抑郁症动物模型与其发病机制研究的进展

抑郁症在全球范围内高发,目前尚无有效的治疗手段,使其成为全球性卫生问题之一。抑郁症动物模型作为疾病机理研究以及药物筛选的主要手段,一直以来备受关注,现有的抑郁模型创新性地融合了比较行为学以及最新的分子生物学等相关技术。本文将结合模型的表面效度、结构效度及预测效度对现有的抑郁症动物模型及发病机制研究的最新进展进行综述,主要包括应激模型、损伤模型、化学诱导模型及转基因模型,这些模型均能不同程度的模拟人抑郁症的特征,在抗抑郁药物开发及发病机理研究中发挥重要作用。     

抑郁症动物模型及评价方法研究进展

抑郁症(depression)是一种严重危害人类身心健康的全球性的主要精神卫生问题。目前病因及病理机制尚不完全清楚,但随着社会经济的发展,生活节奏加快,人们的压力增加,情感冲击加大,造成抑郁症发病率逐年增长。随着对抑郁症研究的深入,抑郁症动物模型及其评价方法被广泛运用于抑郁症发病机制研究和抗抑郁新药的研发。动物模型模拟人类疾病状态的程度以及评价方法的可靠性和准确性直接影响实验研究结果的价值。本综述主要介绍了常用的抑郁症动物模型,及整体、器官、分子水平的评价指标,为后续新型抗抑郁药物的研发提供文献参考。     

昆明动物研究所动物模型与人类疾病机理重点实验室被正式批准成为中国科学院重点实验室

昆明动物研究所动物模型与人类疾病机理重点实验室成立于2005年12月20日,符合中国科学院中长期发展规划和知识创新工程的总体部署,是我所三大中长期发展领域之一。该实验室主要针对艾滋病、抑郁症和毒品成瘾等疾病建设和完善疾病灵长类动物模型,研究疾病发生的细胞分子机理和调控靶点,并致力于具有自主知识产权的新药、疫苗和新技术研发。     

从临床到基础：硝酸甘油实验性偏头痛大鼠模型信度和效度评价

具有良好信度和效度的动物模型是从实验室到临床转译研究成功的保证,为进一步应用硝酸甘油（glycerol trinitrate,GTN）偏头痛大鼠模型,对其信度和效度进行评价。效度包括表面效度、建构效度、标准关联效度。衡量表面效度的标准是症状同源性。GTN偏头痛大鼠模型行为学表现与人类偏头痛有一定的相似性。建构效度主要指动物模型对理论假说的解释度,GTN模型复制了偏头痛的神经源性炎症及痛觉增敏,具有较好的建构效度。标准关联效度即预测效度主要表现为药理学反应及其在临床的干预实验。GTN模型对典型抗偏头痛药物麦角胺的反应较敏感,但是该模型的预测力效度仍未有效建立。GTN偏头痛大鼠在不同的地区、不同的实验室均已成功复制,表明其有较好的信度。     

抽动障碍免疫相关动物模型研究进展

抽动障碍(tic disorders, TD)为儿童常见疾病,发病率不断上升,其病因及发病机制尚不明确,随着临床中感染与TD症状诱发和加重关系的认识及TD免疫炎症相关研究的进展,免疫异常也逐渐被认为是其重要致病因素及病理过程之一,建立TD免疫学动物模型是其免疫相关实验研究的基础,因此本文通过查阅国内外相关文献,系统介绍了国际上TD免疫相关动物模型的研究概况,并依据表面效度、结构效度和预测效度的国际动物模型评价标准对模型优劣进行比较分析,以期为国内TD的相关实验研究提供参考。     

高迁移率族蛋白B1介导神经炎症在抑郁症中的研究进展

抑郁症是一种常见的慢性情感障碍性疾病,带来严重的经济和社会负担。神经炎症机制在抑郁症的研究中逐渐深入。临床和动物模型均证实,抑郁症体内高水平的炎性细胞因子和被激活的小胶质细胞等典型神经炎症反应与抑郁症的发病机制密切相关。高迁移率族蛋白B1(high mobility group box 1 protein, HMGB1)是一种高度保守的染色体结合蛋白,是一种重要的危险相关模式分子,可被免疫活性细胞和坏死细胞释放至细胞外,启动脑内炎症反应。HMGB1拮抗剂的研发也为神经精神类疾病治疗拓宽了治疗途径。该文重点介绍了HMGB1介导神经炎症的分子机制及其在抑郁症发病及治疗中的研究现状,以期为后续临床诊疗提供重要理论基础。     

阿尔茨海默病动物模型研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种以认知功能障碍为主要特征,随着年龄增长症状逐渐加重的神经退行性疾病.由于世界人口结构老龄化愈来愈严重,对AD疾病的研究也成为世界医学界的热点.对疾病机制的研究需要建立与临床病理特征相符的动物模型.关于AD动物模型的建立方法有仿人类衰老过程的自然衰老动物模...     

简述疫苗研发动物模型

在过去的100年里,动物模型的研究已在人类疫苗的发展中起到至关重要的作用。动物模型的使用不仅有助于疫苗从基本研究转到临床应用,而且动物模型通常能够预测疫苗实用的潜能,从而帮助疫苗的生产商预测财政风险。由于每种动物模型都有其自身的优缺点,选择一种合适的动物模型可促进疫苗研发的顺利进行。     

药物临床前研究与转化医学——实验动物的应用与动物实验

本文讨论了药物临床前研究与实验动物和动物模型之间的关系,探讨了实验动物和动物模型在新药研发过程中实现转化研究的要求和条件.讨论了实验动物质量对新药研发的影响,分析了实验动物质量的影响因素;讨论了实验动物模型的主要类型和特点,分析了进行实验动物模型研究的要点和要求;分析了动物模型与新药研发过程中实现转化研究的条件,提出加强转化研究需要实验动物和动物模型研究的支撑.     

人肠道病毒动物模型及其在疫苗研究中的应用

人肠道病毒(human enterovirus, HEV)可引起人类多种疾病,甚至死亡。疫苗的研制与开发是预防HEV感染所致疾病的重要手段。动物模型是疫苗有效性评价的关键工具,在疫苗研发中具有重要意义。建立一个可稳定呈现人类临床疾病或症状甚至可导致死亡的动物模型,可极大地促进相关疫苗研发和应用的顺利进行。现就近年研究关注的HEV动物模型作一综述,为HEV相关疫苗研究提供参考。     

Proteomic analysis of a rat model of depression

Major depression is one of the most disabling disorders, yet the pathogenesis of this mental disorder is poorly understood. The techniques of proteomics provide us with powerful tools, while the animal models of depression enable research that cannot be performed on humans due to practical difficulties or ethical reasons. In this review, we summarize the characteristics of some most commonly applied rat models of depression, and explore what could be done with novel proteomic approaches to offer an insight to the pathogenesis of major depression, biomarker establishment and drug development.     

Proteomic analysis of a rat model of depression

Major depression is one of the most disabling disorders, yet the pathogenesis of this mental disorder is poorly understood. The techniques of proteomics provide us with powerful tools, while the animal models of depression enable research that cannot be performed on humans due to practical difficulties or ethical reasons. In this review, we summarize the characteristics of some most commonly applied rat models of depression, and explore what could be done with novel proteomic approaches to offer an insight to the pathogenesis of major depression, biomarker establishment and drug development.     

Mitochondrial Dysfunction and Psychiatric Disorders

Mitochondrial oxidative phosphorylation is the major ATP-producing pathway, which supplies more than 95% of the total energy requirement in the cells. Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of psychiatric disorders. Tissues with high energy demands, such as the brain, contain a large number of mitochondria, being therefore more susceptible to reduction of the aerobic metabolism. Mitochondrial dysfunction results from alterations in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatric disorders, such as bipolar disorder, depression and schizophrenia. Bipolar disorder is a prevalent psychiatric disorder characterized by alternating episodes of mania and depression. Recent studies have demonstrated that important enzymes involved in brain energy are altered in bipolar disorder patients and after amphetamine administration, an animal model of mania. Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Several works have demonstrated that metabolism is impaired in some animal models of depression, induced by chronic stress, especially the activities of the complexes of mitochondrial respiratory chain. Schizophrenia is a devastating mental disorder characterized by disturbed thoughts and perception, alongside cognitive and emotional decline associated with a severe reduction in occupational and social functioning, and in coping abilities. Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions and also in platelets. Abnormal mitochondrial morphology, size and density have all been reported in the brains of schizophrenic individuals. Considering that several studies link energy impairment to neuronal death, neurodegeneration and disease, this review article discusses energy impairment as a mechanism underlying the pathophysiology of some psychiatric disorders, like bipolar disorder, depression and schizophrenia.     

Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence?

This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer's disease and dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.     

Animal models of social anxiety disorder and their validity criteria

Anxiety disorders pose one of the largest threats to global mental health, and they predominantly emerge early in life. Social anxiety disorder, also known as social phobia, is the most common of all anxiety disorders. Moreover, it has severe consequences and is a disabling disorder that can cause an individual to be unable to perform the tasks of daily life. Social anxiety disorder is associated with the subsequent development of major depression and other mental diseases, as well as increased substance abuse. Although some neurobiological alterations have been found to be associated with social anxiety disorder, little is known about this disorder. Animal models are useful tools for the investigation of this disorder, as well as for finding new pharmacological targets for treatment. Thus, this review will highlight the main animal models of anxiety associated with social phobia.     

Chronic mild stress for modeling anhedonia

Major depressive disorder is a complex disease implicating many brain circuitries. The clinical symptomatology is inconsistent and heterogenous and the pathogenesis is a complicated interplay of genetic and environmental factors. The episodic and recurrent nature of the disease, as well as the fact that several symptoms are only verbally expressed, make it challenging to establish valid and legitimate animal models of this disease. The purpose of this review is to provide some background knowledge and overview of valid rodent models of depression with an emphasis on our own experience with a chronic mild stress model in modeling of anhedonia and cognitive impairments associated with depression. In a final concluding remark, a ‘dying-forward’ hypothesis, for development of depression, is suggested on the basis of mainly our own data on a hippocampal pathology.     

Progress in understanding mood disorders: optogenetic dissection of neural circuits

Major depression is characterized by a cluster of symptoms that includes hopelessness, low mood, feelings of worthlessness and inability to experience pleasure. The lifetime prevalence of major depression approaches 20%, yet current treatments are often inadequate both because of associated side effects and because they are ineffective for many people. In basic research, animal models are often used to study depression. Typically, experimental animals are exposed to acute or chronic stress to generate a variety of depression‐like symptoms. Despite its clinical importance, very little is known about the cellular and neural circuits that mediate these symptoms. Recent advances in circuit‐targeted approaches have provided new opportunities to study the neuropathology of mood disorders such as depression and anxiety. We review recent progress and highlight some studies that have begun tracing a functional neuronal circuit diagram that may prove essential in establishing novel treatment strategies in mood disorders. First, we shed light on the complexity of mesocorticolimbic dopamine (DA) responses to stress by discussing two recent studies reporting that optogenetic activation of midbrain DA neurons can induce or reverse depression‐related behaviors. Second, we describe the role of the lateral habenula circuitry in the pathophysiology of depression. Finally, we discuss how the prefrontal cortex controls limbic and neuromodulatory circuits in mood disorders .     

Candidate genes for panic disorder: insight from human and mouse genetic studies

Panic disorder is a major cause of medical attention with substantial social and health service cost. Based on pharmacological studies, research on its etiopathogenesis has been focused on the possible dysfunction of specific neurotransmitter systems. However, recent work has related the genes involved in development, synaptic plasticity and synaptic remodeling to anxiety disorders. This implies that learning processes and changes in perception, interpretation and behavioral responses to environmental stimuli are essential for development of complex anxiety responses secondary to the building of specific brain neural circuits and to adult plasticity. The focus of this review is on progress achieved in identifying genes that confer increased risk for panic disorder through genetic epidemiology and the use of genetically modified mouse models. The integration of human and animal studies targeting behavioral, systems-level, cellular and molecular levels will most probably help identify new molecules with potential impact on the pathogenetic aspects of the disease.     

Animal models of NAFLD from a hepatologist's point of view

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder closely linked to obesity, hyperlipidemia and type 2 diabetes and is increasingly recognized as a major health problem in many parts of the world. While early stages of NAFLD are characterized by a bland accumulation of fat (steatosis) in hepatocytes, the disease can progress to non-alcoholic steatohepatitis (NASH) which involves chronic liver inflammation, tissue damage and fibrosis and can ultimately lead to end-stage liver disease including cirrhosis and cancer. As no approved pharmacological treatment for NAFLD exists today, there is an urgent need to identify promising pharmacological targets and develop future therapies. For this purpose, basic and translational research in NAFLD animal models is indispensable. While a large number of diverse animal models are currently used in the field, there is an ongoing challenge to identify those models that mirror human pathology the closest to allow good translation of obtained results into further clinical development. This review is meant to provide a concise overview of the most relevant NAFLD animal models currently available and will discuss the strengths and weaknesses of these models with regard to their comparability to human disease conditions.     

Social conflict models: can they inform us about human psychopathology?

Social conflict models have been proposed as a powerful way to investigate basic questions of how brain and behavior are altered by social experience. Social defeat, in particular, appears to be a major stressor for most species, and in humans, this stressor is thought to play an important role in the onset of a variety of psychiatric disorders including depression and post-traumatic stress disorder. Aggressive experience, on the other hand, may promote disorders involving inappropriate aggression and violence. Current research using animal models of social conflict involves multiple levels of analysis from genetic and molecular to systems and overt behavior. This review briefly examines a variety of these animal models of social conflict in order to assess whether they are useful for advancing our understanding of how experience can shape brain and behavior and for translating this information so that we have the potential to improve the quality of life of individuals with mental illness and behavioral disorders.