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Effect and regulation ofα-dstroglycan glyco⁃sylation on chronic social defeat induced depressive-like behaviors of mice

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中国药理学与毒理学杂志 2021年第9期35卷 693-694页

作者： LI Yu-ke WANG Fang Department of pharmacology School of basic medicineTongji Medical CollegeHuazhong Uni-versity of Science and TechnologyWuhan 430030China

OBJECTIVEα-Dstroglycan(α-DG)is a predominant component in the dystrophin-glycoprotein complex(DGC)and a recently char⁃acterized receptor for several extracellular matrix components with high affinity.Recent research⁃es have reported that hypoglycosylation ofα-DG is associated with the pathophysiology of diseas⁃es,especially muscular dystrophy,but little is known about major depressive disorder(MDD).Like-acetylglucosaminyl transferase(Large)is a key enzyme for glycosylation ofα-DG,which mainly modifies two points in the middle domain ofα-DG:Thr-317 and Thr-319.Glycosylatedα-DG(GLY-α-DG)can bind with high affinity to extracellular matrix(ECM)molecules that con⁃tain laminin globular(LG)domains,including per⁃lecan,agrin and neurexin.Agrin is mainly derived from neurons rather than glial cells.In cultured hippocampal neurons,it was found that agrin could regulate the homeostatic plasticity of inhibi⁃tory neurons by acting on GLY-α-DG.Mdx mice are transgenetic models for the investigation of Duchenne muscular dystrophy.Many studies have shown that the expression of GLY-α-DG in the peripheral and brain tissues of Mdx mice is significantly down-regulated.Mdx mice show cognitive impairment and high levels of anxiety.In this study,we employed chronic social defeat stress(CSDS)to establish an animal model of depression and detected the expression of GLY-α-DG among the brain areas associated with the pathophysiology of depression.METHODS So⁃cial interaction test(SIT)and sucrose preference test(SPT)were used to evaluate depressive-like behavior.Open field(OF)and elevated plus maze(EPM)test were used to determine the anxiety-like behavior of Mdx mice.Novelty-sup⁃pressed feeding test(NSFT)forced swim test(FST)and tail suspension test(TST)were used to detect the depressive-like behavior of Mdx mice.Novel object recognition test(NOR)was applied to evaluate the cognition of Mdx mice.Subthreshold social defeat stress was used to explore the susceptibility to stress in Mdx mice.Stereotactic infusion of agrin into the ventral hippoca

关键词： α-dstroglycan depressive-like behav⁃iors social defeat

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SB-334867 Improves Anxiety-Like Behavior in social defeat Mouse by Regulating HPA Axis

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神经药理学报 2019年第4期 24-25页

作者： ZHANG Yun-peng CHEN Long CHEN Dan-mei WANG Cui-ting WANG Xiao-kun LI Bing Research Center for Clinical Medicine Jinshan Hospital Affiliated to Fudan University The Institute of Neurology The Academy of Integrative Medicine of Fudan University Department of Neurology Jinshan Hospital Affiliated to Fudan University

Objective:Depression is one of the major disease and becomes a public medical health problem worldwide. Current antidepressant drugs typically require weeks to months before a response to the treatment can be observed in the patients with major depressive disorders( MDD). Therefore,development of novel agents that produce a rapid antidepressant response represents a major unmet medical need for the treatment of MDD. Recently,several studies indicate that Orexin antagonists,and in particular selective OxR1( Orexin-1 receptor) antagonists,can reduce drug-seeking at doses that have minimal effects on natural reward-seeking behavior. With respect to the potential use of orexin receptor antagonists for anxiety and depression,we proposed the use of OxR1 antagonist( SB-334867) in the treatment of depressive disorder. We observed the effects of SB-334867 on behavioral stress reactivity and the plasma levels of ACTH and cortisol in social defeat mouse depression model,confirming that SB-334867 can improve the anxiety-like behavior of socially failing mice by modulating the HPA axis. Methods:The social defeat mouse(C57 BL/6 J) model was prepared according to the method of Tatsuhiko Goto et al.,and SB-334867( 2 mg·kg-1) was injected through the tail vein. Elevated O maze test and social Avoidance Test were performed on the social defeat mouse,and the plasma levels of ACTH and cortisol were detected by Elisa. Besides,Western blot was used to detect the changes of Orexin-A and Orexin-1 receptor in the hypothalamus. Results:The social interaction ratio( SI ratio) illustrated that the depression animal model induced by modified chronic social defeat stress is reliable. The SI ratio of the model group,the vehicle group and the drug-administered group were significantly lower than those of the control group;however,after 14 days of intravenous injection of SB-334867,the SI ratio of the mice in the drug-administered group was significantly higher than that in the model group and the vehicle group. The percentage of time spent on t

关键词： social defeat anxiety Orexin receptor HPA axis

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Selectively activate Kv7.4channel in DRN 5-HT neurons reverses depression-like behavior in social defeat model

Selectively activate Kv7.4channel in DRN 5-HT neurons revers...

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中国神经科学学会第十二届全国学术会议

作者： Chen Zhao Yingzi Wang Li Li Min Su Jing Wang Hailin Zhang Deparment of Pharmacology Hebei Medical University

Objective It’s well known that serotonergic system originating in dorsal raphe nuclei（DRN） play essential roles in the control of mood, the pharmacotherapy of anxiety and depression. Here we describe the crucial roles of Kv7.4 potassium channels in modulating the excitability of 5-HT neurons in DRN and the development of depressionlike behaviors in social defeat depression models. Methods（1） Whole-cell patch clamp was used to record Kv7 currents and elicited firing activity of DRN 5-HT neurons. And non-invasive loose-seal cell-attached patch clamp was used to record the spontaneous firing activity.（2） Cell types were identified via single-cell PCR.（3） The depression-like behaviors were measured by social interaction test and sucrose preference test. Results（1） Among the subunits of Kv7 channels, Kv7.4 selectively expressed in DRN 5-HT neurons.（2） Fasudil potently augments Kv7.4 current in DRN 5-HT neurons.（3） Kv7.4 activity modulates the excitability of DRN 5-HT neurons.（4） Fasudil reversed the depression-like behaviors in the social defeat models of depression. Conclusion Since the expression of Kv7.4 in the CNS is limited, selectively targeting Kv7.4 channel is likely to produce fewer side effects than non-selective Kv7 channel openers and, thus, Kv7.4 may offer an alternative novel target for treating depression.

关键词： Kv7.4 5-HT DRN social defeat depression-like behavior

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Resilience to the effects of social stress on vulnerability to developing drug addiction

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World Journal of Psychiatry 2022年第1期12卷 24-58页

作者： Claudia Calpe-López Maria A Martínez-Caballero Maria P García-Pardo Maria A Aguilar Department of Psychobiology University of ValenciaValencia 46010Spain Faculty of social and Human Sciences University of ZaragozaTeruel 44003Spain

We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse.We define the concept of resilience and how it is applied to the field of drug addiction research.We also describe the internal and external protective factors associated with resilience,such as individual behavioral traits and social support.We then explain the physiological response to stress and how it is modulated by resilience factors.In the subsequent section,we describe the animal models commonly used in the study of resilience to social stress,and we focus on the effects of chronic social defeat(SD),a kind of stress induced by repeated experience of defeat in an agonistic encounter,on different animal behaviors(depression-and anxiety-like behavior,cognitive impairment and addiction-like symptoms).We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depressionand anxiety-related behaviors in rodents.Finally,we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse,describing the current state of knowledge and suggesting future research directions.

关键词： Resilience Stress Depression Drug addiction Animal models social defeat

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Repeated social defeat stress induces depressive-like and anxiety-like behaviours in mice

Repeated social defeat stress induces depressive-like and an...

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中国神经科学学会第十届全国学术会议

作者： Qiuqin Han Liu Yang Na Yue Xiaocang Zhu Bing Li Gencheng Wu Jin Yu Department of integrative medicine and neurobiology State key lab of medical neurobiologyInstitutes of brain scienceShanghai medical collegeFudan University

Objective The present research was designed to study the depressive-like and anxiety-like behaviours as well as the social interactions in a repeated social defeat stress,a mice model of depression.Methods In this model,C57BL/6J mice were repeatedly subjected to bouts of social defeat stress on 10 consecutive days by different larger and aggressive CD-1 mouse.After 10 days of social defeat stress or control home cage housing,a battery of behavioral tests（i.e.,social interaction test,elevated plus-maze test,forced swimming test,sucrose preference test） were performed.Results In social interaction test,susceptible mice spent significantly more time in the corner zone than in the interaction zone;meanwhile both control and resilient mice spent significantly more time in the interaction zone when CD-1 mouse as a target was present.Moreover,susceptible mice spent less time in open arms in elevated plus-maze test and had reduced struggling time and enhanced immobility time in forced swimming test,compared with control mice.However,the social defeat stress did not significantly lower the percentage of sucrose water the susceptible mice drank.Conclusion Repeated social defeat stress induced not only defeated and subordinate behavior but also some depressive-like and anxiety-like behaviors.

关键词： social defeat depression social interaction test elevated plus-maze test forced swimming test sucrose preference test

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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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CDK5-mediated nuclear translocation of Sirt2 contributes to depressive-like behaviour induced by social defeat stress

CDK5-mediated nuclear translocation of Sirt2 contributes to ...

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中国神经科学学会第十二届全国学术会议

作者： Zheng Zhang Pei Zhang Guang-Jian Qi Feng-Juan Jiao Qing-Zhi Wang Jian-Guo Yan Feng He Qian Zhang Ze-Xi Lv Xiang Peng Hong-Wei Cai Bo Tian Department of Neurobiology Tongji Medical School Huazhong University of Science and Technology Nanyang Medical College Institute for Brain Research Huazhong University of Science and Technology

Objective Major depressive disorder（MDD） is a common, severe and recurrent psychiatric disorder worldwide;however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases, such as sirtuins（Sirt）, appear to play an essential role in depression. Indeed, chronic stress decreased Sirt1 activity and downregulated Sirt1 gene expression in MDD;however, there is a paucity of literature on the role of Sirt2. We established a MDD mouse model in wild type and Sirt2 knockout C57 BL/6 mice using social defeat stress（SDS） to study the role of Sirt2. Methods social interaction, forced swimming, elevated plus maze, open field and sucrose preference tests were used for behavioural analyses. Western blotting and immunofluorescence were utilised to analyse Sirt2 protein. Tet Tag-pharmacogenetic method was used to study the regulation of ventral tegmental area（VTA）.Results SDS led to Sirt2 nuclear translocation in the amygdala, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS-induced Sirt2 nuclear import. We also discovered that this mechanism was involved in VTA-amygdala modulation. Conclusion These results suggest that CDK5 mediates Sirt2 nuclear translocation in the amygdala and contributes to the depressive-like behaviour induced by SDS.

关键词： CDK5 Sirt2 Major depressive disorder social defeat

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