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.

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.

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.

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.

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.

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.

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.

A modified model of a single rock joint's shear behavior in limestone specimens

The shear behavior of a single rock joint in limestone specimens,under a constant normal load(CNL),was analyzed in this study.Test specimens with different asperity roughness were prepared and tested.Goodman's model of a rock joint's shear behavior,under CNL,was modified to render a better representation of the data obtained.The model's applicability was validated.The proposed model showed better correlation with experimental data.It also,requires fewer variables.The steps to calculate all the necessary variables for the model are discussed.

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.

Effects of zinc on static and dynamic mechanical properties of copper-zinc alloy

The effects of adding alloy element zinc on the static and dynamic mechanical properties of copper-zinc alloy were investigated. Tensile and low cycle fatigue behaviors of the C11000 copper and H63 copper-zinc alloy were obtained by using a miniature tester that combined the functions of in situ tensile and fatigue testing. A piezoelectric actuator was adopted as the actuator for the fatigue testing, and the feasibility of the fatigue actuator was verified by the transient harmonic response analysis based on static tensile preload and dynamic sinusoidal load. The experimental results show that the yield strength and tensile strength of the C11000 copper are improved after adding 37%(mass fraction) zinc, and H63 copper-zinc alloy presents more obvious cyclic hardening behavior and more consumed irreversible plastic work during each stress cycle compared with C11000 copper for the same strain controlled cycling. Additionally, based on the Manson-Coffin theory, the strain-life equations of the two materials were also obtained. C11000 copper and H63 copper-zinc alloy show transition life of 16832 and 1788 cycles, respectively.

Predicting test data of aluminum honeycomb sandwich board based on volterra adaptive filters

Random vibration test was done on aluminum honeycomb sandwich board. The result suggested that chaotic behavior is found in the test data. The Volterra expression can not be gained from the input and output data directly in this paper. The state space reconstruction was used to convert the system observed data into the quasi-input/output pairs, and the second-order Voherra adaptive filter was used to predict the test data. It is shown that combining the state space reconstruction with the Volterra adaptive filter, these chaotic series could be accurately predicted.

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.

Cyclic behavior test of a new double-arch steel gate

A new double-arch structure for the gate used as tidal barrage and sluice was adopted in Caoe River Dam in China. It was a spatial structure made up of the right arch, the invert arch, the chord, etc., and was designed to bear bilateral loads. To research the cyclic behavior of the new double-arch structure, a scale-model cyclic test was conducted. First, the test setup and test method were presented in detail, and according to the test results, the cyclic behavior and failure characteristics of this structure were discussed. Then by analyzing the test cyclic envelope curve, it was found the curve was divided into three stages: the elastic stage, the local plastic stage and the failure stage at the local yield point and structural yield point. The gate model has local yield strength and structural yield strength, with both their values being bigger than that of the designing load. Therefore, the gate is safe enough for the projects. At last, dynamic property of the gate was analyzed considering additional mass of the water. It was found that the tidal bore shock would not cause resonance vibration of the gate.

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.

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.

Biochemical and behavioral characterization of the double transgenic mouse model (APPswe/PS1dE9) of Alzheimer’s disease

Objective The double transgenic mouse model （APPswe/PSldE9） of Alzheimer＇s disease （AD） has been widely used in experimental studies. β-Amyloid （Aβ） peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches. Methods Blood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels ofAβ1-40, Aβ1-42 and 8-hydroxydeoxyguanosine （8-OHdG） in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays. Results The pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Aβ1-40 and Aβ1-42 were detected in these dead mice brains with a ratio of 1 ： 1 0. The level of blood-borne Aβ at 6-month age was similar with that at 12-month age. Besides, Aβ1-40 level in the blood was significantly higher than Aβ1-42 level at the ages of 6 and 12 months （ratio 2.37：1）. In contrast, the level of Aβ1-42 in the brain （160.6 ng/mg protein） was higher than that of Aβ1-40 （74 ng/mg protein） （ratio 2.17：1）. In addition, the levels of Aβ1-40 and Aβ1-42 varied markedly among different brain regions. Aβ1-42 level was significantly higher than Aβ1-40 level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher 7-secretase activity but was more efficient in producing Aβ1-42 peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild-type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors. Conclusion These results suggest that this mouse model mimics the early-onset human AD and may represent full-blown disease at as early as 6-month age for experimental studies.

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.