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Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis

Zoological Research 2024年第2期45卷 398-414页

作者： Poornima D.E.Weerasinghe-Mudiyanselage Sohi Kang Joong-Sun Kim Sung-Ho Kim Hongbing Wang Taekyun Shin Changjong Moon Department of Veterinary Anatomy and Animal behavior College of Veterinary Medicine and BK21 FOUR ProgramChonnam National UniversityGwangju 61186Republic of Korea Department of Anatomy and Convergence Medical Science Institute of Health SciencesCollege of MedicineGyeongsang National UniversityJinju 52727Republic of Korea Department of Physiology and Neuroscience Program Michigan State UniversityEast LansingMI 48824USA Department of Veterinary Anatomy College of Veterinary Medicine and Veterinary Medical Research InstituteJeju National UniversityJeju 63243Republic of Korea

Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking its key pathological features(inflammation,demyelination,axonal loss,and gliosis)and clinical symptoms(motor and non-motordysfunctions).Recentstudieshave demonstrated the importance of synaptic plasticity in EAE pathogenesis.In the present study,we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase(11 days post-immunization,DPI)and chronic phase(28DPI).EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases.Dendritic complexity was largely affected in the cornu ammonis 1(CA1)and CA3 apical and dentate gyrus(DG)subregions of the hippocampus during the chronic phase,while this effect was only noted in the CA1 apical subregion in the early phase.Moreover,dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE,but only reduced in the DG subregion during the chronic phase.Furthermore,mRNA levels of proinflammatory cytokines(Il1β,Tnfα,and Ifnγ)and glial cell markers(Gfap and Cd68)were significantly increased,whereas the expression of activity-regulated cytoskeletonassociated protein(ARC)was reduced during the chronic phase.Similarly,exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression.Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase(ERK)phosphorylation upon treatment with proinflammatory cytokines.Collectively,these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus,possibly through the ERK-ARC pathway,indicating that this alteration may be associated with hippocampal dysfunctions in EAE.

关键词： Activity-regulated cytoskeleton-associated protein anxiety-like behavior Experimental autoimmune encephalomyelitis Hippocampal dysfunction Neuroinflammation

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Effects of LW-AFC on anxiety-like behavior and immune function in corticosterone-induced mice

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中国药理学与毒理学杂志 2019年第9期33卷 678-679页

作者： ZENG Ju CHENG Xiao-rui ZHOU Wen-xia ZHANG Yong-xiang Beijing Institute of Pharmacology and Toxicology Beijing 100850China State Key Laboratory of Toxicology and Medical Countermeasures Beijing 100850China

OBJECTIVE Chronic stress is one of the important factors in the development of many mental and neurological diseases,and cause damage to the central nervous system,affect animal emotions and damage the immune function of the body.The purpose of this study was to investigate the effects of LW-AFC which extracting from traditional Chinese medicine prescription Liuwei Dihuang decoctionon the anxiety-like behaviorand immune dysfunction abnormalities caused by chronic stress,and whether immune intervention affect the action of LW-AFC.METHODS Male BALB/c mice were subcutaneously injected with corticosterone(25 mg·kg^-1)for 28 d to establish a chronic stress model.Cyclophos⁃phamide(Cy,80 mg·kg^-1)was injected continuously for the initial three days,followed by once a week,LW-AFC(1.6 g·kg^-1)was given continuously for 28 d.Then investigate the emotion changes by open field and elevated plus maze tests,and detected the lymphocyte proliferation,lymphocyte subsets in peripheral blood,microglia and astrocyte expression,and inflammatory cytokines in peripheral blood and brain tissue.RESULTS The mice showed obvious depressive-like behaviorafter 28 d of continuous corticosterone injection.LW-AFC could significantly improve the anxietybehavior induced by corticosterone injection,but LW-AFC could not improve the anxietybehavior of mice by Cy intervention.The expression of glial cells in hippocampus of corticosterone-induced mice showed an upward trend,and the activation of microglia and astrocytes have significantly increase in corticosterone and Cy injected mice.LW-AFC significantly decreased the activation of microglia and astrocytes in corticosterone-induced mice with Cy intervention.This suggested that LW-AFC can reduce the damage of stress on the immune function of central nervous system under immunosuppres⁃sive state.Furthermore,LW-AFC could significantly up-regulate the proliferation of splenic lymphocyte stimulated by LPS and ConA,up-regulate the proportion of CD3+CD8+cells,reduce the proportion of CD4+/CD8+cells,decrease

关键词： LW-AFC corticosterone cyclophosphamide anxiety-like behavior glia cells lymphocyte inflammatory factors

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Tmem74 Regulates anxiety-like behavior through HCN1 Channels in BLA Neurons

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神经药理学报 2019年第Z1期 37-38页

作者： LU Ying-mei HAN fen SHAO Ling-xiao JIANG Quan LIU Xiu-xiu Department of Neurobiology Nanjing Medical University Key Laboratory of Cardiovascular & Cerebrovascular Medicine School of PharmacyNanjing Medical University Institute of Pharmacology and Toxicology College of Pharmaceutical SciencesZhejiang University

Objective:anxiety disorders are the most prevalent psychiatric disorders,but their pathogenic mechanism remains poorly understood. TMEM74 is an autophagosomeand lysosome-associated protein,which overexpression of TMEM74 protein induces autophagy,whereas its knockdown hampers autophagy. RNA expression of TMEM74 is expressed at especially high levels in human brain tissue. Thus,understanding the function of TMEM74 in the brain might have profound implications for the treatment of mental illness. Methods and Results:TMEM74 was decreased in the serum of patients with anxiety and the basolateral amygdaloid nucleus（BLA） in chronic stress mice through western blot analysis. Furthermore,genetic deletion of Tmem74 or selective knockdown of Tmem74 in BLA pyramidal neurons resulted in anxiety-like behaviors in mice. Whole-cell recordings in BLA pyramidal neurons revealed lower hyperpolarization-activated cation current（Ih） and greater input resistance and excitability in Tmem74;neurons than in wild-type neurons. Accordingly,surface expression of hyperpolarization-activated cyclic nucleotide-gated 1（HCN1） channels was also lower in the BLA of Tmem74;mice. The Ih current blocker ZD7288 mimicked these effects in BLA pyramidal neurons in wild-type mice but not in Tmem74;mice. Consistent with the improvement in anxiety-like behaviors,Tmem74 overexpression restored HCN1 channel trafficking and pyramidal neuron excitability in the BLA of Tmem74;and chronic stress mice. Mechanistically,we demonstrate that interactions between Tmem74 and HCN1 are physiologically relevant and that transmembrane domain 1（TM1） is essential for the cellular membrane localization of Tmem74 to enhance Ih. Together. Conclusion:our findings suggest that Tmem74 coupling with HCN1 acts as a critical component in the pathophysiology of anxiety and provide new insights into therapeutic interventions for anxiety.

关键词： Tmem74 anxiety-like behavior hyperpolarization-activated cation current HCN1

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Neuropeptide S Counteracts Paradoxical Sleep Deprivation-Induced anxiety-like behavior and Sleep Disturbances

Neuropeptide S Counteracts Paradoxical Sleep Deprivation-Ind...

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中国睡眠研究会第十届全国学术年会

作者： Jun-Fan Xie Yu-Feng Shao Hai-Liang Wang Can Wang Guang-Fu Cui Xiang-Pan Kong Lin-Xin Wang Yu-Nong Chen Chao-Yu Cong Hai-Lin Chen Yi-Ping Hou Departments of Neuroscience AnatomyHistologyand EmbryologyKey Laboratory of Preclinical Study for New Drugs of Gansu ProvinceSchool of Basic Medical SciencesLanzhou University Department of Human Anatomy School of MedicineHunan Normal University

Disturbed sleep is a common subjective complaint among individuals with anxiety disorders.Sleep deprivation increases general and specific anxiety symptoms among healthy individuals.The amygdala is critical for regulating anxiety and also involved in mediating the effects of emotions on sleep.Neuropeptide S（NPS） and NPS receptors（NPSR） are reported as a novel endogenous arousal and anxiolytic system,but it is unclear yet whether this system is involved in anxiety-like behavior and sleep caused by sleep deprivation,and how it plays anxiolytic effect underlying the comorbid condition.In the present study,we demonstrate that paradoxical sleep deprivation（PSD） induced by modified multiple platform method（MMPM） for 24 h caused anxiety-like behavior,a prolonged sleep latency and subsequent paradoxical sleep（PS） rebound accompanied by an increase in electroencephalogram（EEG） theta（4.5–8.5 Hz） activities across light and dark phase in rats.The increase of PS after PSD was due to an increase of episode number during light phase and both episode number and duration during dark phase.Central action of NPS（1 nmol） attenuated PSD-induced anxiety-like behavior,and altered PSD-induced sleep-wake disturbances through increasing wakefulness,and suppressing PS and EEG theta activities.The reduction in PS time following NPS administration during light phase was because of a decreased episode number.Furthermore,sleep amount in 24 h in PSD rats given NPS was lesser than that given saline.PSD significantly enhanced NPSR mRNA expression level in the amygdala.NPS remarkably increased the number of Fos-ir neurons in the basolateral amygdala（BLA）,the central amygdala（CeA） and medial amygdala（MeA）.The majority of Fos-ir neurons induced by NPS also expressed NPSR.These results suggest that NPSR upregulation in the amygdala is presumably related to the PSD-induced anxiety-like behavior and sleep disturbances,and that NPS counteracts PSD-induced anxiety-like behavior and sleep disturbances possibly through activating the neurons bearing NPSR

关键词： neuropeptide S neuropeptide S receptor paradoxical sleep deprivation anxiety-like behavior sleep-wake states amygdala

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An α-hemoglobin-derived peptide(m)VD-hemopressin(α) antagonizes yohimbine-induced anxiety-like behavior and sleep disorder via CB1 cannabinoid receptor

An α-hemoglobin-derived peptide(m)VD-hemopressin(α) antago...

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中国睡眠研究会第十一届全国学术年会

作者： Junfan Xie Linxin Wang Hailin Chen Jinxian Gao Yunong Chen Fengqiu Dai Xin Zheng Chenchen Cai Guangfu Cui Yufeng Shao Yiping Hou Lanzhou University

Objective Disturbed sleep is a common manifestation of individuals with anxiety disorders. Yohimbine, an α receptor antagonist, is a commonly used pharmacological stressor that induced anxiety-like behavior. Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. Cannabinoid receptors including CB and CB receptors are class A members of the G protein coupled receptors superfamily. The previous data demonstrated that cannabinoids play important roles in modulating several physiological functions such as sleep, olfaction, emotion, learning and memory, and reward behaviors. Mouse VD-hemopressin(α)((m)VD-HPα), an 11-residue peptide derived from the α chain of hemoglobin, was recently presumed as a selective agonist of CB cannabinoid receptor. The present study we investigated the effect of(m)VD-HPα on yohimbine-induced anxiety-like behavior and sleep disorder, and the potential neurons in the brain activated by(m)VD-HPα. Methods The behavioral tests of open field test(OFT), elevated plus maze(EPM), light-dark box(LDB) and marble burying test(MBT), and the polysomnographic recording(8:00-8:00 h) and sleep-wake states analysis were employed to evaluate, respectively, the anxiety-like behavior and sleep-wake cycle pattern following yohimbine injection, and the effect of central action of(m)VD-HPα on yohimbine-induced anxiety-like behavior and sleep disdorder. Furthermore, immunohistochemistry of c-Fos was performed to reveal the activated neurons induced by(m)VD-HPα. Results Intraperitoneal injection of yohimbine(2.5 mg/kg) induced anxiety-like behavior which was characterized by diminishing the time spent in center area and increasing the time spent in grooming in OFT;reducing the percentage of time spent in open arms and entries into the open arms in EPM;decreasing the time spent in light box in LDB, and increasing the number of marbles buried in MBT. Yohimbine also prolonged sleep latency of non-rapid eye movement(NREM) and rapid eye movement(REM) s

关键词： VD-hemopressin（α） anxiety-like behavior sleep-wake states yohimbine agonist of CB1 receptor antagonist of CB1 receptor antagonist of CB2 receptor

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Resveratrol ameliorates lipopolysaccharide-induced anxiety-like behavior by attenuating YAP-mediated neuroinflammation and promoting hippocampal autophagy in mice

Resveratrol ameliorates lipopolysaccharide-induced anxiety-l...

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第七届全国呼吸系统重大疾病转化医学学术论坛

作者： Junming Fan Hui Guang Qiuyun Tian Yongyu Wang Xiaofang Fan Yongsheng Gong Institute of Hypoxia Medicine Wenzhou Medical University

AIM:Resveratrol（RSV） has been well documented to protect against inflammatory responses and exert neuroprotective effects.Yes-associated protein（YAP） is a major downstream effector of hippo signaling pathway that plays critical roles in inflammation.However,little is known about the role of RSV on YAP-mediated neuroinflammation associated with mental disorders.The present study was sought to explore whether the anxiolytic effect of RSV was in relation to suppression of YAP pathway and identify the potential mechanism.METHODS and RESULTS:We found that RSV significantly attenuated the anxietylike behavior deficits induced by lipopolysaccharide（LPS）,which was blocked by EX-527,a sirtuin 1（SIRT1） antagonist.The anxiolytic effect of RSV was accompanied by a marked decrease in the expression of YAP,IL-1β,and Iba-1, whereas RSV treatment can reverse the LPS-induced a decrease in autophagic proteins expression.Coimmunoprecipitation assay illustrated that SIRT1 functioned by counteracting with YAP activation.Pharmacological study using XMU,a YAP activator,showed that activating YAP pathway potentiated LPS-induced anxiety-like behavior,while blockade of YAP activation with verteporfin,a YAP inhibitor,attenuated LPS-induced anxiety-like behavior by abrogating neuroinflammation and alleviating hippocampal autophagy caused by LPS.We finally found that rapamycin-mediated promotion of autophagy attenuated LPS-induced anxiety-like behavior,whereas chloroquine,a lysosomal inhibitor,augmented autophagic flux and ameliorated LPS-induced anxietylike behavior.CONCLUSION:Taken together,these results suggest that the amelioration of RSV in LPS-induced anxiety-like behavior is through attenuating YAP-mediated neuroinflammation and promoting hippocampal autophagy,and indicate the concept that inhibiting YAP pathway could be a potential therapeutic target for anxiety-like behavior during the process of neuroinflammation.

关键词： Resveratrol Lipopolysaccharide anxiety-like behavior Autophagy Yes-associated protein

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电针对创伤后应激障碍大鼠行为学及海马SYN、PSD95表达的影响

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World Journal of Acupuncture-Moxibustion 2023年第2期33卷 135-141页

作者：宋凯王亚婷熊凡捷黄爱玲张虹成都中医药大学针灸推拿学院成都610000 成都中医药大学临床医学院成都610000

Objective: Electroacupuncture (EA) in the treating principle of “soothing the liver and regulating the kidney” was applied to intervion the rats with post-traumatic stress disorder (PTSD), and its effect on anxiety-like behavior, spatial learning and memory ability, and expressions of synaptophysin (SYN) and postsynaptic dense 95 (PSD95) in hippocampus of rats were observed to explore the underlying mechanism.Methods: Twenty-four male SD rats were randomly divided into control group, model group, and EA group, with 8 rats in each group. There was no intervention in the control group. The rest 16 rats were prepared for modeling. The single-prolonged stress & shock (SPS&S) method was used to establish the PTSD models. There was no intervention in the model group after modeling. In the EA group, “Bǎihuì (百会GV20)”“ Shéntíng (神庭GV24)”“Gānshū (肝俞BL18)”“Shènshū (肾俞BL23)” were manipulated with EA stimulation, intensity 1 mA, frequency 2/100 Hz, disperse-dense wave, and treatment was performed once a day, 20 min each time, for a total of 21 days. Open field test, elevated plus maze and Morris water maze tests were used to observe the behavioral differences of rats in each group. Immunohistochemical method was used to observe the differences of positive expressions of proteins SYN and PSD95 in hippocampus.Results: In the open field test, compared with the control group, the total traveling distance, the percentage of the time spent in the central cell and the numbers of the central cells crossing in the model group were all decreased (all P < 0.05). Compared with the model group, these indicators in the EA group were significantly all increased (all P < 0.05). In the elevated plus maze test, compared with the control group, the percentages of open arm staying time and entering times in the model group were both decreased (both P < 0.05). Compared with the model group, these indicators in the EA group were both significantly increased (both P < 0.05). The results of Morris water maze test showed that compared with the contr

关键词： Post-traumatic stress disorder(PTSD) anxiety-like behavior Learning and memory Electroacupuncture(EA) Acupuncture Synaptic plasticity

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Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain’s pain circuitry

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World Journal of Gastroenterology 2021年第9期27卷 794-814页

作者： Sabrina L McIlwrath Marlene E Starr Abigail E High Hiroshi Saito Karin N Westlund Research Service New Mexico Veterans Affairs Healthcare SystemAlbuquerqueNM 87108United States Department of Surgery University of KentuckyLexingtonKY 40536United States College of Liberal Arts University of TexasAustinTX 78712United States Department of Anesthesiology and Critical Care Medicine University of New Mexico Health Sciences CenterAlbuquerqueNM 87131United States

BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.AIM To determine efficacy of acetyl-L-carnitine(ALC)to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.METHODS Pancreatitis was induced with 6 hly intraperitoneal(i.p.)injections of CAE(50μg/kg),3 d a week for 6 wk in male C57BL/6J mice.Starting in week 4,mice received either vehicle or ALC until experiment’s end.Mechanical hypersensitivity was assessed with von Frey filaments.Heat hypersensitivity was determined with the hotplate test.anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests.Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1(Iba1).RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies,indicating ongoing pain.Treatment with ALC attenuated inflammation-induced hypersensitivity,but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted.Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls.Treatment with ALC resulted in increased numbers of rearing activity events,but time spent in“safety”was not changed.After all the abdominal injections,pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day,indicative of spontaneous healing.Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC.Microglial Iba1

关键词： Acute recurrent pancreatitis Neuropathic pain Mechanical hypersensitivity Heat hypersensitivity anxiety-like behavior Ionized calcium-binding adaptor molecule 1

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Social avoidance and anxiety-like behaviors induced by social defeat stress in adult male tree shrews

Social avoidance and anxiety-like behaviors induced by socia...

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中国神经科学学会第十届全国学术会议

作者： Rong-Jun NI Yu-Mian SHU Hui FANG Jing WANG Lin XU Jiangning ZHOU Chinese Academy of Science Key Laboratory of Brain Function and Diseases School of Life SciencesUniversity of Science and Technology of China Key Laboratory of Animal Models and Human Disease Mechanisms Chinese Academy of Sciences & Yunnan ProvinceKunming Institute of Zoology

Objective Adult male tree shrews（Tupaia belangeri chinensis） display an intense territoriality and live singly or in pairs in territories that they defend vigorously against intruding conspecifics.Coexistence of two males in one cage may lead to a stable dominant-subordinate relationship.In this study,we investigated the behavioral phenotype after social defeat stress and the underlying mechanisms in stress-related brain areas.Methods Before the sequence of behavioral tests,subordinate（SUB） and dominant（DOM） subgroups were identified according to the results of social behavioral analysis after social defeat stress in adult male tree shrews.The Cortisol levels in plasma were measured by ELISA.Results Social stress for 2 months induced significant reduction of social interaction time of SUB（P＜0.05）.SUB showed significant reduction in distance moved following social-defeat stress（P＜0.05）.However,there is no significant difference in locomotor activity between SUB and DOM in the open field test.There is a significant difference in social interaction ratio（time spent in the interaction zone in the presence of a social targel/time spent in interaction zone without a social target） between SUB and DOM（P＜0.05）.In the novelty-suppressed feeding,social stress significantly increased the feeding latency of SUB（P＜0.05）.In addition,there is a significant difference in mean distance from the center point of SUB and DOM to center point of food zone（P＜0.05）.However,there is no significant difference in sucrose preference and Cortisol levels in plasma between SUB and DOM.Conclusion These results indicate that social defeat stress induces social avoidance and anxiety-like behaviors in subordinate tree shrews,which is not involved in HPA-axis activity.

关键词： social avoidance anxiety-like behavior social defeat tree shrew

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