Impaired Brain Development Research Articles

Isolated Sagittal Craniosynostosis and Open or Endoscopic Cranial Vault Remodeling: An Evaluation of Developmental Outcomes.

Craniosynostosis, a condition involving the premature fusion of cranial sutures, can impair brain development and potentially lead to developmental delays. This study compares open cranial vault remodeling versus endoscopic strip craniectomy treatment for isolated sagittal craniosynostosis, primarily focusing on development outcomes. A retrospective cohort study was conducted at a tertiary pediatric surgery center, involving all 45 patients treated surgically for isolated sagittal craniosynostosis from 2013 to 2024. Patients were categorized into 2 groups based on surgical intervention: open cranial vault remodeling (n=17) and endoscopic strip craniectomy (n=28). Data collected included patient demographics, intraoperative specifics, and postoperative outcomes. Developmental outcomes were assessed using postoperative progress notes. Of the 45 patients, those undergoing open surgery were older (10.7mo and 9.4kg versus 3.3mo and 6.4kg, P<0.001) and experienced higher use of intraoperative drains (65% versus 0%, P<0.001), more prolonged procedures (189 versus 58min, P<0.001), more significant blood loss (102 versus 62mL, P=0.009), longer stays (3.3 versus 2.6d, P=0.011), and higher opioid prescription rates (82% versus 43%, P=0.013) compared to the endoscopic group. Within 12 months postoperatively, social delays were more common in the open group (19 versus 0%, P=0.049), and, postoperatively in general, cognitive delays were more common in the open group (31% versus 4%, P=0.023) when compared to the endoscopic group. Endoscopic cranial vault remodeling produces preferentially better hemodynamic, postoperative, and hospital stay outcomes. Although inferences into long-term developmental delay outcomes were limited due to sample size, a preferential benefit toward endoscopic intervention may exist.

Plastic is one of the root causes of endocrine disorders

Endocrine-disrupting chemicals (EDCs) found in various products, including electronics, carpets, paints, cosmetics, and plastics, can disrupt human endocrine systems, potentially affecting reproductive health, thyroid function, metabolic alterations, diabetes, cardiovascular disease, obesity, impaired brain development, compromised immune responses, and cancers in hormone-sensitive tissues. Exposure to EDCs during gestation and early postnatal life has significant impacts, and hazardous compounds in plastics can lead to further damage.

Mitochondrial fission is required for thermogenesis in brown adipose tissue.

Brown adipose tissue (BAT) thermogenesis is pivotal for maintaining body temperature and energy balance. Mitochondrial morphology is dynamically controlled by a balance between fusion and fission, which is crucial for cell differentiation, response to metabolic insults, and heat production. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. This study investigates the role of Drp1 in BAT development and thermogenesis by generating Drp1-deficient mice. These mice were created by crossing Drp1 floxed mice with fatty acid-binding protein 4-Cre (aP2-Cre) transgenic mice, resulting in aP2-Cre+/-Drp1flox/flox (aP2-Drp1f/f) mice. The aP2-Drp1f/f mice exhibited severe BAT and brain hypoplasia, with the majority dying within 48 hours postnatally, highlighting Drp1's crucial role in neonatal survival. Impaired thermogenic responses were observed in aP2-Drp1f/f mice, characterized by significantly decreased expression of thermogenic and lipogenic genes in BAT. Ultrastructural analysis revealed disrupted mitochondrial morphology and reduced lipid droplet content in BAT. The few surviving adult aP2-Drp1f/f mice also showed impaired BAT and brain development, along with BAT thermogenesis dysfunction during cold exposure. Our findings underscore the essential role of Drp1-mediated mitochondrial fission in BAT thermogenesis and neonatal survival, providing insights into potential therapeutic approaches for metabolic disorders.

Effects of Cumulative Duration of Repeated Anesthesia Exposure on Fetal Brain Development in the Ovine Model

(J Clin Anesth. 2023;85:111050. https://doi.org/10.1016/j.jclinane.2022.111050) During nonobstetric surgeries, general anesthesia is necessary in ∼1% of pregnant women. In a recent population cohort, 91% of these women underwent a single anesthesia exposure, averaging 89 minutes. However, 9% experienced multiple exposures. The duration of anesthesia varied: 29% had less than an hour, 49% had 1 to 2 hours, 12% had 2 to 3 hours, 6% had 3 to 5 hours, and 2% had 7 to 13 hours. The FDA issued a warning about potential fetal brain development impairment from repeated or prolonged anesthesia exposure (&gt;3 h). A meta-analysis confirmed that in laboratory animals, repeated or prolonged exposure to general anesthesia results in neuronal injury and neurobehavioral impairments in fetuses. Short exposures (≤3 h) to ≤1 MAC of volatile anesthetics did not show significant neurodevelopmental impairments. Most studies were conducted in mice and rats, whose short gestation periods limit direct human comparisons. The 3-hour exposure in rodents equates to 40 to 47 hours in humans. A recent clinical study found no general population evidence linking prenatal anesthesia exposure to impaired neurodevelopment, though small sample sizes limited findings on prolonged exposure effects.

Association between SMOFlipid and impaired brain development on term-equivalent age brain magnetic resonance imaging in very preterm infants

Soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOFlipid) is used without evidence of benefits. We investigated the relationship between lipid emulsions and brain injury in term-equivalent age magnetic resonance imaging (MRI) in 148 very preterm infants with a birth weight of < 1500 g at ≤ 32 gestational weeks in a neonatal intensive care unit. Infants who received soybean-based lipid emulsions between January 2015 and December 2018 were compared with those who received SMOFlipids between January 2019 and December 2022. A negative binomial generalized linear model was applied for bivariate analysis. Modified log-Poisson regression with generalized linear models and a robust variance estimator (Huber–White) were applied to adjust for potential confounders. The Kidokoro score was used to determine if lipid emulsion type would affect brain morphology and growth at term-equivalent age. Eighty-six (58.9%) received SMOFlipid. SMOFlipid was associated with lower focal signal abnormality, myelination delay, increased extracerebral space, and cerebellar volume reduction (P = 0.02, P = 0.007, P = 0.01, P = 0.02, respectively). SMOFlipidis are associated with brain insult, especially in white matter, cortical gray matter, and the cerebellum. Well-designed studies are needed to investigate the effect of lipid emulsions on the central nervous system.

Breastfeeding in the prevention of long-term consequences of neuropsychiatric pathology in offspring with gestational diabetes mellitus

This literature review summarizes modern concepts of gestational diabetes mellitus as an independent risk factor for the development of long-term neuropsychiatric diseases in offspring and the mechanisms of their programming in this complication of pregnancy in the absence of the protective role of maternal melatonin as a consequence of chronodestruction. The article presents literature data on the composition of breast milk and the participation of its endogenous melatonin, microRNAs, long non-coding RNAs, stem cells, and microbiome in reprogramming epigenetic disorders as a result of adverse effects in the antenatal period, which helps to reduce the likelihood of developing neuropsychiatric pathology later in life. It is emphasized that breastfeeding during the first six months of life and later, along with complementary foods under the age of two years and older, is exclusively a physiological and unsurpassed method of preventing long-term consequences of impaired brain development in offspring with gestational diabetes mellitus.

New CRISPR/Cas9-based Fgfr2C361Y/+ mouse model of Crouzon syndrome exhibits skull and behavioral abnormalities.

Crouzon syndrome (CS), a syndromic craniosynostosis, is a craniofacial developmental deformity caused by mutations in fibroblast growth factor receptor 2 (FGFR2). Previous CS mouse models constructed using traditional gene editing techniques faced issues such as low targeting efficiency, extended lineage cycles, and inconsistent and unstable phenotypes. In this study, a CRISPR/Cas9-mediated strategy was employed to induce a functional augmentation of the Fgfr2 point mutation in mice. Various techniques, including bone staining, micro-CT, histological methods, and behavioral experiments, were employed to systematically examine and corroborate phenotypic disparities between mutant mice (Fgfr2C361Y/+) and their wild-type littermates. Confirmed via PCR-Sanger sequencing, we successfully induced the p.Cys361Tyr missense mutation in the Fgfr2 IIIc isoform of the extracellular domain (corresponding to the p.Cys342Tyr mutation in humans) based on Fgfr2-215 transcript (ENSMUST00000122054.8). Fgfr2C361Y/+ mice exhibited characteristics consistent with the phenotypic features associated with CS, including skull-vault craniosynostosis, skull deformity, shallow orbits accompanied by exophthalmos, midface hypoplasia with malocclusion, and shortened skull base, notably without any apparent limb defects. Furthermore, mutant mice displayed behavioral abnormalities encompassing deficits in learning and memory, social interaction, and motor dysfunction, without anxiety-related disorders. Histopathological examination of the hippocampal region revealed structural abnormalities, suggesting possible brain development impairment secondary to craniosynostosis. In conclusion, we constructed a novel gene-edited Fgfr2C361Y/+ mice strain based on CRISPR/Cas9, which displayed skull and behavioral abnormalities, serving as a new model for studying genetic molecular mechanisms and exploring treatments for CS. KEY MESSAGES: CRISPR/Cas9 crafted a Crouzon model by enhancing Fgfr2-C361Y in mice. Fgfr2C361Y/+ mice replicate CS phenotypes-craniosynostosis and midface anomalies. Mutant mice show diverse behavioral abnormalities, impacting learning and memory. Fgfr2C361Y/+ mice offer a novel model for cranial suture studies and therapeutic exploration.

Individualized cortical gyrification in neonates with congenital heart disease.

Congenital heart disease is associated with impaired early brain development and adverse neurodevelopmental outcomes. This study investigated how individualized measures of preoperative cortical gyrification index differ in 142 infants with congenital heart disease, using a normative modelling approach with reference data from 320 typically developing infants. Gyrification index Z-scores for the whole brain and six major cortical areas were generated using two different normative models: one accounting for post-menstrual age at scan, post-natal age at scan and sex, and another additionally accounting for supratentorial brain volume. These Z-scores were compared between congenital heart disease and control groups to test the hypothesis that cortical folding in infants with congenital heart disease deviates from the normal developmental trajectory. The relationships between whole-brain gyrification index Z-scores from the two normative models and both cerebral oxygen delivery and neurodevelopmental outcomes were also investigated. Global and regional brain gyrification was significantly reduced in neonates with congenital heart disease, but not when supratentorial brain volume was accounted for. This finding suggests that whilst cortical folding is reduced in congenital heart disease, it is primarily driven by a reduction in brain size. There was a significant positive correlation between cerebral oxygen delivery and whole-brain gyrification index Z-scores in congenital heart disease, but not when supratentorial brain volume was accounted for. Cerebral oxygen delivery is therefore likely to play a more important role in the biological processes underlying volumetric brain growth than cortical folding. No significant associations between whole-brain gyrification index Z-scores and motor/cognitive outcomes or autism traits were identified in the 70 infants with congenital heart disease who underwent neurodevelopmental assessment at 22-months. Our results suggest that chronic in utero and early post-natal hypoxia in congenital heart disease is associated with reductions in cortical folding that are proportional to reductions in supratentorial brain volume.

The Conundrum of Mechanics Versus Genetics in Congenital Hydrocephalus and Its Implications for Fetal Therapy Approaches: A Scoping Review.

Recent advances in gene therapy, particularly for single-gene disorders (SGDs), have led to significant progress in developing innovative precision medicine approaches that hold promise for treating conditions such as primary hydrocephalus (CH), which is characterized by increased cerebrospinal fluid (CSF) volumes and cerebral ventricular dilation as a result of impaired brain development, often due to genetic causes. CH is a significant contributor to childhood morbidity and mortality and a driver of healthcare costs. In many cases, prenatal ultrasound can readily identify ventriculomegaly as early as 14-20weeks of gestation, with severe cases showing poor neurodevelopmental outcomes. Postnatal surgical approaches, such as ventriculoperitoneal shunts, do not address the underlying genetic causes, have high complication rates, and result in a marginal improvement of neurocognitive deficits. Prenatal somatic cell gene therapy (PSCGT) promises a novel approach to conditions such as CH by targeting genetic mutations in utero, potentially improving long-term outcomes. To better understand the pathophysiology, genetic basis, and molecular pathomechanisms of CH, we conducted a scoping review of the literature that identified over 160 published genes linked to CH. Mutations in L1CAM, TRIM71, MPDZ, and CCDC88C play a critical role in neural stem cell development, subventricular zone architecture, and the maintenance of the neural stem cell niche, driving the development of CH. Early prenatal interventions targeting these genes could curb the development of the expected CH phenotype, improve neurodevelopmental outcomes, and possibly limit the need for surgical approaches. However, further research is needed to establish robust genotype-phenotype correlations and develop safe and effective PSCGT strategies for CH.

A Simple MRI Score Predicts Pathological General Movements in Very Preterm Infants with Brain Injury-Retrospective Cohort Study.

Very preterm infants are at increased risk of brain injury and impaired brain development. The Total Abnormality Score and biometric parameters, such as biparietal width, interhemispheric distance and transcerebellar diameter, are simple measures to evaluate brain injury, development and growth using cerebral magnetic resonance imaging data at term-equivalent age. The aim of this study was to evaluate the association between the Total Abnormality Score and biometric parameters with general movements in very preterm infants with brain injury. This single-center retrospective cohort study included 70 very preterm infants (≤32 weeks' gestation and/or <1500 g birth weight) born between January 2017 and June 2021 in a level-three neonatal intensive care unit with brain injury-identified using cerebral magnetic resonance imaging data at term-equivalent age. General movements analysis was carried out at corrected age of 8-16 weeks. Binary logistic regression and Spearman correlation were used to examine the associations between the Total Abnormality Score and biometric parameters with general movements. There was a significant association between the Total Abnormality Score and the absence of fidgety movements [OR: 1.19, 95% CI = 1.38-1.03] as well as a significant association between the transcerebellar diameter and fidgety movements (Spearman ρ = -0.269, p < 0.05). Among very preterm infants with brain injury, the Total Abnormality Score can be used to predict the absence of fidgety movements and may be an easily accessible tool for identifying high-risk very preterm infants and planning early interventions accordingly.

V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities.

Vacuolar-type ATPase (v-ATPase) is a multimeric protein complex that regulates H+ transport across membranes and intra-cellular organelle acidification. Catabolic processes, such as endocytic degradation and autophagy, strictly rely on v-ATPase-dependent luminal acidification in lysosomes. The v-ATPase complex is expressed at high levels in the brain and its impairment triggers neuronal dysfunction and neurodegeneration. Due to their post-mitotic nature and highly specialized function and morphology, neurons display a unique vulnerability to lysosomal dyshomeostasis. Alterations in genes encoding subunits composing v-ATPase or v-ATPase-related proteins impair brain development and synaptic function in animal models and underlie genetic diseases in humans, such as encephalopathies, epilepsy, as well as neurodevelopmental, and degenerative disorders. This review presents the genetic and functional evidence linking v-ATPase subunits and accessory proteins to various brain disorders, from early-onset developmental epileptic encephalopathy to neurodegenerative diseases. We highlight the latest emerging therapeutic strategies aimed at mitigating lysosomal defects associated with v-ATPase dysfunction.

The Influence of Emo Demo on Mother’s Knowledge and Attitudes in Providing Infant Feeding

Children under two years old are a critical period in child development, characterized by rapid growth and development. One nutritional issue, stunting, can arise from inappropriate feeding practices and leads to impaired brain development, intelligence, physical growth, and metabolic function. To address this, we implemented Emotional Demonstration education on baby and child feeding schedules for young mothers. This study aimed to analyze the impact of Emotional Demonstration education on mothers’ knowledge and attitudes regarding toddler feeding practices at Dahlia Posyandu, Pabuaran Village, Bogor Regency. A Pre-Experimental One Group Pre-Test Post-Test design was employed involving 32 young women from the Bojonggede Community Health Center. Data were collected through pre-test and post-test questionnaires, analyzed using the Wilcoxon test. Results indicate a significant improvement in mothers’ knowledge following Emotional Demonstration education. However, no significant change was observed in their attitudes. In conclusion, Emotional Demonstration education effectively enhances maternal knowledge about baby and child feeding schedules but does not influence their attitudes

T2*-Relaxometry MRI to Assess Third Trimester Placental and Fetal Brain Oxygenation and Placental Characteristics in Healthy Fetuses and Fetuses With Congenital Heart Disease.

Congenital heart disease (CHD) has been linked to impaired placental and fetal brain development. Assessing the placenta and fetal brain in parallel may help further our understanding of the relationship between development of these organs. 1) Placental and fetal brain oxygenation are correlated, 2) oxygenation in these organs is reduced in CHD compared to healthy controls, and 3) placental structure is altered in CHD. Retrospective case-control. Fifty-one human fetuses with CHD (32 male; median [IQR] gestational age [GA] = 32.0 [30.9-32.9] weeks) and 30 from uncomplicated pregnancies with normal birth outcomes (18 male; median [IQR] GA = 34.5 [31.9-36.7] weeks). 1.5 T single-shot multi-echo-gradient-echo echo-planar imaging. Masking was performed using an automated nnUnet model. Mean brain and placental T2* and quantitative measures of placental texture, volume, and morphology were calculated. Spearman's correlation coefficient for determining the association between brain and placental T2*, and between brain and placental characteristics with GA. P-values for comparing brain T2*, placenta T2*, and placental characteristics between groups derived from ANOVA. Significance level P < 0.05. There was a significant positive association between placental and fetal brain T2* (⍴ = 0.46). Placental and fetal brain T2* showed a significant negative correlation with GA (placental T2* ⍴ = -0.65; fetal brain T2* ⍴ = -0.32). Both placental and fetal brain T2* values were significantly reduced in CHD, after adjusting for GA (placental T2*: control = 97 [±24] msec, CHD = 83 [±23] msec; brain T2*: control = 218 [±26] msec, CHD = 202 [±25] msec). Placental texture and morphology were also significantly altered in CHD (Texture: control = 0.84 [0.83-0.87], CHD = 0.80 [0.78-0.84]; Morphology: control = 9.9 [±2.2], CHD = 10.8 [±2.0]). For all fetuses, there was a significant positive association between placental T2* and placental texture (⍴ = 0.46). Placental and fetal brain T2* values are associated in healthy fetuses and those with CHD. Placental and fetal brain oxygenation are reduced in CHD. Placental appearance is significantly altered in CHD and shows associations with placental oxygenation, suggesting altered placental development and function may be related. 3 TECHNICAL EFFICACY: Stage 3.

Midline structures and cortical development in late-onset fetal growth restriction according to Doppler status: prospective study.

Fetuses with late-onset growth restriction (FGR) have a higher risk of suboptimal neurocognitive performance after birth. Previous studies have reported that impaired brain and cortical development can start in utero. The primary aim of this study was to report midline structure growth and cortical development in fetuses with late-onset FGR according to its severity; the secondary aim was to elucidate whether the severity of FGR, as defined by the presence of abnormal Doppler findings, plays a role in affecting brain growth and maturation. This was a prospective observational study that included fetuses with late-onset FGR (defined according to the Delphi FGR criteria) undergoing neurosonography between 32 and 34 weeks' gestation. Midline structure (corpus callosum (CC) and cerebellar vermis (CV)) length and cortical development, including the depth of the Sylvian (SF), parieto-occipital (POF) and calcarine (CF) fissures, were compared between late-onset FGR, small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) fetuses. Subgroup analysis according to the severity of FGR (normal vs abnormal fetal Doppler) was also performed. Univariate analysis was used to analyze the data. A total of 52 late-onset FGR fetuses with normal Doppler findings, 60 late-onset FGR fetuses with abnormal Doppler findings, 64 SGA fetuses and 100 AGA fetuses were included in the analysis. When comparing AGA controls with SGA fetuses, late-onset FGR fetuses with normal Doppler findings and late-onset FGR fetuses with abnormal Doppler findings, there was a progressive and significant reduction in the absolute values of the following parameters: CC length (median (interquartile range (IQR)), 43.5 (28.9-56.1) mm vs 41.9 (27.8-51.8) mm vs 38.5 (29.1-50.5) mm vs 31.7 (23.8-40.2) mm; K = 26.68; P < 0.0001), SF depth (median (IQR), 14.5 (10.7-16.8) mm vs 12.7 (9.8-15.1) mm vs 11.9 (9.1-13.4) mm vs 8.3 (6.7-10.3) mm; K = 75.82; P < 0.0001), POF depth (median (IQR), 8.6 (6.3-11.1) mm vs 8.1 (5.6-10.4) mm vs 7.8 (6.1-9.3) mm vs 6.6 (4.2-8.0) mm; K = 45.06; P < 0.0001) and CF depth (median (IQR), 9.3 (6.7-11.5) mm vs 8.2 (5.7-10.7) mm vs 7.7 (5.2-9.4) mm vs 6.3 (4.5-7.2) mm; K = 46.14; P < 0.0001). Absolute CV length was significantly higher in AGA fetuses compared with all other groups, although the same progressive pattern was not noted (median (IQR), 24.9 (17.6-29.2) mm vs 21.6 (15.2-26.1) mm vs 19.1 (13.8-25.9) mm vs 21.0 (13.5-25.8) mm; K = 16.72; P = 0.0008). When the neurosonographic variables were corrected for fetal head circumference, a significant difference in the CC length and SF, POF and CF depths, but not CV length, was observed only in late-onset FGR fetuses with abnormal Doppler findings when compared with AGA and SGA fetuses. Fetuses with late-onset FGR had shorter CC length and delayed cortical development when compared with AGA fetuses. After controlling for fetal head circumference, these differences remained significant only in late-onset FGR fetuses with abnormal Doppler. These findings support the existence of a link between brain development and impaired placental function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Characterisation of ciclesonide metabolism in human placentae across gestation

IntroductionCurrent clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development, creating a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only when converted to des-CIC by specific enzymes, including acetylcholinesterase (ACHE) and carboxylesterase 1 and 2 (CES1, CES2). Importantly, the human placenta expresses ACHE and CES, and could potentially produce des-CIC, resulting in systemic fetal exposure and GR activation in all fetal tissues. We therefore investigated CES gene expression and conversion of CIC to des-CIC in human placentae collected during the second trimester (Tri2), and at preterm and term birth. MethodsDifferential expression analysis was performed in Tri2 (n = 27), preterm (n = 34), and term (n = 40) placentae using the DESeq2 R-package. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n = 7, preterm n = 26, term n = 20) using functional assays. ResultsACHE mRNA expression was higher in Tri2 male than preterm and term male placentae only, whereas CES1 mRNA expression was higher in Tri2 than preterm or term placentae of both sexes. Conversion of CIC to des-CIC did not differ between gestational ages. DiscussionConversion of CIC to des-CIC by the human placenta may preclude its use as a novel GR-agonist in threatened preterm birth. In vivo studies are required to confirm the extent to which placental activation occurs after maternal treatment.

Intrauterine inflammation and postnatal intravenous dopamine alter the neurovascular unit in preterm newborn lambs

BackgroundIntrauterine inflammation is considered a major cause of brain injury in preterm infants, leading to long-term neurodevelopmental deficits. A potential contributor to this brain injury is dysregulation of neurovascular coupling. We have shown that intrauterine inflammation induced by intra-amniotic lipopolysaccharide (LPS) in preterm lambs, and postnatal dopamine administration, disrupts neurovascular coupling and the functional cerebral haemodynamic responses, potentially leading to impaired brain development. In this study, we aimed to characterise the structural changes of the neurovascular unit following intrauterine LPS exposure and postnatal dopamine administration in the brain of preterm lambs using cellular and molecular analyses.MethodsAt 119–120 days of gestation (term = 147 days), LPS was administered into the amniotic sac in pregnant ewes. At 126-7 days of gestation, the LPS-exposed lambs were delivered, ventilated and given either a continuous intravenous infusion of dopamine at 10 µg/kg/min or isovolumetric vehicle solution for 90 min (LPS, n = 6; LPSDA, n = 6). Control preterm lambs not exposed to LPS were also administered vehicle or dopamine (CTL, n = 9; CTLDA, n = 7). Post-mortem brain tissue was collected 3–4 h after birth for immunohistochemistry and RT-qPCR analysis of components of the neurovascular unit.ResultsLPS exposure increased vascular leakage in the presence of increased vascular density and remodelling with increased astrocyte “end feet” vessel coverage, together with downregulated mRNA levels of the tight junction proteins Claudin-1 and Occludin. Dopamine administration decreased vessel density and size, decreased endothelial glucose transporter, reduced neuronal dendritic coverage, increased cell proliferation within vessel walls, and increased pericyte vascular coverage particularly within the cortical and deep grey matter. Dopamine also downregulated VEGFA and Occludin tight junction mRNA, and upregulated dopamine receptor DRD1 and oxidative protein (NOX1, SOD3) mRNA levels. Dopamine administration following LPS exposure did not exacerbate any effects induced by LPS.ConclusionLPS exposure and dopamine administration independently alters the neurovascular unit in the preterm brain. Alterations to the neurovascular unit may predispose the developing brain to further injury.

Two thyroperoxidase-inhibiting chemicals induce shared transcriptional changes in hippocampus of developing rats

Thyroid hormone (TH) system disrupting compounds can impair brain development by perturbing TH action during critical life stages. Human exposure to TH system disrupting chemicals is therefore of great concern. To better protect humans against such chemicals, sensitive test methods that can detect effects on the developing brain are critical. Worryingly, however, current test methods are not sensitive and specific towards TH-mediated effects. To address this shortcoming, we performed RNA-sequencing of rat brains developmentally exposed to two different thyroperoxidase (TPO) inhibiting compounds, the medical drug methimazole (MMI) or the pesticide amitrole. Pregnant and lactating rats were exposed to 8 and 16 mg/kg/day(d) MMI or 25 and 50 mg/kg/d amitrole from gestational day 7 until postnatal day 16. Bulk-RNA-seq was performed on hippocampus from the 16-day old male pups. MMI and amitrole caused pronounced changes to the transcriptomes; 816 genes were differentially expressed, and 425 gene transcripts were similarly affected by both chemicals. Functional terms indicate effects from key cellular functions to changes in cell development, migration and differentiation of several cell populations. Of the total number of DEGs, 106 appeared to form a consistent transcriptional fingerprint of developmental hypothyroidism as they were similarly and dose-dependently expressed across all treatment groups. Using a filtering system, we identified 20 genes that appeared to represent the most sensitive, robust and dose-dependent markers of altered TH-mediated brain development. These markers provide inputs to the adverse outcome pathway (AOP) framework where they, in the context of linking TPO inhibiting compounds to adverse cognitive function, can be used to assess altered gene expression in the hippocampus in rat toxicity studies.

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates

Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces δ-catenin mRNA levels in cultured human neurons. δ-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking δ-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces δ-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced δ-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was partially reversed by elevating δ-catenin expression. Prenatal VPA exposure significantly reduced synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals’ USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of δ-catenin functions.

Leptin receptor reactivation restores brain function in early-life Lepr-deficient mice.

Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) is involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has crucial developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems in young adult mice, including an imbalance in energy homeostasis, alterations in melanocortin and the reproductive system and a reduction in brain mass. Given that in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early-life leptin deficiency on brain structure and memory function. Here, we demonstrate that leptin-deficient (LepOb) mice exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, in addition to neurogenesis and memory impairments in older animals. Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signalling in adulthood.

Delta like 4 regulates cerebrovascular development and endothelial integrity via DLL4-NOTCH-CLDN5 pathway and is vulnerable to neonatal hyperoxia.

The mechanisms governing brain vascularization during development remain poorly understood. A key regulator of developmental vascularization is delta like 4 (DLL4), a Notch ligand prominently expressed in endothelial cells (EC). Exposure to hyperoxia in premature infants can disrupt the development and functions of cerebral blood vessels and lead to long-term cognitive impairment. However, its role in cerebral vascular development and the impact of postnatal hyperoxia on DLL4 expression in mouse brain EC have not been explored. We determined the DLL4 expression pattern and its downstream signalling gene expression in brain EC using Dll4+/+ and Dll4+/LacZ mice. We also performed in vitro studies using human brain microvascular endothelial cells. Finally, we determined Dll4 and Cldn5 expression in mouse brain EC exposed to postnatal hyperoxia. DLL4 is expressed in various cell types, with EC being the predominant one in immature brains. Moreover, DLL4 deficiency leads to persistent abnormalities in brain microvasculature and increased vascular permeability both in vivo and in vitro. We have identified that DLL4 insufficiency compromises endothelial integrity through the NOTCH-NICD-RBPJ-CLDN5 pathway, resulting in the downregulation of the tight junction protein claudin 5 (CLDN5). Finally, exposure to neonatal hyperoxia reduces DLL4 and CLDN5 expression in developing mouse brain EC. We reveal that DLL4 is indispensable for brain vascular development and maintaining the blood-brain barrier's function and is repressed by neonatal hyperoxia. We speculate that reduced DLL4 signalling in brain EC may contribute to the impaired brain development observed in neonates exposed to hyperoxia. KEY POINTS: The role of delta like 4 (DLL4), a Notch ligand in vascular endothelial cells, in brain vascular development and functions remains unknown. We demonstrate that DLL4 is expressed at a high level during postnatal brain development in immature brains and DLL4 insufficiency leads to abnormal cerebral vasculature and increases vascular permeability both in vivo and in vitro. We identify that DLL4 regulates endothelial integrity through NOTCH-NICD-RBPJ-CLDN5 signalling. Dll4 and Cldn5 expression are decreased in mouse brain endothelial cells exposed to postnatal hyperoxia.