indian squid Uroteuthis duvaucelii to gain insights into cephalopod evolution and enrich the existing cephalopod database. Around 72 million short Illumina reads were generated from five different tissues, including the brain, eye, gill, heart and gonads, and assembled using the Trinity assembler. About 26230 protein-coding sequences were annotated from the assembled transcripts. The BUSCO completeness of the assembly was 71.71% compared to the Mollusca_Odb10 gene set. KEGG and REACTOME pathway analyzes revealed that U. duvaucelii shares many genes and pathways with higher vertebrates. [ABSTRACT FROM AUTHOR]

Oxidative stress from environmental exposures is thought to play a role in neurodevelopmental disorders; therefore, understanding the underlying molecular regulatory network is essential for mitigating its impacts. In this study, we analysed the competitive endogenous RNA (ceRNA) network mediated by circRNAs, a novel class of regulatory molecules, in an SH-SY5Y cell model of oxidative stress, both prior to and during neural differentiation, using RNA sequencing and in silico analysis. We identified 146 differentially expressed circRNAs, including 93 upregulated and 53 downregulated circRNAs, many of which were significantly co-expressed with mRNAs that potentially interact with miRNAs. We constructed a circRNA–miRNA–mRNA network and identified 15 circRNAs serving as hubs within the regulatory axes, with target genes enriched in stress- and neuron-related pathways, such as signaling by VEGF, axon guidance, signaling by FGFR, and the RAF/MAP kinase cascade. These findings provide insights into the role of the circRNA-mediated ceRNA network in oxidative stress during neuronal differentiation, which may help explain the regulatory mechanisms underlying neurodevelopmental disorders associated with oxidative stress. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate receptors (NMDARs) are critical components of the mammalian central nervous system, involved in synaptic transmission, plasticity, and neurodevelopment. This review focuses on the structural and functional characteristics of NMDARs, with a particular emphasis on the GRIN2 subunits (GluN2A-D). The diversity of GRIN2 subunits, driven by alternative splicing and genetic variants, significantly impacts receptor function, synaptic localization, and disease manifestation. The temporal and spatial expression of these subunits is essential for typical neural development, with each subunit supporting distinct phases of synaptic formation and plasticity. Disruptions in their developmental regulation are linked to neurodevelopmental disorders, underscoring the importance of understanding these dynamics in NDD pathophysiology. We explore the physiological properties and developmental regulation of these subunits, highlighting their roles in the pathophysiology of various NDDs, including ASD, epilepsy, and schizophrenia. By reviewing current knowledge and experimental models, including mouse models and human-induced pluripotent stem cells (hiPSCs), this article aims to elucidate different approaches through which the intricacies of NMDAR dysfunction in NDDs are currently being explored. The comprehensive understanding of NMDAR subunit composition and their mutations provides a foundation for developing targeted therapeutic strategies to address these complex disorders. [ABSTRACT FROM AUTHOR]

Febrile seizures (FSs) are defined as seizures occurring in children aged 6 months to 5 years with a background of elevated body temperature. It is one of the most common neurological disorders of childhood, emphasizing the importance of understanding the causes of FSs and their impact on the developing nervous system. However, there are significant limitations to the technologies currently available for studying the etiology and pathophysiology of seizures in humans. It is currently not possible to adequately capture the subtle molecular and structural rearrangements of the nervous system that can occur after seizures in humans. The use of animal models can be invaluable for these purposes. The most commonly used models in modern research are hyperthermic models in rats and mice aged 10–12 days. While these models can reproduce many of the characteristics of FSs, they have certain limitations. This review outlines the key considerations when working with models of FSs, provides an overview of current approaches to producing seizures in different model subjects, and presents a summary of key findings regarding morphological and functional changes in the brain and behavioral alterations that have been identified in studies using animal models of FSs. [ABSTRACT FROM AUTHOR]