Xylooligosaccharides Alleviate Inflammatory Dermatoses and Related Depression-Like Behaviors in Atopic Dermatitis Mice Induced by 2,4-Dinitrofluorobenzene

Objective:To investigate the influence of xylooligosaccharides on skin inflammation,behavioral characteristics,neurotransmitters,and gut flora in a mouse model of atopic dermatitis(AD)induced by 2,4-dinitrofluorobenzene(DNFB).Methods:The AD mouse model was created by administration of DNFB for 14 consecutive days.The scoring atopic dermatitis index,enzyme-linked immunosorbent assay(ELISA),histopathology,and immunohistochemical analyses were used to assess inflammation and depression-like behaviors.Furthermore,high-throughput 16S rRNA gene sequencing was used to determine the composition of fecal microbiota.Results:Xylooligosaccharides treatment reduced the number of scratches and skin thickness,mast cell infiltration and the levels of immunoglobulin(Ig)E and T-helper cytokines compared with the AD model group.Meanwhile,xylooligosaccharides treatment reduced the immobility time of mice in the forced swimming test and increased the total movement distance and movement distance in the center area in the open-field test.Furthermore,5-hydroxytryptamine and dopamine expression in the brain was increased following xylooligosaccharides treatment.Using network pharmacology,Gene Ontology analysis showed that the targets were mainly enriched in phosphatase binding and the regulation of leukocyte differentiation,which ameliorated AD mainly through the hypoxia inducible factor-1 and phosphatidylinositide 3-kinase-protein kinase B pathways.16S rRNA gene sequencing,diversity indices,and gut microbial taxonomic composition analysis showed DNFB-induced changes in intestinal microbiota diversity in AD mice.Comparative analysis indicated that xylooligosaccharides intake improved the gut microbiome by dramatically enhancing the concentration of Lactobacillus while decreasing the concentration of Bacteroides in mice.Conclusion:Xylooligosaccharides reduce inflammatory dermatosis and related depression-like behaviors via regulating intestinal homeostasis,having medicinal value as a nutritional and functional ingredient.

Effect of Chronic Administration of Cadmium on Anxiety-Like, Depression-Like and Memory Deficits in Male and Female Rats: Possible Involvement of Oxidative Stress Mechanism

The main objective of this work is to study the effect of chronic administration of cadmium (Cd) on the level of depression-like, anxiety-like, memory state and oxidative stress in male and female Wistar rats. For this purpose, this study was conducted with 24 rats for each gender. Four groups were constituted: (Group 1: Control): received saline solution NaCl (0.9%), (Group 2: Cd-0.25;Group 3: Cd-0.5;Group 4: Cd-1): received daily 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg of Cd respectively during 8 weeks. After treatment period, animals were tested in the open-field, elevated plus maze tests for anxiety-like behavior, and forced swimming test for depression-like behavior. The Y maze was used to evaluate the working memory and the Morris Water Maze, to evaluate space learning and spatial memory. The results revealed that in males, all doses of Cd provoke depression-like, while in females only the group treated with 1 mg/kg Cd shows elevated depression-like behavior. In regard to anxiety-like behavior, Cd induces an anxiogenic effect in both genders tests. In the Y-Maze test, both males and females expressed a low percentage of alternations, suggesting that working memory was affected by Cd at 1 mg/kg. In the Morris Water Maze test, the space learning and spatial memory were significantly impaired in the group Cd-1. Neurochemical analysis showed that levels of nitric oxide and lipid peroxidation in the hippocampus were significantly increased after Cd treatments. Overall analysis of our data revealed that Cd caused significant alterations in the examined parameters that were sex-dependent and dose-dependent.

Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor-and Cygb-associated signaling pathways

A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.

Sphingosine 1-phosphate receptor 1 regulates bloodbrain barrier permeability in epileptic mice

Destruction of the blood-brain barrier is a critical component of epilepsy pathology.Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity.However,its effect on blood-brain barrier permeability in epileptic mice remains unclear.In this study,we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice.S1P1 expression was increased in the hippocampus after status epilepticus,whereas tight junction protein expression was decreased in epileptic mice compared with controls.Intraperitoneal injection of SEW2871,a specific agonist of sphingosine-1-phosphate receptor 1,decreased the level of tight junction protein in the hippocampus of epileptic mice,increased blood-brain barrier leakage,and aggravated the severity of seizures compared with the control.W146,a specific antagonist of sphingosine-1-phosphate receptor 1,increased the level of tight junction protein,attenuated blood-brain barrier disruption,and reduced seizure severity compared with the control.Furthermore,sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1βand tumor necrosis factor-αand caused astrocytosis.Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline,a neuroinflammation inhibitor.Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors.Additionally,specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage,seizure severity,and epilepsy-associated depression-like behaviors.Taken together,our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.

A novel aged mouse model of recurrent intracerebral hemorrhage in the bilateral striatum

The current animal models of stroke primarily model a single intracerebral hemorrhage(ICH)attack,and there is a lack of a reliable model of recurrent ICH.In this study,we established 16-month-old C57 B L/6 male mouse models of ICH by injecting collagenaseⅦ-S into the left striatum.Twenty-one days later,we injected collagenaseⅦ-S into the right striatum to simulate recurrent ICH.Our results showed that mice subjected to bilateral striatal hemorrhage had poorer neurological function at the early stage of hemorrhage,delayed recovery in locomotor function,motor coordination,and movement speed,and more obvious emotional and cognitive dysfunction than mice subjected to unilate ral striatal hemorrhage.These findings indicate that mouse models of bilateral striatal hemorrhage can well simulate clinically common recurrent ICH.These models should be used as a novel tool for investigating the pathogenesis and treatment targets of recurrent ICH.

Overexpression of brain-derived neurotrophic factor in the hippocampus protects against post-stroke depression

Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor （BDNF）. In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of post-stroke depression. The middle cerebral artery was occluded to produce a model of focal cerebral ischemia. These rats were then subjected to isolation-housing combined with chronic unpredictable mild stress to generate a model of post-stroke depression. A BDNF gene lentiviral vector was injected into the hippocampus. At 7 days after injection, western blot assay and real-time quantitative PCR revealed that BDNF expression in the hippo- campus was increased in depressive rats injected with BDNF lentivirus compared with depressive rats injected with control vector. Furthermore, sucrose solution consumption was higher, and horizontal and vertical movement scores were increased in the open field test in these rats as well. These findings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors.

Dynamic changes of behaviors, dentate gyrus neurogenesis and hippocampal miR-124 expression in rats with depression induced by chronic unpredictable mild stress

The depression-like behavior phenotype,neurogenesis in the dentate gyrus and miR-124 expression in the hippocampus are the focus of current research on the pathogenesis of depression and antidepressant therapy.The present study aimed to clarify the dynamic changes of depression-like behavior,dentate gyrus neurogenesis and hippocampal miR-124 expression during depression induced by chronic stress to reveal pathological features at different stages of depression and to further provide insight into depression treatment.Chronic unpredictable mild stress depression models were established by exposing Sprague-Dawley rats to various mild stressors,including white noise,thermal swimming,stroboscopic illumination,soiled cages,pairing with three other stressed animals,cold swimming,tail pinch,restraint and water and food deprivation.Chronic unpredictable mild stress model rats underwent dynamic observation from 1 to 8 weeks and were compared with a control group(normal feeding without any stressors).To observe changes in the depression-like behavior phenotype during chronic unpredictable mild stress-induced depression,a sucrose preference test was used to evaluate the degree of anhedonia.An open-field test was used to evaluate locomotor activity and anxiety status.Compared with the control group,chronic unpredictable mild stress rats lost weight but did not have a depression-like behavioral phenotype at 1-4 weeks.Chronic unpredictable mild stress rats presented decreased sucrose preference and locomotor activity at 5-8 weeks.In addition,chronic unpredictable mild stress rats did not have significant anxiety-like behavior during 1-8 weeks of modeling.To observe neurogenesis dysfunctions and changes in neuronal number in the dentate gyrus during chronic unpredictable mild stress-induced depression,markers(DCX and DCX/BrdU)of neural proliferation and differentiation and the neuronal marker NeuN were assessed by immunofluorescence.Compared with the control group,neurogenesis and the neuronal number in the dentate gyrus did not change from 2 to 6 weeks;however,neural proliferation and differentiation in the dentate gyrus decreased,and the number of neurons decreased until the eighth week in the chronic unpredictable mild stress group.Real-time quantitative reverse transcription polymerase chain reaction assays and fluorescence in situ hybridization were used to measure the expression of hippocampal miR-124 during chronic unpredictable mild stress-induced depression.The results showed that the expression of hippocampal miR-124 was unchanged during the first 4 weeks but increased from 5 to 6 weeks and decreased from 7 to 8 weeks compared with the control group.These findings indicate that during chronic unpredictable mild stress-induced depression,the behavioral phenotype,miR-124 expression in the hippocampus,neurogenesis in the dentate gyrus and neuronal numbers showed dynamic changes,which suggested that various pathological changes occur at different stages of depression.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2015.

Affective Behavior Dysregulation Was Induced by Chronic Administration of Copper in Wistar Rats

As both deficiency and excess of copper (Cu) can be harmful, dysregulation in its homeostasis has been connected with various neurological disorders. The present study was undertaken to examine whether Cu chronic administration can induce alterations of affective behavior especially anxiety and depression levels in male and female rats. Twenty-four rats, for each gender, divided in control and three test groups (n = 6), were injected intraperitoneally with saline (0.9% NaCl) or CuCl2 (0.25 mg/kg, 0.5 mg/kg and 1 mg/kg) for 8 weeks. After treatment period, animals were tested in the open-field, elevated plus maze tests for anxiety-like behavior, and forced swimming test for depression-like behavior. Results demonstrated that Cu administered chronically, exerts an anxiogenic effect in rats. In the OFT, Cu decreases the TCA and NRC parameters without modifying the locomotor activity represented by the NTS parameter. With regard to EPM, Cu decreases TOA and EOA parameters without modifying the TAE parameter. A significant increase in depression-like symptoms was also exhibited by Cu treated rats (p 2 showed maximum anxiety-like and depression-like symptoms as compared to controls as well as from the other two doses indicating dose-dependent effects of chronic Cu administration. Overall, these results suggest that intoxication with Cu has potentially deleterious effects on brain as reflected in behavioral dysfunctions such as depression and anxiety.

A Short Glance at the Neural Circuitry Mechanism Underlying Depression

Depression leads to a large social burden because of its substantial impairment and disability in everyday activities. The prevalence and considerable impact of this disorder call for a better understanding of its pathophysiology to improve the diagnosis, treatment and prevention. Though productive animal models and pathophysiological theories have been documented, it is still very far to uncover the complex array of symptoms caused by depression. Moreover, the neural circuitry mechanism underlying behavioral changes in some depression-like behavior animals is still limited. Changes in the neural circuitry of amygdala, dorsal raphe nucleus, ventral tegmental area, hippocampus, locus coeruleus and nucleus accumbens are related to depression. However, the interactions between individual neural circuitry of different brain areas, have not yet been fully elucidated. The purpose of the present review is to examine and summarize the current evidence for the pathophysiological mechanism of depression, with a focus on the neural circuitry, and emphasize the necessity and importance of integrating individual neural circuitry in different brain regions to understand depression.

Effect of tetrahedral DNA nanostructures on LPS-induced neuroinflammation in mice

Neuroinflammation plays a significant role in inducing depression-like behavior. Tetrahedral DNA nanostructures(TDNs) are molecules that exhibit anti-inflammatory properties and can effectively penetrate the blood-brain barrier. Thus, researchers have hypothesized that TDNs regulate the secretion of proinflammatory cytokines and consequently alleviate depression-like behavior. To test this hypothesis, we investigated the effect of TDNs on the depression-like behavior of C57 mice induced by lipopolysaccharide(LPS). We performed open-field, tail suspension, and sucrose preference tests on LPS-and LPS/TDNtreated mice. The results indicated that the injection of TDNs into LPS-treated mice resulted in increased velocity, center zone duration, frequency to the center zone, and sucrose preference, and decreased immobility time. Immunofluorescence results indicated that peripheral administration of LPS in the mice activated inflammation, which culminated in distinct depression-like behavior. However, TDNs effectively alleviated the inflammation and depression-like behavior through the reduction of the expression levels of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α in the brain. Additionally, TDNs normalized the expression level of microglia cell activation markers, such as ionized calcium binding adaptor molecule 1, in the hippocampus of mice. These results indicated that TDNs attenuated the LPS-induced secretion of inflammatory factors and consequently alleviated depression-like behavior.