Postnatal Day Research Articles

Exposure to a 0.9-GHz electromagnetic field on postnatal days 21-45 may trigger the renin-angiotensin system in male rat: a histological and biochemical study.

The aim of this study was to examine the relationship between the renin-angiotensin system (RAS) and histological and biochemical changes occurring in the kidney tissue of male rats exposed to a 0.9GHz electromagnetic field (EMF). Twelve male rats aged 21 days were randomly assigned to control (C-Gr) and EMF (EMF-Gr) groups. No procedure was performed on C-Gr, while the EMF-Gr rats were exposed to a 0.9GHz EMF on postnatal days 21-45 (one hour a day for 25 days). Tissues were removed at the end of the experiment and evaluated using biochemical, and histopathological methods. Increased kidney tissue volume and weight and total body weight were determined in the group exposed to EMF. Lipid peroxidation, glutathione, catalase, and superoxide dismutase also increased in the kidney tissue of the EMF-Gr rats. Histopathological evaluation revealed cortical/medullary bleeding/obstruction and widespread fibrosis, dilatation, vacuolization, and degeneration in distal and proximal tubules, decreased and atypical parietal cells, and degeneration in epithelial cells. Additionally, dilated and degenerated glomeruli in the Malpighian body, Bowman's membrane degeneration and degeneration in the vascular pole, podocyte, pedicel and mesangial cells were also observed. As a result of exposure to EMF, oxidative stress, tissue volume and weight increased, and histopathological changes caused the formation of a pathway that triggers RAS in kidney tissues. In conclusion, long-term exposure to 0.9GHz EMF can activate the renin-angiotensin system in the rat kidney, and we think that such activation may be associated with structural, histopathological, and biochemical changes occurring in renal tissue.

Development of an Open-Source Dataset of Flat-Mounted Images for the Murine Oxygen-Induced Retinopathy Model of Ischemic Retinopathy.

To describe an open-source dataset of flat-mounted retinal images and vessel segmentations from mice subject to the oxygen-induced retinopathy (OIR) model. Flat-mounted retinal images from mice killed at postnatal days 12 (P12), P17, and P25 used in prior OIR studies were compiled. Mice subjected to normoxic conditions were killed at P12, P17, and P25, and their retinas were flat-mounted for imaging. Major blood vessels from the OIR images were manually segmented by four graders (JSC, HKR, KBL, JM), with cross-validation performed to ensure similar grading. Overall, 1170 images were included in this dataset. Of these images, 111 were of normoxic mice retina, and 1048 were mice subject to OIR. The majority of images from OIR mice were obtained at P17. The 50 images obtained from an external dataset, OIRSeg, did not have age labels. All images were manually segmented and used in the training or testing of a previously published deep learning algorithm. This is the first open-source dataset of original and segmented flat-mounted retinal images. The dataset has potential applications for expanding the development of generalizable and larger-scale artificial intelligence and analyses for OIR. This dataset is published online and publicly available at dx.doi.org/10.6084/m9.figshare.23690973. This open access dataset serves as a source of raw data for future research involving big data and artificial intelligence research concerning oxygen-induced retinopathy.

Juvenile toxicity of atropine sulfate eye drops in young rats

Objectives This study was to investigate the effects of atropine sulphate eye drops (ASED)on the development of partial systems in young rats and their toxic reactions following repeated eye-drop administration over a period of 40 days. Methods SD rats of 20 days old were randomly assigned to control group, 0.01, 0.02, and 0.04% ASED groups, with 60 females and 25 males per group. ASED was given by eye drops from PND21 onwards and normal saline was given in the control group at 10 μL/eye once a day for 40 days, in both right and left eyes. Rats of ASED groups were instilled with eye drops at the 10 μL/day per eye, from postnatal day 21 (PND21) to PND60 for 40 consecutive days. The clinical observation, body weight, food intake, physical development, physiological development, reproductive development, ophthalmic examination, intraocular pressure, and axial length of the rats were examined during the study period. Results ASED at concentrations of 0.01, 0.02, 0.04%, dose levels of 0.002, 0.004, 0.008 mg/day per rat, had no toxicological effects on the clinical observation, body weight, food intake, physical development, physiological development, reproductive development, ophthalmic examination, intraocular pressure, and axial length in rats. Conclusion The no-observed-adverse-effect-level (NOAEL) of ASED in young SD rats equivalent to human over 2 years old was 0.008 mg/day at a concentration of 0.4 mg/mL.

Shear Wave Optical Coherence Elastography and Structural Analysis of the Postnatal Mouse Cornea Through Development

ABSTRACTThe cornea is a transparent lens at the forefront of the eye, serving as a structural barrier that protects the eye and provides the majority of the eye's refractive power. In this study, we utilized the postnatal mouse eye to characterize corneal structure and biomechanics. Between postnatal day (PN) 6 and PN24, we observed that elastic wave speeds are highest at PN6, gradually decrease through PN24, and then start to rise in adulthood (6 months). We found that corneal thickness is uncoupled from elastic wave speed and that the content and organization of the cornea primarily influence its mechanical properties. To the best of our knowledge, this work is the first detailed assessment of the postnatal mouse cornea's structure and biomechanics and warrants further investigation into the dynamic properties of the postnatal eye.

Characteristics of gut microbiota of premature infants in the early postnatal period and their relationship with intraventricular hemorrhage

BackgroundStudies have shown correlations between gut microbiota and neurocognitive function, but little was known about the early postnatal gut microbiota and intraventricular hemorrhage (IVH). We aimed to explore the characteristics of gut microbiota in premature infants and their relationship with IVH, further exploring potential therapeutic targets.MethodsPremature infants delivered at Peking University First Hospital from February 2023 to August 2023 were recruited as a cohort. Feces samples were collected on postnatal days 1, 3, and 5. Premature infants were divided into normal, mild IVH, and severe IVH groups based on cranial ultrasound. 16S rRNA amplicon sequencing technology was used to determine the fecal microbiota, and the results were analyzed.ResultsThirty-eight premature infants were enrolled. There was a significant difference in alpha and beta diversity among the three groups. The relative abundance of E. coli and A. muciniphila was different among the three groups. Further random forest analysis indicated that S. lutetiensis, L. mirabilis, and N. macacae can effectively distinguish premature infants with IVH. Finally, the phylogenetic investigation of communities by reconstruction of unobserved states2 (PICRUSt2) functional gene analysis predicted significant differences in energy metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, and membrane transport between normal and severe IVH groups.ConclusionsThe gut microbiota in the early postnatal period of premature infants is closely associated with the IVH status. As age increases, the differences in gut microbiota of premature infants with different degrees of IVH continue to increase, and the trend of changes with severity of IVH becomes more and more obvious. E. coli, A. muciniphila, S. lutetiensis, L. mirabilis, N. macacae, G. haemolysans, and S. oralis can effectively distinguish between IVH infants and normal premature infants. The results indicate that gut microbiota is expected to provide effective therapeutic targets for the diagnosis and treatment of IVH.

Tendon-targeted knockout of collagen XI disrupts patellar and Achilles tendon structure and mechanical properties during murine postnatal development

ABSTRACT Background Collagen XI is a fibril-forming collagen typically associated with type II collagen tissues but is also expressed in type I collagen-rich tendons, especially during development. We previously showed that tendon-targeted (Scx-Cre) Col11a1 knockout mice have smaller tendons in adulthood with aberrant fibril structure and impaired mechanical properties. However, the manifestation of this phenotype is not clearly understood. Therefore, our objective is to define the spatiotemporal roles of collagen XI in tendon structure-function during postnatal development. Given the high expression of collagen XI during embryonic development, we hypothesized that collagen XI knockout leads to the deposition of weakened extracellular matrix during early postnatal timepoints, disrupting the establishment of tendon structure and function. Methods Patellar and Achilles tendons from postnatal (P) days 0, 10, 20, and 30 tendon-targeted scleraxis-Cre heterozygous and homozygous Col11a1 knockout mice were evaluated for morphology, nuclear organization, fibril morphology, mechanical properties, and gene expression. Results At P0, there were no differences in tendon length or fibril diameter of either tendon. By P10, striking structural and functional differences emerged, with collagen XI deficiency resulting in increased tendon length, a heterogeneous and larger diameter population of fibrils, and inferior mechanical properties in both patellar and Achilles tendons. Differences increased in magnitude through P30, supporting our hypothesis that impaired structure-function during postnatal development may drive tendon lengthening and reduced mechanical properties. Conclusions Though collagen XI is a quantitatively minor component of the tendon extracellular matrix, these results highlight the critical role of collagen XI in the acquisition of tendon structure-function.

Altered purine and pentose phosphate pathway metabolism in uteroplacental insufficiency-induced intrauterine growth restriction offspring rats impairs intestinal function

BackgroundThis study aimed to identify metabolic alterations in the small intestine of newborn rats with intrauterine growth restriction (IUGR), a condition linked to intestinal dysfunction. MethodsPregnant Sprague Dawley rats underwent bilateral uterine artery ligation on gestational day 17 to induce intrauterine growth restriction or sham surgery. Rat pups were delivered spontaneously on gestational day 22. Small intestine tissues were collected on postnatal days 0 and 7 from offspring. Liquid chromatography-mass spectrometry analysis was performed to investigate untargeted metabolomic profiles. Western blot analysis assessed protein expression of key regulators. ResultsNewborn rats with intrauterine growth restriction exhibited distinct small intestine metabolic profiles compared to controls on postnatal day 0. Notably, significant alterations were observed in purine metabolism, the pentose phosphate pathway, and related pathways. Western blot analysis revealed a decrease expression in transketolase, a key enzyme of the pentose phosphate pathway, suggesting impaired activity of the pentose phosphate pathway. Additionally, decreased expression of tight junction proteins ZO-1 and occludin indicated compromised intestinal barrier function in rats with intrauterine growth restriction. Similar metabolic disruptions persisted on postnatal day 7, with further reductions in tricarboxylic acid cycle intermediates and folate biosynthesis precursors. Interestingly, lysyl-glycine, a protein synthesis marker, was elevated in rats with intrauterine growth restriction. ConclusionsOur findings reveal a distinct metabolic signature in the small intestine of neonatal rats with intrauterine growth restriction, characterized by disruptions in the pentose phosphate pathway, purine metabolism, and energy production pathways. These novel insights suggest potential mechanisms underlying IUGR-associated intestinal dysfunction and impaired growth.

Effects of serotonergic manipulation in the brainstem and hypothalamus of overnourished rats during lactation

Previous studies suggest that being overweight and obese is capable of altering brain function during critical periods due to the higher plasticity of the brain during development. However, more literature still needs to be on the immediate effect of overnutrition and serotonin modulation in brain areas. In this study, we aimed to evaluate the effects of serotoninergic manipulation on oxidative stress and pro-inflammatory markers in the brainstem and hypothalamus of overnourished rats. The fluoxetine treatment was performed from postnatal day 3 (PND3) to postnatal day 21 (PND21) to evaluate mitochondrial function, oxidative balance, and the mRNA levels of monoaminergic molecules such as serotonin and dopamine, pro-inflammatory cytokines, and BDNF. Neonatal overnutrition induces molecular and biochemical changes in the brainstem and hypothalamus. These nutritional disturbances during lactation dysregulate energy balance and cellular redox, inducing oxidative stress. Conversely, modulation of the serotoninergic system through pharmacological use of fluoxetine was able to reverse the deleterious effects of overnutrition during lactation, enabling better brain development and delaying the development of pathologies and oxidative stress.

Cranial bone microarchitecture in a mouse model for syndromic craniosynostosis.

Crouzon syndrome is a congenital craniofacial disorder caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2). It is characterized by the premature fusion of cranial sutures, leading to a brachycephalic head shape, and midfacial hypoplasia. The aim of this study was to investigate the effect of the FGFR2 mutation on the microarchitecture of cranial bones at different stages of postnatal skull development, using the FGFR2C342Y mouse model. Apart from craniosynostosis, this model shows cranial bone abnormalities. High-resolution synchrotron microtomography images of the frontal and parietal bone were acquired for both FGFR2C342Y/+ (Crouzon, heterozygous mutant) and FGFR2+/+ (control, wild-type) mice at five ages (postnatal days 1, 3, 7, 14 and 21, n = 6 each). Morphometric measurements were determined for cortical bone porosity: osteocyte lacunae and canals. General linear model to assess the effect of age, anatomical location and genotype was carried out for each morphometric measurement. Histological analysis was performed to validate the findings. In both groups (Crouzon and wild-type), statistical difference in bone volume fraction, average canal volume, lacunar number density, lacunar volume density and canal volume density was found at most age points, with the frontal bone generally showing higher porosity and fewer lacunae. Frontal bone showed differences between the Crouzon and wild-type groups in terms of lacunar morphometry (average lacunar volume, lacunar number density and lacunar volume density) with larger, less dense lacunae around the postnatal age of P7-P14. Histological analysis of bone showed marked differences in frontal bone only. These findings provide a better understanding of the pathogenesis of Crouzon syndrome and will contribute to computational models that predict postoperative changes with the aim to improve surgical outcome.

Impaired brainstem auditory evoked potentials after in utero exposure to high dose paracetamol exposure

Paracetamol is an analgesic and antipyretic medication regarded as the safest over-the-counter pain and fever relief option during pregnancy. Paracetamol and its metabolites are known to reach the developing fetus through direct placental transfer and can cross the blood brain barrier. Several recent, large-scale epidemiologic studies suggest that in utero paracetamol exposure can increase the risk of neurodevelopmental conditions, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and developmental delay (DD). Since auditory processing deficits are a common feature of ASD, we hypothesized that animals exposed to paracetamol in utero will have impaired auditory brainstem function. We investigated this hypothesis by recording and analyzing click-evoked auditory brainstem responses (ABR) at postnatal day 21 and 29 in Sprague-Dawley rats. In utero exposure to high dose paracetamol exposure had no impact on body or brain weight. However, high dose paracetamol exposure did significantly delay ear opening and resulted in elevated ABR thresholds, and longer wave and interwave latencies. These changes in wave latency extended to the highest click intensity tested but were most severe near threshold. This data suggests that development and function of the auditory brainstem may be impacted by high dose paracetamol exposure and that simple, non-invasive tests of auditory function have utility as an early screening tool for neurodevelopmental disorders.

Modified neuroimmune processes and emotional behaviour in weaned and late adolescent male and female mice born via caesarean section

Elective and emergency Caesarean section (C-section) procedures are on the rise, exceeding the recommended guidelines by the World Health Organization. Higher morbidities and long-term health conditions are correlated to C-section deliveries, including neurodevelopmental disorders. During C-section delivery, newborns are not exposed to the vaginal commensal flora, which impedes the early establishment of the gut microbiota. The latter is essential for adequate neuro-immune processes to take place during infancy. In this study, we used a validated model of mice born by C-section (CSD), which mimics clinical observations of dysregulated gut microbiota. Animals were either born naturally or by CSD, before being adopted by dams who underwent delivery within the 12 preceding hours. Behavioural analyses were conducted at post-natal day (PND) 21 and 55. Our results indicate that animals born by C-section present significantly higher body weight in late (PND40-P53) but not early adolescence (PND21-P27), compared to animals born by vaginal delivery (VD). Male animals delivered by C-section presented significantly lower exploration time of the novel arm in the Y Maze test at PND55. However, at PND21, abnormal social interaction was witnessed in male and female animals born by CSD, with significantly decreased time spent interacting during the social interaction test. At both PND21 and PND55, animals from both sexes born by C-section presented significantly decreased time spent in the open arm of the Elevated Plus Maze test, compared to control animals. We then measured the expression of genes associated to neuroimmune interactions (microglia phenotype), inflammatory mediators and lipids in several brain structures of VD and CSD mice at PND21 and PND55. At weaning, animals born by CSD presented altered microglia, inflammatory and lipid metabolism signatures, with increased expression of Cd36, Csf1r and Tnfα in different brain regions of males, but not in females. At PND64, Csf1r, Tmem119 as well as C3ar1 were significantly increased in males born by C-section, but not in females. In males born by vaginal delivery, the expression of Cd36 at PND64 was correlated to anxiety at PND55, whilst a correlation between the expression of Clec7a and the number of head dippings in the elevated plus maze was also noted in males born by CSD. Altogether, our study shows altered emotional behaviour in animals delivered by CSD, which is likely explained by underlying neuro-inflammatory processes in different brain regions. Our work further supports the long-term consequences of CSD on brain health.

Development and validation of the prediction model based on autophagy-associated genes in bronchopulmonary dysplasia

Background Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease among preterm infants. Owing to the limitations in current diagnostic methods, developing a predictive model for BPD is crucial. Methods Using 243 autophagy-associated genes and dataset GSE32472, differential expression of autophagy-associated genes was identified at postnatal days 5, 14, and 28 between BPD patients and controls. LASSO and multivariate logistic regression analyses were performed to screen for diagnostic prediction genes. Receiver Operating Characteristic, Harrell’s concordance index, and decision curve analysis (DCA) were used to evaluate the diagnostic prediction model in GSE32472 and GSE220135. A BPD mouse model was constructed and qRT-PCR and Western blot were used to verify gene expression in lung tissue. Results Based on p < 0.05, we constructed a diagnostic prediction model for BPD using WIPI1, TOMM70A, BAG3, and PRKCQ. For the training database, the model’s C-index and Area under Curve were both 0.941, and a high applicability value was demonstrated by the DCA curve. These outcomes were also confirmed in the validation cohort GSE220135, demonstrating the superior diagnostic prediction capability of our approach. In addition, significant variations in immune cell infiltration were observed between BPD patients and controls. According to the results of qRT-PCR, BPD model mice had significantly lower expression levels of WIPI1, TOMM70A, BAG3, and PRKCQ than controls. Conclusions We constructed and validated a diagnostic prediction model for BPD based on WIPI1, TOMM70A, BAG3, and PRKCQ. These four genes may influence BPD development by regulating immune responses and immune cells.

Right ventricular volume overload reboots cardiomyocyte proliferation via immune responses

BackgroundRight ventricular volume overload (RVVO) is one of the most important hemodynamic characteristics in children with congenital heart disease (CHD) and heart failure, and cardiomyocyte (CM) proliferation is one of the most vital factors for improving cardiac performance. However, whether and how RVVO reboots CM proliferation remains elusive.Methods and resultsWe first created a neonatal RVVO mouse model via abdominal aorta and inferior vena cava-fistula microsurgery at postnatal day 7 (P7), the edge of CM proliferation window. We subsequently performed bulk RNA-seq, single cell RNA-seq/flow cytometry, and immunofluorescence staining on the right ventricles (RV) of RVVO mice at P14/P21, defined as prepubertal stage, revealing that RVVO temporarily reboots prepubertal CM proliferation via immune responses.ConclusionsIn considering the importance of RVVO and CM proliferation, this study may bring an opportunity to create a novel paradigm to treat pediatric CHDs or heart failure.Graphical

Developmental expression patterns of gonadal hormone receptors in arcuate kisspeptin and GABA neurons of the postnatal female mouse.

The arcuate nucleus of the hypothalamus (ARC) is central in the neuronal regulation of fertility and reproduction through translating gonadal steroid hormone cues into the GnRH signaling pathway in the brain. Evidence suggests that circulating gonadal steroids play an important role in modulating female reproduction via kisspeptin and γ-aminobutyric acid (GABA) neurons in the ARC in both development and adulthood. However, the temporal onset of these ARC neurons' sensitivity to gonadal steroids is unknown. Using RNAscope® in situ hybridization, we localized androgen receptor (Ar), estrogen receptor alpha (Esr1), and progesterone receptor (Pgr) expression in ARC kisspeptin or GABA neurons of female mice at postnatal day (P)4, P8, P12, P20, and P60. A probe that binds to kiss1 mRNA or vGat mRNA was used to produce signal in kisspeptin or GABA neurons, respectively. In adult, we identified that the vast majority of kisspeptin neurons coexpressed Esr1 (95%) and Pgr (93%), while a smaller proportion coexpressed Ar (66%). Similar proportions of Ar- or Esr1-positive kisspeptin neurons were seen from P4, suggesting that kisspeptin neurons develop adult-like sensitivity to androgen and estrogen in early postnatal life. In contrast, the proportion of Pgr-positive kisspeptin cells in early life was significantly lower than in adulthood, suggesting that progesterone sensitivity develops over time in the ARC kisspeptin population. ARC GABA neurons also colocalized with Ar (70%), Esr1 (64%), or Pgr (85%) in adulthood. GABA neurons continuously expressed Esr1 or Pgr from the postnatal stages to adulthood, while the proportion of Ar-positive GABA neurons gradually increased from P4 (24%) to P20 (59%). These results suggest that while ARC GABA neurons can respond to circulating estrogen and progesterone from early postnatal ages, this same population may become more sensitive to androgens during later postnatal life. Our findings identified the expression patterns of Ar, Esr1, and Pgr by ARC kisspeptin and GABA neurons during early postnatal life. These data provide the understanding for the hormone sensitivity of these populations during early postnatal life, the critical time for the formation and regulation of female reproductive physiology.Esr1 (95%) and Pgr (93%), while a smaller proportion coexpressed Ar (66%). Similar proportions of Ar- or Esr1-positive kisspeptin neurons were seen from P4, suggesting that kisspeptin neurons develop adult-like sensitivity to androgen and estrogen in early postnatal life. In contrast, the proportion of Pgr-positive kisspeptin cells in early life was significantly lower than in adulthood, suggesting that progesterone sensitivity develops over time in the ARC kisspeptin population. ARC GABA neurons also colocalized with Ar (70%), Esr1 (64%), or Pgr (85%) in adulthood. GABA neurons continuously expressed Esr1 or Pgr from the postnatal stages to adulthood, while the proportion of Ar-positive GABA neurons gradually increased from P4 (24%) to P20 (59%). These results suggest that while ARC GABA neurons can respond to circulating estrogen and progesterone from early postnatal ages, this same population may become more sensitive to androgens during later postnatal life. Our findings identified the expression patterns of Ar, Esr1, and Pgr by ARC kisspeptin and GABA neurons during early postnatal life. These data provide the understanding for the hormone sensitivity of these populations during early postnatal life, the critical time for the formation and regulation of female reproductive physiology.

From Nutritional Patterns to Behavior: High-Fat Diet Influences on Inhibitory Control, Brain Gene Expression, and Metabolomics in Rats.

Impulsive and compulsive behaviors are associated with inhibitory control deficits. Diet plays a pivotal role in normal development, impacting both physiology and behavior. However, the specific effects of a high-fat diet (HFD) on inhibitory control have not received adequate attention. This study aimed to explore how exposure to a HFD from postnatal day (PND) 33 to PND77 affects impulsive and compulsive behaviors. The experiment involved 40 Wistar rats subjected to HFD or chow diets. Several tasks were employed to assess behavior, including variable delay to signal (VDS), five choice serial reaction time task (5-CSRTT), delay discounting task (DDT), and rodent gambling task (rGT). Genetic analyses were performed on the frontal cortex, and metabolomics and fatty acid profiles were examined by using stool samples collected on PND298. Our results showed that the HFD group exhibited increased motor impulsive behaviors while not affecting cognitive impulsivity. Surprisingly, reduced impulsive decision-making was shown in the HFD group. Furthermore, abnormal brain plasticity and dopamine gene regulation were shown in the frontal cortex, while metabolomics revealed abnormal fatty acid levels.

The Shh-p38-NFATc1 signaling pathway is essential for osteoclastogenesis during tooth eruption

Tooth eruption, a critical stage in tooth development, is related to osteoclastogenesis. Intraperitoneal injection of Shh agonists into neonatal mice promoted tooth eruption at postnatal day (PN) 15, whereas treatment with the Shh inhibitor (LDE225) suppressed this process. When RAW264.7 osteoclast precursor cells were treated with RANKL, NFATc1 translocated from the cytoplasm to the nucleus and induced cell differentiation into TRAP+ osteoclasts; this process was activated by Shh but inhibited by LDE225. Treating RAW264.7 cells with the p38 inhibitor, BIRB796, also inhibited NFATc1 nuclear localization. p-p38 expression in the alveolar bone of PN3 and PN5 mice was decreased by treatment with LDE225, and RAW264.7 cell differentiation was reduced by BIRB796, regardless of treatment with Shh. Furthermore, Shh activated p38 signaling pathway in RAW264.7 cells, while p38 phosphorylation was reduced by LDE225, which ultimately inhibited osteoclast precursor differentiation. Therefore, we concluded that Shh promotes osteoclast precursor differentiation via the p38-NFATc1 signaling pathway.

Effect of histone demethylase KDM5B on long-term cognitive impairment in neonatal rats induced by sevoflurane

IntroductionWhether repeated inhalation of sevoflurane during the neonatal period causes long-term learning and memory impairments in humans is unclear. Some recent investigations have indicated that general anesthesia drugs affect histone methylation modification and may further affect learning and memory ability. This study aimed to explore the role and mechanism of histone methylation in long-term cognitive dysfunction caused by repeated inhalation of sevoflurane during the neonatal period.MethodsNeonatal SD rats were assigned into three groups. Sevoflurane group and sevoflurane +AS8351 group were exposed to 2% sevoflurane for 4 h on postnatal day 7 (P7), day 14 (P7) and day 21 (P21), and the control group was inhaled the air oxygen mixture at the same time. From postnatal day 22 to 36, rats in the +AS8351 group were treated with AS8351 while those in the Sevoflurane group and control group were treated with normal saline. Half of the rats were carried out Y-maze, Morris water maze (MWM), western blot and transmission electron microscope at P37, and the remaining rats were fed to P97 for the same experiment.ResultsNeonatal sevoflurane exposure affected histone demethylase expression in hippocampus, changed histone methylation levels, Down-regulated synapse-associated protein expression, impaired synaptic plasticity and long-term cognitive dysfunction and KDM5B inhibitors partially restored the negative reaction caused by sevoflurane exposure.DiscussionIn conclusion, KDM5B inhibitor can save the long-term learning and memory impairment caused by sevoflurane exposure in neonatal period by inhibiting KDM5B activity.

Dysregulation of the mTOR-FMRP pathway and synapticplasticity in an environmental model of ASD.

Autism Spectrum Disorder (ASD) is caused by genetic, epigenetic, and environmental factors. Mutations in the human FMR1 gene, encoding the Fragile X Messenger Ribonucleoprotein 1 (FMRP), cause the most common monogenic form of ASD, the Fragile X Syndrome (FXS). This study explored the interaction between the FMR1 gene and a viral-like infection as an environmental insult, focusing on the impact on core autistic-like behaviors and the mGluR1/5-mTOR pathway. Pregnant heterozygous Fmr1 mouse females were exposed to maternal immune activation (MIA), by injecting the immunostimulant Poly (I:C) at the embryonic stage 12.5, simulating viral infections. Subsequently, ASD-like behaviors were analyzed in the adult offspring, at 8-10 weeks of age. MIA exposure in wild-type mice led to ASD-like behaviors in the adult offspring. These effects were specifically confined tothe intrauterine infection, as immune activation at later stages, namely puberty (Pubertal Immune Activation, PIA) at post-natal day 35 or adulthood (Adult Immune Activation, AIA) at post-natal day 56, did not alter adult behavior. Importantly, combining the Fmr1 mutation with MIA exposure did not intensify core autistic-like behaviors, suggesting an occlusion effect. Mechanistically, MIA provided a strong activation of the mGluR1/5-mTOR pathway, leading to increased LTP and downregulation of FMRP specifically in the hippocampus. Finally, FMRP modulates mTOR activity via TSC2. These findings further strengthen the key role of the mGluR1/5-mTOR pathway in causing ASD-like core symptoms.

Agathisflavone Modulates Reactive Gliosis After Trauma and Increases the Neuroblast Population at the Subventricular Zone

Background: Reactive astrogliosis and microgliosis are coordinated responses to CNS insults and are pathological hallmarks of traumatic brain injury (TBI). In these conditions, persistent reactive gliosis can impede tissue repopulation and limit neurogenesis. Thus, modulating this phenomenon has been increasingly recognized as potential therapeutic approach. Methods: In this study, we investigated the potential of the flavonoid agathisflavone to modulate astroglial and microglial injury responses and promote neurogenesis in the subventricular zone (SVZ) neurogenic niche. Agathisflavone, or the vehicle in controls, was administered directly into the lateral ventricles in postnatal day (P)8-10 mice by twice daily intracerebroventricular (ICV) injections for 3 days, and brains were examined at P11. Results: In the controls, ICV injection caused glial reactivity along the needle track, characterised immunohistochemically by increased astrocyte expression of glial fibrillary protein (GFAP) and the number of Iba-1+ microglia at the lesion site. Treatment with agathisflavone decreased GFAP expression, reduced both astrocyte reactivity and the number of Iba-1+ microglia at the core of the lesion site and the penumbra, and induced a 2-fold increase on the ratio of anti-inflammatory CD206+ to pro-inflammatory CD16/32+ microglia. Notably, agathisflavone increased the population of neuroblasts (GFAP+ type B cells) in all SVZ microdomains by up to double, without significantly increasing the number of neuronal progenitors (DCX+). Conclusions: Although future studies should investigate the underlying molecular mechanisms driving agathisflavone effects on microglial polarization and neurogenesis at different timepoints, these data indicate that agathisflavone could be a potential adjuvant treatment for TBI or central nervous system disorders that have reactive gliosis as a common feature.

The Homeobox Transcription Factor Cux1 Coordinates Postnatal Epithelial Developmental Timing but Is Dispensable for Lung Organogenesis and Regeneration.

Lung epithelial progenitors use a complex network of known and predicted transcriptional regulators to influence early lung development. Here, we evaluate the function of one predicted regulator, Cux1, that we identified from transcriptional regulatory analysis of the SOX9+ distal lung progenitor network. We generated a new Cux1-floxed mouse model and created an epithelial-specific knockout of Cux1 using Shh-Cre (Cux1ShhCre-LOF). Postnatal Cux1ShhCre-LOF animals recapitulated key skin phenotypic features found in prior constitutive Cux1 knockout animals, confirming functionality of our new floxed model. Postnatal Cux1ShhCre-LOF mice displayed subtle alveolar simplification and a transient delay in alveologenesis and alveolar type 1 cell development without persistent lung phenotypes. Cux1ShhCre-LOF mice developed failure to thrive in their second and third weeks of life due to delayed ileal maturation, which similarly resolves by postnatal day 35. Finally, we challenged Cux1ShhCre-LOF with influenza-mediated lung injury to demonstrate that Cux1ShhCre-LOF mice undergo productive alveolar regeneration that is indistinguishable from WT animals. Together, these findings indicate that epithelial-specific loss of Cux1 leads to transient developmental delays in the skin, lung, and intestine without defects in definitive organogenesis. We conclude that Cux1 function is required for temporal optimization of developmental maturation in multiple organs with implications for susceptibility windows in developmental disease pathogenesis.