Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory

Bromodomain and plant homeodomain(PHD)finger containing protein 1(Brpf1)is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase(KAT)6A/6B/7.Brpf1,KAT6A,and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual disability.Our previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain,especially the hippocampus,which has essential roles in learning and memory.Here,we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons,and that its deficiency leads to learning and memory deficits.To test this,we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre.We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1,Slc16a7,Robo3,and Rho,which are related to neural development,synapse function,and memory,thereby damaging spatial and fear memory in mice.These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation.

Single Exposure to Antidepressants during Infancy Is Associated with Delayed Behavioral Changes in C57BL/6 Mice

As serotoninergic transmission plays a crucial role in higher brain function in mammals, the disturbance of this system will likely have significant effects on emotion and cognition. Previous studies have reported that chronic treatment with Specific Serotonin Reuptake Inhibitors (SSRIs) during both late pregnancy and lactation was associated with abnormal behavior in adult rats. These data imply that disturbances in serotoninergic transmission during neurodevelopment may have negative effects on both the structure and function of the resultant adult brain. Therefore, the effect of a single exposure to an SSRI or a tricyclic antidepressant that preferentially inhibits serotonin reuptake during the pre-weaning period was examined in adult mice. An oral infusion of paroxetine (70 mg/kg), fluvoxamine (250 mg/kg), clomipramine (180 mg/kg), or saline was administered on postnatal day 14. Starting at 11 weeks of age, mice were assessed using a comprehensive behavioral test battery. Mice treated with paroxetine demonstrated altered behavior on the open field and hole-board tasks;those treated with fluvoxamine had behavioral changes on the light-dark box, hole-board, and sucrose preference tasks, while alteration in forced swimming and cued fear behavior were noted in mice treated with clomipramine. These results suggest that even a single administration of an antidepressant could have profound effects on behavior in adulthood, although the effects might differ dependent on the specific drug that was administered.

Numerical simulation of the behaviors of test square for prehistoric earthen sites during archaeological excavation

During the process of archaeological excavation in the regions of Southeast China, collapse of test square usually occurs due to poor site-specific conditions. In this paper, the fast Lagrangian analysis of continua in three dimensions（FLAC3D） is employed to reveal the behaviors of test square. Taking the archaeological works in Liangzhu prehistoric earthen sites as the research background, the paper first introduces the geological setting, excavation procedure and monitoring scheme of the studied test square. Then, the deformation of four sides of the test square is modeled using FLAC3D. By comparison, it shows that the numerical results are consistent with the results from field monitoring. The result suggests that the numerical simulation can be effectively applied to representing the actual behaviors of the test square,which is helpful for determination of excavation scheme and stability evaluation of the test square during archaeological excavation.

Death-associated protein kinase 1 is associated with cognitive dysfunction in major depressive disorder

We previously showed that death-associated protein kinase 1(DAPK1)expression is increased in hippocampal tissue in a mouse model of major depressive disorde and is related to cognitive dysfunction in Alzheimer's disease.In addition,depression is a risk factor for developing Alzheimer's disease,as well as an early clinical manifestation of Alzheimer's disease.Meanwhile,cognitive dysfunction is a distinctive feature of major depressive disorder.Therefore,DAPK1 may be related to cognitive dysfunction in major depressive disorder.In this study,we established a mouse model of major depressive disorder by housing mice individually and exposing them to chronic,mild,unpredictable stressors.We found that DAPK1 and tau protein levels were increased in the hippocampal CA3 area,and tau was hyperphosphorylated at Thr231,Ser262,and Ser396 in these mice.Furthermore,DAPK1 shifted from axonal expression to overexpression on the cell membrane.Exercise and treatment with the antidepressant drug citalopram decreased DAPK1 expression and tau protein phosphorylation in hippocampal tissue and improved both depressive symptoms and cognitive dysfunction.These results indicate that DAPK1 may be a potential reason and therapeutic target of cognitive dysfunction in major depressive disorder.

Recent advances in anxiety disorders:Focus on animal models and pathological mechanisms

Anxiety disorders have become one of the most severe psychiatric disorders,and the incidence is increasing every year.They impose an extraordinary personal and socioeconomic burden.Anxiety disorders are influenced by multiple complex and interacting genetic,psychological,social,and environmental factors,which contribute to disruption or imbalance in homeostasis and eventually cause pathologic anxiety.The selection of a suitable animal model is important for the exploration of disease etiology and pathophysiology,and the development of new drugs.Therefore,a more comprehensive understanding of the advantages and limitations of existing animal models of anxiety disorders is helpful to further study the underlying pathological mechanisms of the disease.This review summarizes animal models and the pathogenesis of anxiety disorders,and discusses the current research status to provide insights for further study of anxiety disorders.

Developing a novel quantitative parameter for characterizing spatial distribution of fish following exposure to chemicals and wastewater:Behavioral Gini coefficient

While the spatial distribution pattern of fish is increasingly used for toxicological test o chemicals or wastewater,no ideal parameter is available for quantitative assessment of spa tial distribution,especially uneven distribution with multiple hotspots.Here,to develop a quantitative assessment parameter for spatial distribution,the zebrafish were exposed to ethanol,pentylenetetrazole(PTZ),paraquat dichloride(paraquat)and wastewater,followed by a behavioral test in a narrow tank.Behavioral data was acquired and analyzed by id Tracker and MATLAB.By comparing the effects of all treatments on behavior parameters we confirmed that the spatial distribution was more easily altered rather than general loco motor parameters,e.g.0.7-70 mg/L PTZ and 5-20 mg/L paraquat being effective for altering spatial distribution but having little effects on general locomotor parameters.Based on the heatmap,i.e.,the cumulative proportion of grids and that of frequency in grids,we calcu lated the behavioral Gini coefficient(G_(b))for quantitative assessment of fish spatial distri bution.The Gini coefficient ranged from zero to 1,with larger values meaning poorer even ness of spatial distribution.Of note,G_(b)showed smaller coefficient of variations(CV)with3%-19%between replicate tanks in all treatments than the highest frequency(4%-79%),dis playing well robustness.Especially,G_(b)addressed the challenge of the complicated heatmap with multiple hotspots.Overall,the behavioral Gini coefficient we established is an idea parameter to quantitatively assess spatial distribution of fish shoal,which is expected to be applied in toxicity testing for chemicals and wastewater and automatic quality monitoring for surface water and aquaculture water.

Di-(n-butyl)-phthalate-induced Oxidative Stress and Depression-like Behavior in Mice with or without Ovalbumin Immunization

Objective To investigate the relationship between atopic allergy and depression and the role of DBP in the development of depression. Methods BALB/c mice were randomly divided into eight groups：saline;ovalbumin （OVA）-immunized;saline＋DBP （0.45 mg/kg·183;d）; saline＋DBP （45 mg/kg·d）; DBP （0.45 mg/kg·d） OVA-immunized; DBP （45 mg/kg·d） OVA-immunized; saline＋hydrocortisone （30 mg/kg·d）; and hydrocortisone （30 mg/kg·d）-exposed OVA-immunized. Behavior （e.g. open-field, tail suspension, and forced swimming tests）, viscera coefficients （brain and spleen）, oxidative damage [e.g. reactive oxygen species （ROS）, malondialdehyde （MDA）, and glutathione （GSH）], as well as levels of IgE and IL-4, were then analyzed. Results In the saline and OVA groups, the degree of depression symptoms in mice increased with increasing DBP concentration. Additionally, the OVA-immunity groups were associated with more serious depressive behavior compared with the same exposure concentration in the saline group. Oxidative damage was associated with a dose-dependent increase in DBP in the different groups. IL-4 and IgE levels were associated with low-dose DBP stimulation, which changed to high-dose inhibition with increasing DBP exposure, possibly due to spleen injury seen at high DBP concentrations.Conclusion Development of an atopic allergy has the potential to increase the risk of depression in mice, and it seems that DBP helps OVA to exert its effect in our present model. Moreover, the results of our study implicate a certain connection between brain oxidative stress and depression, which deserves a further exploration.

Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease

There is currently no treatment for effectively slowing the progression of Alzheimer＇s disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The present study investigated the effects of myricetin, a member of the flavonoids, on intracerebroventricular streptozotocin induced neuronal loss and memory impairment in rat models of Alzheimer＇s disease. Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 m L/kg saline. Behavioral test（the shuttle box test） was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer＇s disease. These findings suggest that myricetin is beneficial for treatment of Alzheimer＇s disease.

The neuroprotective role of Panax notoginseng saponins in APP/PS1 transgenic mice through the modulation of cerebrovascular

Background:Panax notoginseng saponins(PNS)is extracted from Sanqi(Panax notoginseng),which is a valuable herb and has been widely used in traditional Chinese medicine for the treatment of cerebrovascular diseases and pain.PNS has been proved to promote blood circulation and angiogenesis by inhibiting platelet aggregation.In our previous study,PNS accompanied with geniposide can prevent Alzheimer’s disease(AD).However,the efficacy of PNS and its potential mechanism in AD remain unclear.Methods:Amyloid precursor protein/presenilin-1(APP/PS1)transgenic(Tg)mice were used as AD-like animal models.Wild-type mice and APP/PS1 transgenic were administrated with saline solution while mice in PNS treatment group were administrated with PNS at a dosage of 17 mg/kg/day for three months.Morris water maze(MWM)was applied to evaluate the spatial learning and memory and step-down test was used to evaluate the cognitive function.1%Thioflavin-S staining was used to calculate the average number amyloid plaques in cortex and hippocampus.CD31 staining was detected to observe the density of cerebrovascular in hippocampus areas and CD105 staining was further detected to evaluate angiogenesis.Laser Doppler PeriFlux 5000 was further measured the change of cerebrovascular blood flow.ChemDraw was used to draw the molecular structures of five main ingredients of PNS.AlzPlatform were used to estimate the potential targets of PNS.Results:By a bench of behavioral tests,PNS showed a better tendency in proving cognitive functions.In addition,the amyloid plaques in both cortex and hippocampus were significantly reduced after PNS intervention(P<0.05 and P<0.001 respectively).Furthermore,the density of cerebrovascular in the hippocampus areas was increased under PNS administration(P<0.001),which accompanied with angiogenesis in dentate gyrus areas and cerebrovascular blood flow promotion(P<0.05).By AlzPlatform docking serve,we screened five major ingredients of PNS-R1,Rd,Rb1,Re and Rg1.These screening data suggested that vascular related proteins could be the one of potential targets of PNS,such as platelet activating factor receptor and vasopressin V1a receptor.Conclusion:By modulating cerebrovascular function,PNS can reduce the deposition of amyloid plaques and exhibit the role of neuroprotection in a preventive strategy.

A red pomegranate fruit extract-based formula ameliorates anxiety/depression-like behaviors via enhancing serotonin (5-HT) synthesis in C57BL/6 male mice

This study investigated the anti-anxiety/anti-depression potential of a formula containing red pomegranate fruit extract(RPFE;40%,m/m),Lactobacillus rhamnosus(JB-1)(34%,m/m),magnesium gluconate(25%,m/m)and vanillin(1%,m/m).The RPFE formula(dose:2.0,1.5 or 1.0 mg/g·day)reversed behavioral dysfunctions and body weight gain induced by chronic restraint stress combined with corticosterone injection in C57BL/6 male mice.The RPFE formula exhibited the abilities to normalize the levels of serum infl ammatory cytokines(NF-κB,TNF-α,IL-6,IL-1βand IFN-γ)and malondialdehyde(MDA),and activities of superoxide dismutase(SOD),catalase(CAT)and nitric oxide synthase(NOS),as well as relieve the injury of hippocampal neurons.The serotonin(5-HT)levels in hippocampus were increasingly enhanced,which might be mediated by reducing the activity of indoleamine-2,3-dioxygenase(IDO)and increasing the activity of tryptophan hydroxylase(TPH).Thus,the neuroprotective and ameliorating effects on anxiety/depression-like behaviors resulting from the RPFE formula ingestion were possibly related to serotonergic activation,which might be mediated via anti-infl ammatory and anti-oxidant actions.

Impact of social isolation and resident intruder stress on aggressive behavior in the male rat

Stress studies frequently utilize physical stressors to establish animal models of stress. In the majority of cases, these models are not consistent with human circumstances. The present study simulated a social isolation plus resident intruder stress model in the rat. The rats were subjected to daily social isolation and resident intruder stress for 2 weeks. Behaviors were then tested. Rats subjected to social stress exhibited different aggressive behavior styles; some rats had greater scores on composite aggression behaviors, as well as locomotor and exploratory activity, but lower scores on latency than others. The high-aggressive group exhibited predominantly anger-out, while the low-aggressive group exhibited anger-in. Results suggest that social isolation plus resident intruder may serve as an appropriate model for anger-in and anger-out emotion modeling in the rat.

Experimental study on the shear behavior of the interface between cushion materials and the concrete raft

Cushion is a layer of granular materials between the raft and the ground. The shear behavior of the interface between the cushion and the raft may influence the seismic performance of the superstructure. In order to quantify such influences, horizontal shear tests on the interfaces between different cushion materials and concrete raft under monotonic and cyclic loading were carried out. The vertical pressure P_v, material type and cushion thickness h_c were taken as variables. Conclusions include： 1） under monotonic loading, P_v is the most significant factor; the shear resistance P_（hmax） increases as P_v increases, but the normalized factor of resistance μ_n has an opposite tendency; 2） for the materials used in this study, μ_n varies from 0.40 to 0.70, the interface friction angle δ_s varies from 20° to 35°, while u_（max） varies from 3 mm to 15 mm; 3） under cyclic loading, the interface behavior can be abstracted as a ＂three-segment＂ back-bone curve, the main parameters include μ_n, the displacement u_1 and stiffness K_1 of the elastic stage, the displacement u_2 and stiffness K_2 of the plastic stage; 4） by observation and statistical analysis, the significance of different factors, together with values of K_1, K_2 and μ_n have been obtained.

An integrative multivariate approach for predicting functional recovery using magnetic resonance imaging parameters in a translational pig ischemic stroke model

Magnetic resonance imaging(MRI)is a clinically relevant,real-time imaging modality that is frequently utilized to assess stroke type and severity.However,specific MRI biomarkers that can be used to predict long-term functional recovery are still a critical need.Consequently,the present study sought to examine the prognostic value of commonly utilized MRI parameters to predict functional outcomes in a porcine model of ischemic stroke.Stroke was induced via permanent middle cerebral artery occlusion.At 24 hours post-stroke,MRI analysis revealed focal ischemic lesions,decreased diffusivity,hemispheric swelling,and white matter degradation.Functional deficits including behavioral abnormalities in open field and novel object exploration as well as spatiotemporal gait impairments were observed at 4 weeks post-stroke.Gaussian graphical models identified specific MRI outputs and functional recovery variables,including white matter integrity and gait performance,that exhibited strong conditional dependencies.Canonical correlation analysis revealed a prognostic relationship between lesion volume and white matter integrity and novel object exploration and gait performance.Consequently,these analyses may also have the potential of predicting patient recovery at chronic time points as pigs and humans share many anatomical similarities(e.g.,white matter composition)that have proven to be critical in ischemic stroke pathophysiology.The study was approved by the University of Georgia(UGA)Institutional Animal Care and Use Committee(IACUC;Protocol Number:A2014-07-021-Y3-A11 and 2018-01-029-Y1-A5)on November 22,2017.

A modified light-dark box test for the common marmoset

The common marmoset （Callithrix jacchus） has attracted extensive attention for use as a non-human primate model in biomedical research, especially in the study of neuropsychiatric disorders. However, behavioral test methods are still limited in the field of marmoset research. The light-dark box is widely used for the evaluation of anxiety in rodents, but little is known about light-dark preference in marmosets. Here, we modified the light-dark test to study this behavior. The modified apparatus consisted of three compartments： one transparent open area and two closed opaque compartments. The closed compartments could be dark or light. We found that both adult and young marmosets liked to explore the open area, but the young animals showed more interest than adults. Furthermore, when one of the closed compartments was light and the other dark, the adult marmosets showed a preference for the dark compartment, but the young animals had no preference. These results suggest that the exploratory behavior and the light-dark preference in marmosets are age-dependent. Our study provides a new method to study exploration, anxiety, and fear in marmosets.

Behavioral evidence for the origin of Chinese Kunming dog

As the only working dog independently developed and bred in China,Chinese Kunming dog(CKD)was approved as a new breed by the Chinese National Livestock and Poultry Genetics Commission in 2007.Now CKD is widely used by the Chinese army and police and has been exported to Singapore,Thailand,Vietnam,North Korea,and other more than 10 countries as working dog.Previously published studies of CKD have focused on coat color genetics(Wang et al.2013)and reproduction performance(Wei et al.2018).The study by Wang et al.(2013)pointed out that the breed of CKD was developed in the 1950s by hybridizing German shepherd dogs(GSDs)imported from the Soviet Union with Kunming indigenous village dogs.

Comparison of SETAM with Security Use Case and Security Misuse Case:A Software Security Testing Study

A software security testing behavior model,SETAM,was proposed in our previous work as the integrated model for describing software security testing requirements behavior,which is not only compatible with security functions and latent typical misuse behaviors,but also with the interaction of them.In this paper,we analyze the differences between SETAM with security use case and security misuse case in different types of security test requirements.To illustrate the effectiveness of SETAM,we compare them in a practical case study by the number of test cases and the number of faults detected by them.The results show that SETAM could decrease about 34.87% use cases on average,and the number of faults detected by SETAM increased by 71.67% in average,which means that our model can detect more faults with fewer test cases for software security testing.

A suture-free, shape self-adaptive and bioactive PEG-Lysozyme implant for Corneal stroma defect repair and rapid vision restoration

limitation of donor tissue shortage clinically. In addition, suturing-needed transplantation potentially causes postoperative complications. Herein, we design a PEG-Lysozyme injective hydrogel as a suture-free, shape self-adaptive, bioactive implant for corneal stroma defect repair. This implant experiences a sol-gel phase transition via an in situ amidation reaction between 4-arm-PEG-NHS and lysozyme. The physicochemical properties of PEG-Lysozyme can be tuned by the components ratio, which confers the implant mimetic corneal modulus and provides tissue adhesion to endure increased intraocular pressure. In vitro tests prove that the implant is beneficial to Human corneal epithelial cells growth and migration due to the bioactivity of lysozyme. Rabbit lamellar keratoplasty experiment demonstrates that the hydrogel can be filled into defect to form a shape-adaptive implant adhered to native stroma. The implant promotes epithelialization and stroma integrity, recovering the topology of injured cornea to normal. A newly established animal forging behavior test prove a rapid visual restoration of rabbits when use implant in a suture free manner. In general, this work provides a promising preclinical practice by applicating a self-curing, shape self-adaptive and bioactive PEG-Lysozyme implant for suture-free stroma repair.

针刺应答是否随针刺剂量增加而增大:一项基于睡眠剥夺大鼠的临床前研究

Background:The effectiveness of acupuncture for insomnia and insomnia-related anxiety and depression has been widely investigated in clinical trials.However,whether higher dosage(more frequent)acupuncture can bring greater responses(a greater size of effect)is less understood.Objective:This study is designed to investigate whether a five-times weekly(5 Ts/w)electroacupuncture(EA)treatment is better than a three-times weekly(3 Ts/w)EA in alleviating sleep deprivation,and sleep disturbance-induced cognitive dysfunctions and negative emotions in rats through four various behavioral te sts.Methods:Forty-six male Sprague-Dawley rats were randomly divided into control group(n=10),model group(n=12),EA-3 Ts/w group(n=12),and EA-5 Ts/w group(n=12).Except for the control group,the other three groups were established as chronic sleep deprivation models via the modified multi-platform water environment methodology.Then,rats in both EA-3 Ts/w group and EA-5 Ts/w group received corresponding dosage of EA therapy,respectively.After modeling and interventions,all four groups received four behavioral tests as follows:(1)sleep behavioral monitoring and evaluation was achieved by Comprehensive Lab Animal Monitoring System(CLAMS).(2)Cognitive functions were assessed by Novel Object Recognition(NOR)test.(3)Depressive-like behaviors was evaluated by Open-Field(OF)test.(4)Anxietylike behaviors was appraised by Elevated Plus-Maze(EPM)test.After finishing the behavioral tests,the hippocampus of each rat was removed and its synaptic structure changes were observed under electron microscope.Results:(1)CLAMS:two EA groups derived more sleep time within 24 h than the model group(both P<0.05),and no statistical differences was found between these two EA groups(P>0.05).(2)NOR test:NOR ratio in the EA-3 Ts/w group was higher than that of the model group(P<0.05)but lower than that of either the control group(P<0.05)or the EA-5 Ts/w group(P<0.05).(3)OF test:the difference of horizontal movements between the EA-3 Ts/w group and the EA-5 Ts/w group was not significant(P>0.05),although both of them were lower than that of the control group(both P<0.05)but higher than that of the model group(P<0.05).(4)EPM test:no significant decline of open-arm total time(OT)was found in EA-3 Ts/w group(P>0.05)but was found in both the model group(P<0.05)and the EA-5 Ts/w group(P<0.05)compared to the control group.Conclusion:(1)Five-week EA treatment can partially mitigate cognitive dysfunctions,anxiety-like behaviors,and depressive behaviors in rats with sleep deprivation,and this effect might be associated with the repairs on mitochondrial damage in hippocampal neurons.(2)There is insufficient evidence supporting 3 Ts/w EA treatment is less effective than 5 Ts/w EA treatment in mitigating sleep deprivation symptoms and depressive behaviors induced by sleep deprivation among rats.(3)5 Ts/w EA treatment might be more effective than 3 Ts/w EA treatment in attenuating sleep deprivation-induced cognitive impairments while it might further increase rat’s anxiety-like behaviors at the same time.

Labial tip sensilla of Blissus leucopterus leucopterus （Hemiptera： Blissidae）： Ultrastructure and behavior

The cuticular sensory receptors that are found on the apex of the labium of hemipterans play an important role in their feeding behavior. In this study we describe the ultrastructure, number, and distribution of sensilla on the labium apex of the chinch bug, Blissus leucopterus leucopterus. Each apical field of sensilla on the labium contains 11 uniporous peg sensilla and one sensillum chaeticum. The uniporous peg sensilla are innervated by 4-5 bipolar neurons that send dendrites in the lumen of each peg. Three neurons are associated with each sensillum chaeticum, two neurons have dendrites in the lumen of the sensillum, and the third dendrite ends in a tubular body at the base of the sensillum. Behavioral tests that involve chemical blockage of the sensory receptors show the importance of the labial sensilla in feeding behavior. Both morphological and behavioral evidence indicate that the labial sensilla have a chemosensitive function.