This study aimed to clarify the neuroprotective effect of Acer truncatum Bunge seed oil (ASO) and its interactions with the gut microbiota in transgenic mice with 5 × Familial Alzheimer's disease (5 × FAD). The AD-transgenic mice were fed with standard diet supplemented with 4% ASO from one to six months of age. The result show that ASO intervention can alleviate learning and memory impairment, enhance motor coordination and endurance, and reduce Aβ deposition in the brains. It also inhibit the proliferation of microglia and astrocytes, decrease the levels of IL-1β, IL-6, and TNF-α in the hippocampus and serum. Then, ASO could increase the Chao1 index and Shannon index, alter the gut microbiota composition, specifically, enhance the growth of gut bacteria correlated with the production of SCFAs, including Ruminococcaceae, Butyricicoccus, Sutterella and others, particularly those related to butyrate production. Additionally, ASO can increase the concentrations of SCFAs in fresh feces and serum, particularly butyric acid. ASO could primarily modulate the biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, and sphingolipids metabolism in serum. At the same time, Fecal microbiota transplantation (FMT) could reduce Aβ deposition, enhance learning and memory. Finally, Supplementation of sodium Buty also mitigate learning and memory impairments. This study highlights the gut microbiota might be a potential therapeutic target for AD and provides a scientific foundation for developing novel pharmaceuticals or nutraceuticals.

Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with elevated gastrointestinal oxidative stress. Although probiotics can mitigate oxidative stress in the gut microbiota, their specific antioxidant mechanisms in ASD remain unclear. In this study, rats were administered Limosilactobacillus fermentum PY-1, a bacterial strain isolated from traditional fermented foods and characterized by robust antioxidant activity, for one month to achieve gut colonization. Results showed that this intervention significantly ameliorated autism-like behaviors including social interaction deficits and repetitive actions, while concurrently reducing oxidative stress markers and inflammation, and enhancing intestinal barrier integrity. Histopathological analysis further revealed that liver damage was also attenuated. Notably, the treatment induced a marked reshaping of the composition of gut microbiota, characterized by the enrichment of beneficial taxa including Adlercreutzia, Christensenellaceae, Turicibacter, and Ruminococcus, while suppressing pathogenic bacteria like Erysipelatoclostridium. Metabolomic profiling validated the upregulation of indole-3-acetate, a metabolite with neuroprotective properties, alongside reduced levels of compounds linked to cognitive impairment, specifically asymmetric dimethylarginine and homogentisic acid. These findings underscore the therapeutic potential of Limosilactobacillus fermentum PY-1 in modulating gut-brain axis dynamics for reducing oxidative stress, and offer a novel strategy for ASD intervention.

Ischemic stroke ranks as the second leading cause of global mortality. The limited time for effective thrombolytic treatment has prompted the exploration of alternative prevention approaches. Eucommia ulmoides (E. ulmoides) Oliv. bark has shown multiple pharmacological effects, including neuroprotection, anti-inflammation and autophagy modulation. This study aims to elucidate the neuroprotective effects of water extract of E. ulmoides (WEU) supplementation in a middle cerebral artery occlusion (MCAO) mouse model and to further explore the underlying molecular mechanisms. Seven bioactive compounds in WEU—aucubin, chlorogenic acid, geniposidic acid, quercetin, protocatechuic acid, betulin and pinoresinol diglucoside—were identified using HPLC-MS. Our results showed that WEU supplementation significantly decreased infarct volume and ameliorated neurological dysfunction in mice following MCAO/reperfusion (MCAO/R) injury. Furthermore, the administration of WEU significantly attenuated microglia activation induced by cortical ischemia in mice and inhibited the production of pro-inflammatory mediators, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Importantly, in contrast with the vehicle group, the protein expression levels of Toll-like receptor 4 (TLR4), phospho-p38 (p-p38) and nuclear factor kappa B (NF-κB) were reduced in the WEU group. Therefore, this present study provides evidence that E. ulmoides improves neurological behaviors by suppressing neuroinflammation and inhibiting the activation of the TLR4/ p38 MAPK and NF-κB pathways in mice after ischemia, which indicates that E.ulmoides is a promising candidate for alleviating gray matter ischemic change.

Acer truncatum is a unique tree species indigenous to northern China. The Chinese government approved the utilization of Acer truncatum leaves as a raw material for food. These leaves have been traditionally used in Inner Mongolia as a form of anti-aging medicine. However, the specific mechanism responsible for the anti-aging properties of Acer truncatum leaves remains unidentified. In this study, an aqueous extract of Acer truncatum leaves (AAL) was prepared and analyzed using UPLC-QTOF-MS/MS. the UPLC-MS/MS profile detected a total of 989 compounds in AAL, with 5 compounds of high concentration selected for quantitative analysis via UPLC-QTOF-MS/MS employing the internal standard method. Subsequently, Drosophila melanogaster served as a model organism to assess the impact of AAL on the lifespan and locomotor abilities. The results demonstrated a significant extension of the lifespan of D. melanogaster in response to AAL supplementation. Moreover, the addition of AAL to the medium enhanced the physical and anti-stress abilities of D. melanogaster, while preserving the integrity of their intestinal barrier. Gut microbiome analysis revealed that AAL administration positively influenced the structure and composition of gut microbes in aged D. melanogaster, notably reducing the prevalence of detrimental bacteria like Enterococcus and increasing beneficial bacteria such as Lactococcus. Metabolomic analysis annotated 30 potentially significant metabolites in AAL that contribute to delaying aging, predominantly associated with Phenylalanine metabolic pathways. Through a comprehensive multi-omics correlation analysis, a strong link was established between gut microbiota and metabolites following AAL treatment, highlighting how AAL prolongs the lifespan of D. melanogaster by modulating metabolic pathways via the gut microbiota. This study offers valuable insights into the anti-aging properties of AAL, emphasizing its ability to delay aging primarily through the regulation of metabolic pathways mediated by the gut microbiota and sets a foundation for the potential future application of AAL as a functional food.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which effective treatment options are still lacking. Xanthoceras sorbifolium oil (XSO), which contains rich nervonic acid and unsaturated fatty acids, shows anti-AD potential. However, its underlying mechanisms remain unclear. This study investigated the neuroprotective effects of XSO and its interactions with the gut microbiota in transgenic mice with 5×Familial Alzheimer's disease (5×FAD). The AD-transgenic mice were fed a standard diet supplemented with 5% XSO from 3 to 6 months of age. Behavioral tests revealed that XSO intervention markedly improved learning and memory in AD mice. Immunofluorescence staining further revealed that XSO-administration effectively reduced β-amyloid (Aβ) deposition in the hippocampus of AD mice. Moreover, XSO supplementation alleviated neuroinflammation by suppressing microglial over-activation and decreasing the pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in the hippocampus of AD mice. In addition, XSO intervention modulated the gut microbiota structure and enhanced microbial richness and diversity in AD mice. Serum metabolomics showed that XSO intervention primarily modulated the unsaturated fatty acid metabolism. Subsequently, a fecal microbiota transplantation (FMT) experiment showed that FMT from XSO-administrated mice regulated the gut microbiota and unsaturated fatty acid metabolism, reduced Aβ deposition, and improved learning and memory in AD mice. This study highlights the gut microbiota might be a potential therapeutic target for AD and demonstrates that XSO holds promise as a natural agent for the treatment of AD and related neurodegenerative diseases.

In recent decades, the incidence of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) has risen continuously, significantly impairing patients’ quality of life while imposing growing economic and social burdens. Traditional treatments exhibit limited effectiveness in halting disease progression. Non-invasive neuromodulation techniques, utilizing electromagnetic fields, light, or ultrasound, have emerged as promising strategies to modulate neural activity and alleviate symptoms. However, achieving spatially precise and targeted neuromodulation remains challenging. The integration of stimuli-responsive nanoplatforms addresses this limitation. These nanoplatforms, engineered to respond to specific stimuli, can deliver therapeutic agents to the desired brain regions. By enabling controlled and localized drug release, they facilitate precise neuromodulation. Despite their potential, several hurdles must be overcome, including the optimization of nanoplatform design, elucidating complex nanoplatform-brain interactions, and ensuring long-term safety and efficacy. Nonetheless, combining non-invasive neuromodulation with stimuli-responsive nanoplatforms holds revolutionary potential for neurodegenerative disease therapy, offering targeted, personalized treatments that may halt or slow disease progression. This comprehensive review explores the therapeutic potential and applications of non-invasive neuromodulation assisted by exogenous stimuli-responsive nanoplatforms for AD and PD therapy.

Diet-related maternal obesity has been implicated in neurodevelopmental disorders in progeny. Although the precise mechanisms and effective interventions remain uncertain, our research elucidates some of these complexities. We established that a prenatal high-fat diet triggered maternal immune activation (MIA), marked by elevated serum lipopolysaccharide levels and inflammatory-cytokine overproduction, which dysregulated the maternal tryptophan metabolism promoting the accumulation of neurotoxic kynurenine metabolites in the embryonic brain. Interventions aimed at mitigating MIA or blocking the kynurenine pathway effectively rescued the male mice social performance. Furthermore, excessive kynurenine metabolites initiated oxidative stress response causing neuronal migration deficits in the fetal neocortex, an effect that was mitigated by administering the glutathione synthesis precursor N-Acetylcysteine, underscoring the central role of maternal immune-metabolic homeostasis in male mice behavioral outcomes. Collectively, our study accentuated the profound influence of maternal diet-induced immuno-metabolic dysregulation on fetal brain development and provided the preventive strategies for addressing neurodevelopmental disorders.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication and repetitive behaviours. The gut microbiota plays a pivotal role in the etiology of autism spectrum disorder, and its modulation represents a promising therapeutic strategy to alleviate autism-like behaviours. The purpose of this study was to evaluate the effects of Acer truncatum oil (ASO) on autism-like behaviours in an autistic mouse model, BTBR T+ Itpr3tf/J (BTBR) mice, and to assess the related molecular mechanisms. The juvenile BTBR mice were administered with ASO for 36 consecutive days by gavage. Behaviour tests showed that ASO remarkably alleviated the autism-like behaviours of BTBR mice. In addition, the supplementation with ASO promoted the maturation of oligodendrocytes and suppressed microglial over-activation, and reduced the IL-1β and TNF-α levels in the hippocampus of the BTBR mice. Oral ASO administration also improved gut microbiota imbalances in BTBR mice by reducing the abundance of the harmful bacterium Mycoplasma and the ratio of Firmicutes to Bacteroidetes. Additionally, ASO decreased the expression of TNF-α and IL-1β, and increased the levels of ZO-1, claudin-1 and occludin in the intestine, thereby reducing intestinal inflammation and repairing intestinal barrier damage. Our results indicate that ASO has great potential in the treatment of autism, providing theoretical basis for the development of autism drugs.

Background Alzheimer’s disease (AD), which is a chronic neurodegenerative disorder, is marked by the progressive deteriorations in learning and memory capabilities. The microbiota-gut-brain axis has come to be regarded as a crucial element in relation to the pathogenesis as well as the treatment of AD. Eucommiae cortex polysaccharides (EPs), being among the most plentiful substances present in the Eucommiae cortex, show the potential to exert immunomodulatory and neuroprotective function. However, whether EPs are protective against AD and their mechanism of action remain to be investigated Objectives We hypothesize that EPs can regulate brain glutamine metabolism through gut microbiota and the butyric acid metabolized by them, improve oxidative stress and autophagy in the brain, and thus alleviate AD. Methods In the present study, we used EPs (0.25 % w/w in food) and fecal microbiota transplantation, as well as butyrate supplementation (0.1 M in water), to intervene in AD mice. Multi-omics were used to determine the mechanism by which EPs improve AD-related learning and memory impairments. Results Our results suggest that EPs, functioning as a prebiotic, alleviated learning and memory impairments in AD mice. Mechanistically, EPs are able to reshape the gut microbiota, promote the growth of gut microbiota involved in short-chain fatty acid metabolism, particularly butyrate-producing microbes. The butyrate produced by these microbes improves the brain microenvironment by modulating oxidative stress and autophagy mediated by brain glutamate metabolism, improving learning and memory impairments in AD mice, and inhibiting the formation and deposition of beta-amyloid proteins. Fecal microbiota transplantation (FMT) and butyrate supplementation further confirm this conclusion. Conclusions Our results highlighted that EPs can alleviate learning and memory impairments in AD with a gut microbiota-dependent manner and that butyric acid metabolized by butyric acid-metabolizing bacteria in the gut plays a central role in regulating brain glutamine metabolism to improve brain microenvironmental homeostasis. Meanwhile, the present study provides new insights into the treatment of AD with natural products.

Evidence suggests that Lactiplantibacillus plantarum (LP) can positively influence gut microbiota, subsequently affecting brain function via the gut-brain axis. However, the oral administration of LP may subject it to damage from gastric acid. To address this issue, a microencapsulation system was developed to protect LP and enhance its viability in the gastrointestinal tract. In the study, zein-microencapsulated LP (MLP) was prepared using the phase separation method. We found that the optimal conditions to encapsulate LP (9 log CFU/mL) were a zein concentration of 10 mg/mL and a zein-to-bacteria mass ratio of 5:1. Scanning electron microscopy and dynamic light scattering analysis demonstrated that MLP exhibited a microstructure with an approximate diameter of 4 mu m. Findings also revealed that microencapsulation markedly improved the in vitro survival rate of LP compared to free cells and allowed for controlled release. Subsequent in vivo studies in mice showed that this encapsulation not only boosted the colonization of LP but also ameliorated the imbalance of gut microbiota associated with depression. An analysis of the intestinal microbiota in mice identified 13 genera that exhibited significant shifts in abundance due to the depressive states. The administration of MLP reversed these microbial changes, underscoring its therapeutic potential. Additionally, the study examined the expression of pro-inflammatory cytokines. The administrated MLP was found to reverse the inflammation in both the intestine and hippocampus of mice with depression. Behavioral assessments in mouse models corroborated the efficacy of MLP in preventing depression, positioning it as a promising daily supplement.

Rationale: Consumption of a high-fat diet (HFD) has been implicated in cognitive deficits and gastrointestinal dysfunction in humans, with the gut microbiota emerging as a pivotal mediator of these diet-associated pathologies. The introduction of plant-based polysaccharides into the diet as a therapeutic strategy to alleviate such conditions is gaining attention. Nevertheless, the mechanistic paradigm by which polysaccharides modulate the gut microbiota remains largely undefined. This study investigated the mechanisms of action of Eucommiae cortex polysaccharides (EPs) in mitigating gut dysbiosis and examined their contribution to rectifying diet-related cognitive decline. Methods: Initially, we employed fecal microbiota transplantation (FMT) and gut microbiota depletion to verify the causative role of changes in the gut microbiota induced by HFD in synapse engulfment-dependent cognitive impairments. Subsequently, colonization of the gut of chow-fed mice with Escherichia coli (E. E. coli) ) from HFD mice confirmed that inhibition of Proteobacteria by EPs was a necessary prerequisite for alleviating HFD-induced cognitive impairments. Finally, supplementation of HFD mice with butyrate and treatment of EPs mice with GW9662 demonstrated that EPs inhibited the expansion of Proteobacteria in the colon of HFD mice by reshaping the interactions between the gut microbiota and colonocytes. Results: Findings from FMT and antibiotic treatments demonstrated that HFD-induced cognitive impairments pertaining to neuronal spine loss were contingent on gut microbial composition. Association analysis revealed strong associations between bacterial taxa belonging to the phylum Proteobacteria and cognitive performance in mice. Further, introducing E. coli from HFD-fed mice into standard diet-fed mice underscored the integral role of Proteobacteria proliferation in triggering excessive synaptic engulfment-related cognitive deficits in HFD mice. Crucially, EPs effectively counteracted the bloom of Proteobacteria and subsequent neuroinflammatory responses mediated by microglia, essential for cognitive improvement in HFD-fed mice. Mechanistic insights revealed that EPs promoted the production of bacteria-derived butyrate, thereby ameliorating HFD-induced colonic mitochondrial dysfunction and reshaping colonocyte metabolism. This adjustment curtailed the availability of growth substrates for facultative anaerobes, which in turn limited the uncontrolled expansion of Proteobacteria. . Conclusions: Our study elucidates that colonocyte metabolic disturbances, which promote Proteobacteria overgrowth, are a likely cause of HFD-induced cognitive deficits. Furthermore, dietary supplementation with EPs can rectify behavioral dysfunctions associated with HFD by modifying gut microbiota-colonocyte interactions. These insights contribute to the broader understanding of the modulatory effects of plant prebiotics on the microbiota-gut-brain axis and suggest a potential therapeutic avenue for diet-associated cognitive dysfunction.

基于网络药理学及小鼠免疫抑制模型方法探讨杜仲叶免疫调节的作用机制.该研究通过TCMSP数据库筛选出3个杜仲叶活性成分,Uniprot和Swiss Target数据库预测到306个相关联的靶基因,经与OMIM、Gene-Cards数据库对比,获得105个免疫失调与杜仲叶的交集基因,通过Cytoscape3.8.2软件构建"活性成分-基因"网络.利用STRING数据库进行蛋白质-蛋白质相互作用分析,构建蛋白质-蛋白质相互作用网络(PPI),CytoNCA进行网络拓扑学分析,筛选出21个核心靶点,并对核心靶点进行基因本体(GO)富集分析与KEGG通路分析.结果发现,杜仲叶中的山奈酚、槲皮素、绿原酸等主要化合物通过调节肿瘤坏死因子(TNF)、白细胞介素6(IL-6)、血管内皮生长因子A(VEGFA)、白细胞介素1β(IL-1β)等关键靶点,参与IL-17、肿瘤坏死因子信号通路等,从而发挥免疫调节作用.通过腹腔巨噬细胞体外试验和环磷酰胺免疫抑制体内试验探讨杜仲叶提取物的免疫调节作用,结果显示,1 000～5 000 μg·mL-1浓度的杜仲叶提取物可促进腹腔巨噬细胞增殖和吞噬能力;与模型组相比,杜仲叶提取物可增加小鼠免疫器官指数、吞噬指数、外周血白细胞和淋巴细胞数量,增强迟发型超敏反应(DTH)的耳廓肿胀.本研究展现了杜仲叶免疫调节多成分、多靶点作用的特点,为杜仲叶在畜禽健康养殖中的应用提供了科学依据.

Abstract Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is distinguished by impairments in learning and memory. The microbiota-gut-brain axis has emerged as a significant factor in the pathogenesis of Alzheimer's disease. Eucommiae cortex polysaccharides (EPs), one of the most abundant substances in the Eucommiae cortex, exhibit potential immunomodulatory and neuroprotective effects. In our study, we discovered that long-term intervention with EPs (0.25%, w/w in food) significantly improved learning and memory in 5×FAD mice, a well recognized mouse model for Alzheimer's disease. Additionally, EPs substantially reduce the generation and deposition of amyloid-beta (Aβ) plaques in AD Mice. EPs reshaped the composition of gut microbiota, increased the abundance of Erysipelotrichaceae, Allobaculum, Bacteroidota, and Muribaculaceae, which are related to gut immunity and short-chain fatty acids(SCFs) production that exert neuroprotective effects through the gut-brain axis. Furthermore, EPs administration was able to correct metabolic disorders in AD mice, particularly glutamate metabolism disturbances. Correlation analysis demonstrates a robust association between the restructuring of gut microbiota and alterations in glutamate metabolism. Importantly, EPs administration significantly inhibited neuroinflammation and restored the oxidative-antioxidative balance in the brains of AD mice, which are potential factors contributing to learning and memory impairments. Interestingly, EPs administration significantly activated autophagy. Our results demonstrate that EPs reshaped gut microbiota, corrected glutamate metabolism disturbances, and significantly alleviated learning and memory impairments in 5xFAD mice through the gut-brain axis. The natural extract EPs holds promising potential for the therapeutic management of neurodegenerative disorders.

Evidence has suggested that Lactobacillus Plantarum (LP) has benefits on major depression disorders. However, gastric acid and bile may damage LP when it is orally administrated. This study developed a microencapsulation system based on zein to protect the L. Plantarum and improve their survival. To investigate the efficacy and mechanism of the microencapsulated L. Plantarum (MLP) on treating depression disorders, chronic restraint stress (CRS) was applied to build depressive mice models. The LP and MLP were administered respectively to the model mice. The results showed that the MLP could significantly remit the depressive behaviors of the mice model, which was proved through the behavioral tests including open filed test, elevated plus maze test, and forced swimming test. The intestinal microbiota of mice was also evaluated, and 14 genera whose amounts can be remarkably influenced by depression were determined to confirm the therapeutic effects of MLP. The expressions of the pro-inflammatory factors, such as TNF-α in the intestine and hippocampus, and IL-6 in the intestine, were also tested, which were upregulated in the model mice being induced with depression. While the addition of MLP reversed the inflammation in the intestine and hippocampus of depressive mice, which could be the mechanism of MLP treating depression.

Aberrant tryptophan (Trp)-kynurenine (Kyn) metabolism has been implicated in the pathogenesis of human disease. In particular, populations with long-term western-style diets are characterized by an excess of Kyn in the plasma. Host-gut microbiota interactions are dominated by diet and are essential for maintaining host metabolic homeostasis. However, the role of western diet-disturbed gut microbiota-colonocyte interactions in Trp metabolism remains to be elucidated. Here, 4-week-old mice were fed with a high-fat diet (HFD), representing a typical western diet, for 4 weeks, and multi-omics approaches were adopted to determine the mechanism by which HFD disrupted gut microbiota-colonocyte interplay causing serum Trp-Kyn metabolism dysfunction. Our results showed that colonocyte-microbiota interactions dominated the peripheral Kyn pathway in HFD mice. Mechanistically, persistent HFD-impaired mitochondrial bioenergetics increased colonic epithelial oxygenation and caused metabolic reprogramming in colonites to support the expansion of Proteobacteria in the colon lumen. Phylum Proteobacteria-derived lipopolysaccharide (LPS) stimulated colonic immune responses to upregulate the indoleamine 2,3-dioxygenase 1 (IDO1)-mediated Kyn pathway, leading to Trp depletion and Kyn accumulation in the circulation, which was further confirmed by transplantation of Escherichia coli (E.coli) indicator strains and colonic IDO1 depletion. Butyrate supplementation promoted mitochondrial functions in colonocytes to remodel the gut microbiota in HFD mice, consequently ameliorating serum Kyn accumulation. Our results highlighted that HFD disrupted the peripheral Kyn pathway in a gut microbiota-dependent manner and that the continuous homeostasis of gut bacteria-colonocytes interplay played a central role in the regulation of host peripheral Trp metabolism. Meanwhile, this study provided new insights into therapies against western diet-related metabolic disorders.

利用网络药理学分析方法,经过动物试验验证,探究杜仲改善小鼠睡眠障碍的作用机制.通过TCMSP数据库获得杜仲的潜在作用靶点,利用OMIM和GeneCards数据库获得睡眠障碍潜在靶点.将两个靶点合集交集后构建蛋白互作网络,筛选核心靶点.通过David在线平台进行基因本体功能(GO)富集分析和京都基因与基因组百科全书(KEGG)通路富集分析.使用Cytoscape软件构建杜仲成分-睡眠障碍靶点-通路网络,之后采用分子对接技术进行检验.最终通过PCPA小鼠睡眠障碍模型进行体内试验验证.网络药理学和分子对接结果显示,杜仲有效成分烟碱单宁、表奎宁定等通过调节多巴胺D2受体基因(DRD2)和GABAA受体α亚基基因(GABRA1)的表达,发挥镇静安神、抗焦虑的作用.动物试验结果显示,杜仲显著减少了睡眠障碍小鼠的运动量(P<0.05),下调睡眠障碍小鼠下丘脑组织中DRD2基因的表达(P<0.01),上调GABRA1基因的表达(P<0.01).预测并验证了杜仲改善睡眠障碍的作用机制,为其临床应用提供了一定的参考依据.

The increased tameness to reduce avoidance of human in wild animals has been long proposed as the key step of animal domestication. The tameness is a complex behavior trait and largely determined by genetic factors. However, the underlying genetic mutations remain vague and how they influence the animal behaviors is yet to be explored. Behavior tests of a wild-domestic hybrid goat population indicate the locus under strongest artificial selection during domestication may exert a huge effect on the flight distance. Within this locus, only one missense mutation RRM1 I241V which was present in the early domestic goat ~6500 years ago. Genome editing of RRM1 I241V in mice showed increased tameness and sociability and reduced anxiety. These behavioral changes induced by RRM1 I241V were modulated by the alternation of activity of glutamatergic synapse and some other synapse-related pathways. This study established a link between RRM1 I241V and tameness, demonstrating that the complex behavioral change can be achieved by mutations under strong selection during animal domestication.

Non-alcoholic fatty liver disease (NAFLD) leads to hippocampal damage and causes a variety of physiopathological responses, including the induction of endoplasmic reticulum stress (ERS), neuroinflammation, and alterations in synaptic plasticity. As an important trace element, strontium (Sr) has been reported to have antioxidant effects, to have anti-inflammatory effects, and to cause the inhibition of adipogenesis. The present study was undertaken to investigate the protective effects of Sr on hippocampal damage in NAFLD mice in order to elucidate the underlying mechanism of Sr in NAFLD. The mouse model of NAFLD was established by feeding mice a high-fat diet (HFD), and the mice were treated with Sr. In the NAFLD mice, we found that treatment with Sr significantly increased the density of c-Fos+ cells in the hippocampus and inhibited the expression of caspase-3 by suppressing ERS. Surprisingly, the induction of neuroinflammation and the increased expression of inflammatory cytokines in the hippocampus following an HFD were attenuated by Sr treatment. Sr significantly attenuated the activation of microglia and astrocytes induced by an HFD. The expression of phospho-p38, ERK, and NF-κB was consistently significantly increased in the HFD group, and treatment with Sr decreased their expression. Moreover, Sr prevented HFD-induced damage to the ultra-structural synaptic architecture. This study implies that Sr has beneficial effects on repairing the damage to the hippocampus induced by an HFD, revealing that Sr could be a potential candidate for protection from neural damage caused by NAFLD.

Scope This study aims to investigate the role of gut microbiota regulation with ketogenic diet (KD) in hypoglycemia‐induced neuroinflammation. Methods and results Immunofluorescence staining and western blotting show that KD alleviates blood‐brain barrier injury induced by hypoglycemia by increasing Podxl and zonula occludens‐1 (ZO‐1) levels. KD‐fed mice show reduced brain edema by decreasing aquaporin‐4 (AQP4) content and maintaining its polarized expression. 16S rRNA gene amplicon sequencing results show that KD reduces the Chao 1 index of gut microbiota α‐diversity, and significant separation is detected in the β‐diversity analysis between the control and KD‐fed mice. KD increases the relative abundance of Firmicutes and Proteobacteria and decreases that of Bacteroidetes . Hypoglycemia can reduce SOD and GSH‐PX levels while increasing TNF‐α, IL‐1β, and IL‐6 mRNA levels in the brain tissues of mice. KD alleviates hypoglycemia‐induced neuroinflammation by inhibiting microglia activation and TLR4/p38MAPK/NF‐κB signaling pathway. Importantly, antibiotic cocktail depletion of the gut microbiota weakens anti‐inflammatory and antioxidation responses in KD‐fed mice. Conclusion Collectively, these findings suggest that KD alleviates hypoglycemia‐induced brain injury via gut microbiota modulation, which may provide novel insights into the therapy for hypoglycemia.