Mitochondrial dysfunction has been recognized as one of the three hallmark biological features of autism spectrum disorder. This study is intended to investigate the molecular mechanisms underlying prenatal psychological fear stress‑induced hippocampal mitochondrial damage in offspring. Bioinformatics analysis revealed that the calcium signaling pathway, particularly the phospholipase C beta 1(PLCβ1)- inositol 1,4,5‑trisphosphate receptor (IP3R)- voltage‑dependent anion channel 1(VDAC1) pathway, may play a key role in prenatal stress‑induced hippocampal mitochondrial damage in offspring. To validate this, we examined pathway activation in the offspring hippocampus of prenatal fear stressed rats and in corticotropin-releasing hormone (CRH; also known as CRF in rodents) overexposed SH‑SY5Y cells, along with mitochondrial calcium levels in the cells. Prenatal fear stress induced depressive-like behavior and HPA axis activation in pregnant dams, and reduced survival and growth in offspring. Placental and neonatal brain CRF levels were elevated. At the early socialization stage (Postnatal day 21–30), model offspring showed normal basal but exaggerated stress-induced HPA responses. Their hippocampus exhibited expanded MAM coverage, reduced ER-mitochondria distance, and upregulated PLCβ1, IP3R1, VDAC1 expression, along with increased GRP75‑VDAC1 co‑localization, confirming MAM remodeling at the molecular level. In vitro, CRH (20 µM for 48 h or 5–20 µM for 96 h) inhibited SH-SY5Y cell proliferation, upregulated CRH receptor 1(CRHR1), PLCβ1, VDAC1, and increased mitochondrial calcium; these effects were reversed by the CRHR1 antagonist CP376395 or PLCβ1 knockdown. Furthermore, the MCU inhibitor DS16570511 partially reversed CRH‑induced mitochondrial calcium elevation and proliferation inhibition, suggesting that mitochondrial calcium overload contributes to the proliferation inhibition. Collectively, these results suggest that prenatal fear stress may, via the CRF-CRFR1 axis, influence the PLCβ1-IP3R-VDAC1 pathway, inducing MAM remodeling and mitochondrial calcium overload, thereby contributing to offspring hippocampal neuronal damage.

PURPOSE:Postpartum depression (PPD) is common, yet its pathophysiology remains unclear and reliable early biomarkers are lacking. METHODS:Mendelian randomization, bioinformatics analyses, and animal experiments were integrated. A prenatal stress-induced rat model of PPD was established. Depressive-like behaviors were assessed using the open field and forced swim tests, and brain histopathology was examined by hematoxylin-eosin staining. Serum HPA-axis hormones, ALDOC, lactic acid, and Th1/Th2 cytokines were measured by ELISA. ALDOC was analyzed by Western blot. T-bet and GATA3 mRNA expression in peripheral blood mononuclear cells was detected by qRT-PCR, and the T-bet/GATA3 ratio was calculated. RESULTS:Sixteen overlapping genes were identified, suggesting the involvement of Th cells in PPD and highlighting ALDOC as a potential candidate biomarker associated with Th1-related immune alterations. PPD rats showed depressive-like behaviors and HPA-axis activation, with increased CRH and ACTH but unchanged CORT levels. ALDOC and lactic acid levels were significantly increased, accompanied by elevated Th1-related cytokines (IFN-γ, TNF-α, and IL-1β) and an increased IFN-γ/IL-4 ratio, whereas Th2-related cytokines showed no significant changes. Consistently, T-bet expression increased, GATA3 expression decreased, and the T-bet/GATA3 ratio was elevated, further supporting a possible Th1-skewed immune response. Brain histopathology showed cellular damage and reduced cell density. In the PFC, ALDOC upregulation was accompanied by increased pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), which may suggest coordinated central neuroinflammation and peripheral immune imbalance. CONCLUSIONS:ALDOC may contribute to PPD pathogenesis by promoting Th1 polarization and inflammatory activation.

BackgroundPre-eclampsia (PE) is a specific type of gestational hypertension associated with high morbidity and mortality. This study aims to identify mitochondria-related regulatory molecules in PE through bioinformatics analysis, which will help pinpoint potential therapeutic targets and elucidate potential mechanisms of action in PE.MethodsThis study integrated three PE placental transcriptome datasets (n = 103/157) to screen for mitochondrial-related hub genes. Key gene screening was performed by combining three machine learning algorithms—Random Forest, LASSO, and SVM—followed by the construction of a diagnostic neural network model. Additionally, single-cell sequencing data were utilized to analyze the cellular expression patterns of candidate genes in the placenta. To further elucidate the underlying mechanisms, functional validation was conducted both in PE rat model and in vitro using HTR-8 cells, supplemented by multi-omics correlation analysis.ResultsMachine learning analysis identified three key genes (GCLM, SNAP23, RHOT2), and the diagnostic model built upon them demonstrated excellent performance (training set AUC = 0.907; validation set AUC = 0.875). Single-cell analysis revealed the expression patterns of these genes within specific cell subtypes, consistent with the transcriptional features of trophoblast cell populations. In the PE rat model, downregulation of GCLM and SNAP23 and upregulation of RHOT2 were significantly correlated with clinical phenotypes such as hypertension and proteinuria, as well as changes in placental inflammatory factor levels (TNF-α, IL-1β, IL-6). Specifically, SNAP23 and GCLM showed negative correlations with inflammatory cytokines but positive correlations with fetal weight, while RHOT2 expression positively correlated with disease severity. In vitro experiments confirmed that overexpression of SNAP23 restored mitochondrial membrane potential, reduced reactive oxygen species levels, and suppressed cytokine release in lipopolysaccharide (LPS)-treated HTR-8 cells. Multi-omics analysis further indicated that these genes are involved in immune dysregulation and mitochondrial dysfunction during PE progression.ConclusionThis study establishes GCLM, SNAP23, and RHOT2 as mechanistically important biomarkers for preeclampsia. Among them, modulation of SNAP23 shows therapeutic potential in alleviating mitochondrial damage and inflammatory responses in PE, providing a new direction for intervention strategies.

This study reveals that maternal stress during pregnancy (MSDP) increases anxiety susceptibility in male offspring through Corticotropin-Releasing Factor Receptor 1 (CRFR1)-mediated time-specific hyperactivation of medial habenula (MHb) cholinergic projections to the interpeduncular nucleus (IPN). Male MSDP offspring exhibited heightened anxiety-like behaviors following 30 minutes of acute restraint stress (ARS). In vivo calcium imaging showed excessive activation of MHb ChAT-IPN projections specifically during the late phase (25-30 min) of ARS in MSDP offspring. Chemogenetic and optogenetic manipulations confirmed that this time-specific circuit hyperactivation drives anxiety susceptibility. Mechanistically, MSDP upregulated CRF/CRFR1 in the MHb. Pharmacological experiments demonstrated that CRFR1 activation directly enhances circuit activity. CRFR1 overexpression recapitulated MSDP phenotypes by increasing circuit activity and anxiety, while CRFR1 antagonism reversed both circuit hyperactivation and anxiety behaviors. Chemogenetic circuit inhibition blocked CRFR1 overexpression-induced anxiety, confirming that CRFR1 drives anxiety through this pathway.

OBJECTIVES:To investigate the impact of prenatal fear stress on placental amino acid transport and emotion and cognition development in offspring rats. METHODS:Thirty pregnant Wistar rats were randomized equally into control and fear stress (induced using an observational foot shock model) groups. In each group, placental and serum samples were collected from 6 dams on gestational day 20, and the remaining rats delivered naturally and the offspring rats were raised under the same conditions until 8 weeks of age. Emotional and cognitive outcomes of the offspring rats were assessed with behavioral tests, and placental structure was examined using HE staining. Bioinformatics analysis was used to identify differentially expressed placental transporter genes under fear stress. The expressions of system A and system L amino acid transporters, along with other specialized transporters, were detected using qRT-PCR and Western blotting. Fetal serum amino acid concentrations were determined by HPLC. The correlations between fetal amino acid levels and behavioral outcomes of the offspring rats were analyzed. RESULTS:The dams with fear stress showed reduced open-field activity and increased freezing behavior with significantly decreased placental weight, fetal weight, and fetal-to-placental ratio. Bioinformatics analysis revealed 28 differentially expressed transporter genes involved mainly in amino acid transport. In the fear stress group, fetal serum amino acid levels were significantly lowered and Slc38a1, Slc43a1, Slc43a2, Slc7a8, Slc6a6, Slc1a1 and Slc6a9 mRNA and protein expressions were all downregulated. The offspring rats in fear stress group exhibited decreased novel object preference and spontaneous alternation with reduced open arm exploration and increased immobility in emotional tests. Lower early-life amino acid levels was found to correlate with impaired adult cognition. CONCLUSIONS:Prenatal fear stress in rats impairs placental amino acid transporter expression and reduces fetal serum amino acid levels, potentially contributing to long-term cognitive deficits in the offspring rats.

This study explores the diagnostic value of dopamine system imaging characteristics in children with autism spectrum disorder. Functional magnetic resonance data from 551 children in the Autism Brain Imaging Data Exchange database were analyzed, focusing on six dopamine-related brain regions as regions of interest. Functional connectivity between these ROIs and across the whole brain was assessed. Machine learning techniques then evaluated the ability of the dopamine system's imaging features to predict autism spectrum disorder. Functional connectivity was significantly higher in autism spectrum disorder children between the ventral tegmental area and substantia nigra, prefrontal cortex, nucleus accumbens, and between the substantia nigra and hypothalamus compared to typically developing children. Additionally, clustering methods identified two autism spectrum disorder subtypes, achieving over 0.8 accuracy. Subtype 1 showed higher stereotyped behavior scores than subtype 2 in both genders, with subtype-specific functional connectivity differences between male and female autism spectrum disorder groups. These findings suggest that abnormal functional connectivity in the dopamine system serves as a diagnostic biomarker for autism spectrum disorder and can support clinical decision-making and personalized treatment optimization.

The female reproductive system is highly complex, making it essential for applied research and translational medicine to accurately model its intricate physiological functions or develop strategies for restoring them. However, significant structural and functional differences between human and animal models, along with the limitations of static 2D cell culture technologies, underscore the need for more dynamic and sophisticated in vitro platforms, as well as in vivo therapies. These advancements are critical for deepening our understanding of reproductive biology and supporting clinical applications. Recent advancements in additive manufacturing technology have opened new frontiers in the study of the female reproductive system. By introducing diverse preclinical models and expanding the range of potential applications, this field has reached new heights, with the rapidly evolving research paradigm reshaping the scientific landscape. This review aims to summarize the growing body of evidence surrounding bioengineering strategies, platforms, and therapies in female reproductive medicine, with the goal of advancing our understanding of female reproductive biology and providing new avenues for fertility restoration. Specifically, we will examine the historical development, technological innovations, and scientific research related to the creation of 3D-engineered tissues for reconstructing the female reproductive system.Impact StatementThis review aims to summarize the growing body of evidence surrounding bioengineering strategies, platforms, and therapies in female reproductive medicine, with the goal of advancing our understanding of female reproductive biology and providing new avenues for fertility restoration. Specifically, the historical development, technological innovations, and scientific research related to the 3D-engineered tissues for reconstructing the female reproductive system were summarized. This review would help the audience, especially bioengineers who study the female reproductive system disease, as well as obstetricians and gynecologists, understand the possible application of additive manufacturing and acquire the strategies to engineer the female reproductive system in vitro.

OBJECTIVE:Prenatal stress has been proven to be associated with dysbiosis of the gut microbiota. Despite the established phenomenon that psychological stress can be transmitted to offspring and the ability of maternal gut microbiota to colonize the offspring's gut through vertical transmission, the intricate relationships linking cross-generational depression with the microbiome remain poorly understood. METHODS:We utilized combined fear stress stimuli to establish a pregnancy psychological stress (PPS) rat model, in which offspring exhibited trans-generational depression-like behavior. The relationship between vertical transmission of the gut microbiome, intergenerational effects, and psychological stress in offspring was investigated using microbiology and metabolomics. RESULTS:We demonstrated that the vertical transmission of co-altered species from PPS dams to their puberty offspring was strongly associated with dysbiosis of the gut microbiota in the offspring. In terms of microbial function, both PPS dams and their offspring exhibited upregulation of glycine, glutamate, and serine metabolism in fecal samples, as revealed by untargeted metabolomics. Additionally, this microbial trans-generational effect was reflected in the prefrontal cortical tissue of PPS offspring, where serine in the pathway and its interconverted glycine was significantly increased. Furthermore, the co-altered species and metabolites of the pathway formed a highly correlated module with disordered inflammatory factors and neurotransmitters in the prefrontal cortex tissue of PPS offspring. This indicates that the microbiome plays a significant role in prefrontal cortex neuroinflammation as well as neurotransmitter disorders in depression-like offspring. CONCLUSIONS:Our findings highlight the gut microbiome as a plausible mediator of prenatal stress effects on offspring neurodevelopment, though further mechanistic validation is required.

Glioma is one of the most common malignancies of the central nervous system. The therapeutic effect has not been satisfactory despite advances in comprehensive treatment techniques. Our previous studies have found that triptolide inhibits glioma proliferation through the ROS/JNK pathway, but in-depth mechanisms need to be explored. Recent studies have confirmed that miRNAs may function as tumor suppressor genes or oncogenes and be involved in cancer development and progression. In this study, we found that let-7b-5p expression levels closely correlated with WHO grades and overall survival in patients in tumor glioma-CGGA-mRNAseq-325, and the upregulation of let-7b-5p can inhibit the proliferation and induce apoptosis of glioma cells. Functionally, upregulation of let-7b-5p increased the inhibitory effect on cell viability and colony formation caused by triptolide and promoted the apoptosis rate of triptolide-treated U251 cells. Conversely, downregulation of let-7b-5p had the opposite effect, indicating that let-7b-5p is a tumor suppressor miRNA in glioma cells. Moreover, target prediction, luciferase reporter assays and functional experiments revealed that IGF1R was a direct target of let-7b-5p. In addition, upregulation of IGF1R reversed the triptolide-regulated inhibition of cell viability but promoted glioma cell apoptosis and activated the ROS/JNK signaling pathway induced by triptolide. The results obtained in vivo experiments substantiated those from the in vitro experiments. In summary, the current study provides evidence that triptolide inhibits the growth of glioma cells by regulating the let-7b-5p-IGF1R-ROS/JNK axis in vitro and in vivo. These findings may provide new ideas and potential targets for molecularly targeted therapies for comprehensive glioma treatment.

Maternal stress experienced during prenatal development is recognized as a significant risk factor for neurodevelopmental and neuropsychiatric disorders across the offspring’s lifespan. The placental barrier serves a crucial function in safeguarding the fetus from detrimental exposures during gestation. However, previous investigations have not yet comprehensively elucidated the extensive connections between prenatal stress and the expression of placental proteins. In this study, we used iTRAQ-based quantitative proteomics to elucidate the placental adaptive mechanisms of pregnant rats in response to fear-induced stress. Our results showed that during pregnancy, exposure to fear-induced stress led to a pathological hypercoagulable state in the mother’s body. Placental circulation was also disrupted, significantly reducing placental efficiency and blood oxygen saturation in newborn rats. Proteomic analyses showed that most of the DEPs were annotated to the PI3K-Akt and ECM-receptor interaction signaling pathway. In addition, the expressions of CDC37, HSP90β, AKT, p-AKT and p-mTOR were down-regulated significantly in the placenta. Our results demonstrated that prenatal fear-induced stress led to inhibition of the cellular signal transduction of placental PI3K/AKT/mTOR, which affected biological processes such as rRNA processing, translation, protein folding, protein stability, and oxygen transport in the placenta. These abnormalities in biological functions could potentially damage the barrier function of the placenta and thereby result in abnormal development in the offspring.

OBJECTIVE:To investigate the effects of umbilical moxibustion therapy on phobic behavior and the contents of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) in different brain regions of the stress-model rats and explore the potential mechanism of umbilical moxibustion on phobic behavior.METHODS:Among 50 Wistar male rats, 45 rates were selected and randomly divided into a control group, a model group and an umbilical moxibustion group, 15 rats in each one; and the rest 5 rats were used for preparing the model of electric shock. The bystander electroshock method was adopted to prepare phobic stress model in the model group and the umbilical moxibustion group. After modeling, the intervention with umbilical moxibustion started in the umbilical moxibustion group, in which, the ginger-isolated moxibustion was applied at "Shenque" (CV 8), once daily, 2 cones for 20 min each time, for consecutively 21 days. After modeling and intervention completed, the rats in each group were subjected to the open field test to evaluate the state of fear. After intervention, the Morris water maze test and fear conditioning test were performed to evaluate the changes in learning and memory ability and the state of fear. Using high performance liquid chromatography (HPLC), the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were determined.RESULTS:Compared with the control group, the horizontal and vertical activity scores were lower (P<0.01), the number of stool particles was increased (P<0.01), the escape latency was prolonged (P<0.01), the times of target quadrant were reduced (P<0.01), and the freezing time was prolonged (P<0.05) in the rats of the model group. The horizontal and vertical activity scores were increased (P<0.05), the number of stool particles was reduced (P<0.05), the escape latency was shortened (P<0.05, P<0.01), the times of target quadrant were increased (P<0.05), and the freezing time was shortened (P<0.05) in the rats of the umbilical moxibustion group when compared with the model group. The trend search strategy was adopted in the control group and the umbilical moxibustion group, while the random search strategy was used in rats of the model group. Compared with the control group, the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were reduced (P<0.01) in the model group. In the umbilical moxibustion group, the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were increased (P<0.05, P<0.01) when compared with the model group.CONCLUSION:Umbilical moxibustion can effectively relieve the state of fear and learning and memory impairment of phobic stress model rats, which may be related to the up-regulation of contents of brain neurotransmitters, i.e. NE, DA, and 5-HT.

Background: Multiple sclerosis (MS) is a chronic debilitating disease characterized by inflammatory demyelination of the central nervous system. Grey matter (GM) lesions have been shown to be closely related to MS motor deficits and cognitive impairment. In this study, GM lesion-related genes for diagnosis and immune status in MS were investigated.Methods: Gene Expression Omnibus (GEO) databases were utilized to analyze RNA-seq data for GM lesions in MS. Differentially expressed genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) algorithm and protein-protein interaction (PPI) network were used to screen related gene modules and candidate genes. The abundance of immune cell infiltration was analyzed by the CIBERSORT algorithm. Candidate genes with strong correlation with immune cell types were determined to be hub genes. A diagnosis model of nomogram was constructed based on the hub genes. Gene set enrichment analysis (GSEA) was performed to identify the biological functions of hub genes. Finally, an MS mouse model was induced to verify the expression levels of immune hub genes.Results: Nine genes were identified by WGCNA, LASSO regression and PPI network. The infiltration of immune cells was significantly different between the MS and control groups. Four genes were identified as GM lesion-related hub genes. A reliable prediction model was established by nomogram and verified by calibration, decision curve analysis and receiver operating characteristic curves. GSEA indicated that the hub genes were mainly enriched in cell adhesion molecules, cytokine-cytokine receptor interaction and the JAK-STAT signaling pathway, etc.Conclusions: TLR9, CCL5, CXCL8 and PDGFRB were identified as potential biomarkers for GM injury in MS. The effectively predicted diagnosis model will provide guidance for therapeutic intervention of MS.

Abstract The proper development of the placental vascular system is a crucial factor in ensuring fetal health. m6A modification is a key pathophysiological mechanism in placental vascular development. However, the specific mechanism by which m6A influences placental vascular development remains unclear. Here, we explored the role of 21 m6A regulators in placental development based on the Gene Expression Omnibus (GEO) database. Following a series of machine learning techniques, METTL3 was recognized as the pivotal m6A regulator. We subsequently employed consensus clustering analysis to delineate two distinct m6A isoforms, and investigated their correlation with immune cells. Further, through weighted gene co-expression network analysis (WGCNA) coupled with correlation analysis, we pinpointed METTL3-associated placental development genes. These genes were notably enriched in immune-related categories. Furthermore, we uncovered immune-related differentially expressed genes that were associated with differentially expressed m6A regulators. Additionally, we performed an immune infiltration analysis to gain a deeper understanding of how these genes interact with immune cells. Ultimately, to validate our findings, we carried out animal experiments. In conclusion, our study found that targeting METTL3 could affect placental vascular development, which may provide guidance for the clinical treatment of placental-like diseases.

目的 探究体质指数(BMI)与老年期痴呆患者全因死亡率的剂量-反应关系,为改善老年期痴呆患者的预后提供循证依据.方法 通过检索 Pubmed、Embase、the Cochrane Library、Web of Science、Scopus、PsycInfo、CINAHL、中国知识基础设施工程(CNKI)、万方数据知识服务平台(Wanfang Database)、中国生物医学文献库(CBM)和维普(VIP)数据库,搜索BMI与老年期痴呆患者全因死亡率关系的队列研究,检索时间均为建库至2022年3月26日.两名研究者独立筛选文献、提取相关信息并使用文献质量评价量表(NOS)评价文献方法学质量.使用Stata 16.0进行Meta分析.结果 共纳入5项研究,15 866例老年期痴呆患者,全因死亡人数为4 313例.与低体重的老年期痴呆患者相比,正常体重(HR=0.56,95％CI:0.51～0.62)与超重及肥胖(HR=0.44,95％CI:0.40～0.48)组的全因死亡风险更低.BMI与老年期痴呆患者全因死亡率为线性关系(x2=37.36,P＜0.01),BMI每增加2 kg/m2,全因死亡风险降低12％.结论 "肥胖悖论"存在于BMI与老年期痴呆患者全因死亡率的关系中,BMI的增加可能是老年期痴呆患者全因死亡的保护因素,应重点关注低体重及营养不良的老年期痴呆患者的预后情况.

Fear, a negative emotion triggered by dangerous stimuli, can lead to psychiatric disorders such as phobias, anxiety disorders, and depression. Investigating the neural circuitry underlying congenital fear can offer insights into the pathophysiological mechanisms of related psychiatric conditions. Research on innate fear primarily centers on the response mechanisms to various sensory signals, including olfactory, visual, and auditory stimuli. Different types of fear signal inputs are regulated by distinct neural circuits. The neural circuits of the main and accessory olfactory systems receive and process olfactory stimuli, mediating defensive responses like freezing. Escape behaviors elicited by visual stimuli are primarily regulated through the superior colliculus and hypothalamic projection circuits. And auditory stimuli-induced responses, including escape, are mainly mediated through auditory cortex projection circuits. As for auditory stimuli, they are mainly triggered by the auditory cortical projection circuits, leading to escape and other responses. In this article, we review the research progress on the neural circuits of innate fear defensive behaviors in animals from different sensory systems, especially the projection circuits of olfactory, visual, and auditory systems, to provide references for the mechanistic study of related mental disorders.

AimsIntegrating bioinformatics and experimental validation to explore the mechanisms of inflammaging in the Brain. MethodAfter dividing the GSE11882 dataset into aged and young groups, we identified co-expressed differentially expressed genes (DEGs) in different brain regions. Enrichment analysis revealed that the co-expressed DEGs were mainly associated with inflammatory responses. Subsequently, we identified 12 DEGs that were related to the inflammatory response and used the DGIdb website for drug prediction. By using both the least absolute shrinkage and selection operator (LASSO) and random forest (RF), four biomarkers were screened and an artificial neural network (ANN) was developed for diagnosis. Subsequently, the biomarkers were validated through animal studies. Then we utilized AgeAnno to investigate the roles of biomarkers at the single cell level. Next, a consensus clustering approach was used to classify the aging samples and perform differential analysis to identify inflammatory response-related genes. After conducting a weighted gene co-expression network analysis (WGCNA), we identified the genes that are correlated with both four brain regions and aging. Wayne diagrams were used to identify seven inflammaging-related genes in different brain regions. Finally, we performed immuno-infiltration analysis and identified macrophage module genes. Key findingsInflammaging may be a major mechanism of brain aging, and the regulation of macrophages by CX3CL1 may play a role in the development of inflammaging. SignificanceIn summary, targeting CX3CL1 can potentially delay inflammaging and immunosenescence in the brain.

Mental disorders (MD), such as anxiety, depression, and cognitive impairment, are very common during pregnancy and predispose to adverse pregnancy outcomes; however, the underlying mechanisms are still under intense investigation. Although the most common RNA modification in epigenetics, N6-methyladenosine (m6A) has been widely studied, its role in MD has not been investigated. Here, we observed that fat mass and obesity-associated protein (FTO) are downregulated in the hippocampus of pregnant rats with MD induced by fear stress and demonstrated that FTO participates in and regulates MD induced by fear stress. In addition, we identified four genes with anomalous modifications and expression (double aberrant genes) that were directly regulated by FTO, namely Angpt2, Fgf10, Rpl21, and Adcy7. Furthermore, we found that these genes might induce MD by regulating the PI3K/Akt and Rap1 signaling pathways. It appears that FTO-mediated m6A modification is a key regulatory mechanism in MD caused by fear stress during pregnancy.

Background: Sleep curtailment is a serious problem in many societies. Clinical evidence has shown that sleep deprivation is associated with mood dysregulation, formation of false memory, cardio-metabolic risk factors and outcomes, inflammatory disease risk, and all-cause mortality. The affective disorder dysregulation caused by insufficient sleep has become an increasingly serious health problem. However, to date, not much attention has been paid to the mild affective dysregulation caused by insufficient sleep, and there is no clear and standard therapeutic method to treat it. The Xiaoyao Pill is a classic Chinese medicinal formula, with the effect of dispersing stagnated hepatoqi, invigorating the spleen, and nourishing the blood. Therefore, it is most commonly used to treat gynecological diseases in China. In the present study, the effects of the Xiaoyao Pill on affective dysregulation of sleep-deprived mice and its underlying molecular mechanisms were investigated. Methods: Forty adult female mice were used in the present study. The sleep deprivation model was established by improving the multi-platform water environment method. After 7 consecutive days of sleep deprivation, the mice were administrated low (LXYP, 0.32mg/kg) and high (HXYP, 0.64 mg/kg) doses of the Xiaoyao Pill for two weeks. Then, the body weight, behavioral deficits, and histopathology were evaluated. Meanwhile, the expression of c-fos protein and the concentrations of monoamine neurotransmitters in the hippocampus and prefrontal cortex were determined after two weeks of treatment. Results: Xiaoyao Pill treatment significantly increased body weight and sucrose consumption and decreased the irritability scores of the sleep-deprived mice. Meanwhile, Xiaoyao Pill treatment prevented brain injury and inhibited the expression of c-fos protein in the hippocampus and prefrontal cortex. In addition, HXYP treatment significantly upregulated the levels of NE in the hippocampus and prefrontal cortex (p < 0.01). LXYP treatment significantly up-regulated the levels of 5-HT in the prefrontal cortex. Meanwhile, both HXYP and LXYP treatment significantly up-regulated the levels of DA in the prefrontal cortex (p < 0.05 or p < 0.01) of sleep-deprived mice. Conclusion: The present study demonstrates that Xiaoyao Pill treatment prevented the behavioral deficits of mice induced by sleep deprivation by promoting the recovery of brain tissue injury and up-regulating the levels of NE, 5-HT, and DA in the brain tissue.

目的:探讨孕期丙戊酸(VPA)暴露对28日龄子代自闭症大鼠肠道不同部位菌群的影响,为VPA自闭症大鼠模型肠道菌群相关研究提供参考.方法:选取受孕0.5 d孕鼠随机分为正常组和模型组,仔鼠延续孕鼠分组.模型组受孕12.5 d时按600 mg/kg腹腔注射丙戊酸钠溶液,通过行为学评价仔鼠模型是否构建成功,正常组腹腔注射无菌生理盐水并正常喂养至分娩,其仔鼠为正常组.对建模成功的雄性仔鼠采用随机数字表法从每组中分别选取4只进行四个肠段内容物取材.采用16S rRNA基因的高通量扩增测序对仔鼠十二指肠、空肠、结肠和直肠部位的肠道内容物菌群样本进行微生物多样性分析.结果:与正常组相比,模型组仔鼠旷场实验评分和社交时间均明显降低(P<0.05),而刻板行为评分升高(P<0.05).正常组十二指肠和空肠部位的菌群丰富度和多样性均降低且分布一致(P<0.05),结肠部位和直肠部位菌群分布一致(R2=0.478,P=0.001).模型组空肠部位的丰富度和多样性降低(P<0.05),不同部位无明显分布差异.与正常组相比,模型组十二指肠部位(R2=0.254,P=0.001)、空肠部位(R2=0.187,P=0.001)和直肠部位(R2=0.175,P=0.021)菌群相似性存在差异,其中十二指肠部位组间差异最大.与正常组相比,在属水平,模型组十二指肠部位Allobaculum属相对丰度提高,乳酸菌属、Romboutsia属、双歧杆菌属和Dubosiella属相对丰度降低;直肠部位乳酸菌属和Prevotellaceae_NK3B31相对丰度增加,Allobaculum属、Dubosiella属和Rom?boutsia属相对丰度降低.结论:VPA自闭症模型大鼠不同部位的肠道菌群出现了不同程度的紊乱,孕期VPA暴露破坏了其子代十二指肠和空肠部位的菌群特异性,这可能是菌群改变的原因.