The chronic psychosocial stress paradigm in male tree shrews: evaluation of a novel animal model for depressive disorders

To improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews, which is based on the territorial behaviour of these animals that can be used to establish naturally occurring challenging situations under experimental control in the laboratory. Co-existence of two males in visual and olfactory contact leads to a stable dominant-subordinate relationship, with subordinates showing distinct stress-induced behavioural and neuroendocrine alterations that are comparable to the symptoms observed during episodes of depression in patients such as constantly elevated circulating glucocorticoid hormones due to a chronic hyperactivity of the hypothalamic-pituitary-adrenal axis. To elucidate whether the chronic psychosocial stress model in tree shrews besides its "face validity" for depression also has "predictive validity", we treated subordinate tree shrews with the tricyclic antidepressant clomipramine and found a time-dependent restoration of both endocrine and behavioural parameters. In contrast, the anxiolytic diazepam was ineffective. Although the chronic psychosocial stress model in tree shrews requires further validation, it has sufficient face, predictive, and construct validity to become an interesting non-rodent model for research on the etiology and pathophysiology of depression.     

树鼩的社会挫败抑郁模型

创制理想的动物模型是突破抑郁症研究的技术难点之一。来自进化研究的证据提示, 树鼩属灵长类近缘的一种小型动物, 具有较为发达的神经系统和与人类相似的应激系统, 因而可能成为创制精神疾病行为模型的较佳选择。已有的研究表明, 树鼩社会挫败模型可能具有比啮齿类更好的表面效度、预测效度及结构效度。由于树鼩与人类的近缘关系, 对其抑郁行为的脑机制研究或药物评价可能更具潜在价值。但是, 该模型仍有待进一步利用、拓展和完善。     

焦虑和抑郁动物模型的研究方法和策略

焦虑和抑郁障碍是严重威胁人们健康的精神疾病。焦虑和抑郁动物模型是通过一定的心理社会应激使动物产生明显的焦虑和抑郁情绪,模拟人类焦虑和抑郁障碍,以探讨其细胞、分子和基因水平机制。情绪障碍动物模型通常通过表面效度、结构效度和预测效度进行评价。目前的动物模型虽然存在一定的缺点,但已经为临床和科研提供了巨大帮助。     

Contextual conditioning in rats as an animal model for generalized anxiety disorder

Animal models of psychiatric disorders are important translational tools for exploring new treatment options and gaining more insight into the disease. Thus far, there is no systematically validated animal model for generalized anxiety disorder (GAD), a severely impairing and difficult-to-treat disease. In this review, we propose contextual conditioning (CC) as an animal model for GAD. We argue that this model has sufficient face validity (there are several symptom similarities), predictive validity (it responds to clinically effective treatments), and construct validity (the underlying mechanisms are comparable). Although the refinement and validation of an animal model is a never-ending process, we want to give a concise overview of the currently available evidence. We suggest that the CC model might be a valuable preclinical tool to enhance the development of new treatment strategies and our understanding of GAD.     

A glass full of optimism: Enrichment effects on cognitive bias in a rat model of depression

Investigations of cognitive biases in animals are conceptually and translationally valuable because they contribute to animal welfare research and help to extend and refine our understanding of human emotional disorders, where biased information processing is a critical causal and maintenance factor. We employed the "learned helplessness" genetic rat model of depression in studying cognitive bias and its modification by environmental manipulations. Using a spatial judgment task, responses to ambiguous spatial cues were assessed before and after environmental enrichment to test whether this manipulation would cause an optimistic shift in emotional state. Twenty-four congenitally helpless and nonhelpless male rats were trained to discriminate two different locations, "rewarded" versus "aversive." After successful acquisition of this spatial discrimination, cognitive bias was probed by measuring responses to three ambiguous locations. Latencies to "reach" and to actively "choose" a goal pot were recorded alongside exploratory behaviors. An overall strain difference was observed, with helpless rats displaying longer "reach" latencies than nonhelpless rats. This implies a "pessimistic" response bias in helpless rats, underscoring their depressive-like phenotype. No strain differences were observed regarding other behavioral measures. Half of the animals were then transferred to enriched cages and retested. Environmental enrichment resulted in reduced "choose" latencies in both rat strains, associating enrichment with more optimistic interpretations of ambiguous cues. Our results emphasize the suitability of cognitive bias measurement for animal emotion assessment. They extend the methodological repertoire for characterizing complex phenotypes and bear implications for animal welfare research and for the use of animal models in preclinical research.     

Successful treatment of obsessive-compulsive disorders

Behavioral therapy and drugs have significantly improved obsessive-compulsive disorder (OCD) symptoms. A variety of behavioral therapy methods have been employed, but exposure and prevention of response, particularly, have reduced ritualistic actions of many OCD patients. Many psychoactive drugs have been tried; the tricyclic antidepressant drugs (clomipramine or Anafranel), especially in research outside the United States, have alleviated OCD symptoms as well as depression. Compulsive rituals have responded more often than obsessive actions to both behavioral and psychopharmacological therapy. Recent research has suggested that psychophysiological as well as traditional psychogenic factors may contribute to the etiology, course, and alleviation of OCD.     

Toward an animal model of type A behavior

Time estimation and dominance tests were used to differentiate the behavior of Mongolian gerbils to be analogous to Type A and Type B human behavior. Preliminary classification of animals as "Type A" or "B" was based upon differential performance on DRL 20-sec and DRL 60-sec reinforcement schedules. To retain their preliminary classification, Type A and Type B animals were required to be dominant and subordinate, respectively, in matches with each of three same-sex animals of opposite behavioral classification. Following classification, breeding pairs were constituted and classification procedures were repeated with two succeeding generations. Animals that exhibited Type A timing "won" significantly more dominance matches than did Type B animals. Incidence rates of Type A and Type B behavior in the two selectively bred generations were significantly greater than frequencies in the original stock generation. The usefulness of the present animal model for investigating the association of Type A behavior with coronary heart disease is discussed.     

海马NMDA受体经SP-NK1受体通路参与慢性应激诱发的抑郁样行为

为探讨海马N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体与P物质(Substance P, SP)及其神经激肽1 (neurokinin1, NK1)受体在慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS) 中的作用及其关系, 通过建立CUMS动物模型, 大鼠海马微量注射给药, 测量大鼠体重, 并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测, 运用高效液相色谱(HPLC)法分析大鼠海马组织中SP和谷氨酸(glutamate, Glu)的含量变化。结果显示, CUMS诱发大鼠表现出明显的抑郁样行为, 海马组织中SP和Glu水平显著增加; 海马注射NMDA, 大鼠表现出与CUMS/SAL组相似的抑郁样行为, 且海马组织中SP的含量比正常对照组显著增加; 微量注射NK1受体阻断剂CP-96345和/或NMDA受体阻断剂MK-801后, 大鼠抑郁样行为明显改善, 且MK-801使CUMS导致的大鼠海马P物质水平升高得到明显控制, 而CP-96345没有明显改变CUMS引起的海马Glu水平升高; CP-96345使NMDA引起的抑郁样行为得到极显著改善。以上结果表明, 慢性应激引起大鼠海马Glu过量释放, 通过激活NMDA受体, 促进P物质合成释放增加, 激活NK1受体, 是导致抑郁样行为发生的重要途径之一。     

Predator odor avoidance as a rodent model of anxiety: learning-mediated consequences beyond the initial exposure

Prey animals such as rats display innate defensive responses when exposed to the odor of a predator, providing a valuable means of studying the neurobiology of anxiety. While the unconditioned behavioral and neural responses to a single predator odor exposure have been well documented, the paradigm can also be used to study learning-dependent adaptations that occur following repeated exposure to a stressor or associated stimuli. In developing preclinical models for human anxiety disorders this is advantageous, as anxiety disorders seldom involve a single acute experience of anxiety, but rather are chronic and/or recurring illnesses. Part 1 of this review summarizes current research on the three most commonly used predator-related odors: cat odor, ferret odor, and trimethylthiazoline (a component of fox odor). Part 2 reviews the learning-based behavioral and neural adaptations that underlie predator odor-induced context conditioning, one-trial tolerance, sensitization, habituation and dishabituation.     

Marmosets as a next-generation model of comparative cognition

Common marmosets have traditionally been used in fields such as comparative psychology, cognitive neuroscience, and ethology, and as animal models of human disease research because of their relatively small body size, high reproductive rate, similar breeding system characteristics to those of humans, high dependency on vocal communication, and behavioral effects from drug administration that resemble those of humans. Although the animal has proved to be quite advantageous in animal model research in comparison to rodents, and has specific ecological and evolutionary characteristics that are worthy of exploration, few attempts have been made until recently to combine both types of approach. Thus, supported by neuroscientific methodologies that have recently been developed using this species, the authors suggest that the evolutionary origins of cognitive and social functions common to or differentiated in primates, could be uncovered through research that explores the behavioral and neural bases of cognition in the marmosets.     

The treatment of depression in older adults in the primary care setting: an evidence-based review.

The objective of this study was to conduct an evidence-based review of treatments for depression in older adults in the primary care setting. A literature search was conducted using PsycINFO and Medline to identify relevant, English language studies published from January 1994 to April 2004 with samples aged 55 and older. Studies were required to be randomized controlled trials that compared psychosocial interventions conducted within the primary care setting with "usual care" conditions. Eight studies with older adult samples met inclusion criteria and were included in the review. Two treatment models were evident: Geriatric Evaluation Management (GEM) clinics and an approach labeled integrated health care models. Support was found for each model, with improvement in depressive symptoms and better outcomes than usual care; however, findings varied by depression severity, and interventions were difficult to compare. Further efforts to improve research and clinical care of depression in the primary care setting for older adults are needed. The authors recommend the use of interdisciplinary teams and more implementation of psychosocial treatments shown to be effective for older adults.     

Extinction-induced "despair" in aged and adult rats: links to neurotrophins in frontal cortex and hippocampus

In the search for animal models of human geriatric depression, we found that operant extinction of escape from water results in the expression of immobility in different age groups, indicative of behavioral "despair", which was also associated with the resistance-to-extinction (RTE) expressed by these animals. With respect to the neurotrophin hypothesis of depression, nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein levels in frontal cortex (FC) and hippocampus (HP) were examined and related to behavioral immobility and RTE in the water maze in aged and adult Wistar rats. Age-related increases in levels of NGF were found in HP and of NT-3 in FC. Indices of immobility showed relationships in the aged with NGF and, in adults, with BDNF, pointing to a dissociation of neurotrophic involvement in extinction trial-induced "despair" in aged and adult rats. The present results support the hypothesis, that extinction-induced immobility in the water maze reflects a state akin to behavioral despair and point to age-related differences of neurotrophic involvement in depressive-like symptoms. The concept of extinction-induced behavioral "despair" in the aged subsumes several aspects of human geriatric depression, such as co-morbidity of learning impairment and anxiety, and, thus could represent a useful paradigm to examine the neuronal mechanisms underlying depression, especially in aged rodents.     

Psychostimulant-induced behavior as an animal model of obsessive-compulsive disorder: an ethological approach to the form of compulsive rituals

Rats treated chronically with the D2/D3 dopamine receptor agonist quinpirole show a pattern of behavior that meets a set of ethologically derived criteria of compulsive behavior in obsessive-compulsive disorder (OCD). Moreover, in both quinpirole-treated rats and OCD patients, the structure of compulsive rituals appear similar in being composed of relatively few motor acts that are organized in a flexible yet recurrent manner. In addition, the development of compulsive behavior in quinpirole-treated rats is attenuated by the OCD pharmacotherapeutic drug clomipramine. These similarities support the validity of quinpirole-treated rats as a psychostimulant-induced animal model of OCD. Considering that the induction of compulsive behavior in the rat model involves chronic hyperstimulation of dopamine receptors, this raises the possibility that dopaminergic mechanisms may play a role in OCD, at least in some subtypes of this disorder.     

Anger and postcombat mental health: Validation of a brief anger measure with U.S. Soldiers postdeployed from Iraq and Afghanistan

The involvement of anger in the psychological adjustment of current war veterans, particularly in conjunction with combat-related posttraumatic stress disorder (PTSD), warrants greater research focus than it has received. The present study concerns a brief anger measure, Dimensions of Anger Reactions (DAR), intended for use in large sample studies and as a screening tool. The concurrent validity, discriminant validity, and incremental validity of the instrument were examined in conjunction with behavioral health data for 3,528 treatment-seeking soldiers who had been in combat in Iraq and Afghanistan. Criterion indices included multiple self-rated measures of psychological distress (including PTSD, depression, and anxiety), functional difficulties (relationships, daily activities, work problems, and substance use), and violence risk. Concurrent validity was established by strong correlations with single anger items on 4 other scales, and discriminant validity was found against anxiety and depression measures. Pertinent to the construct of anger, the DAR was significantly associated with psychosocial functional difficulties and with several indices of harm to self and to others. Hierarchical regression performed on a self/others harm index found incremental validity for the DAR, controlling for age, education, military component, officer rank, combat exposure, PTSD, and depression. The ability to efficiently assess anger in at-risk military populations can provide an indicator of many undesirable behavioral health outcomes. (PsycINFO Database Record (c) 2012 APA, all rights reserved).     

APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder

Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to model Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.     

Acute and chronic stress effects on performance in a forced-swim task

The effects of uncontrollable stressors on performance in a subsequent forced-swim paradigm were assessed in mice. Uncontrollable shock initially induced behavioral invigoration; however, within 24 h of stressor application, swimming behavior was depressed relative to nonstressed mice. The controllability of the stressor did not influence the initial invigoration, being present among escapably shocked mice as well as among mice that received (yoked) inescapable shock. In contrast, the depression of responding evident 24 h after stressor application was related to the availability of behavioral coping methods. Finally, following repeated exposure to footshock there was no indication of adaptation to the behavioral changes ordinarily induced by acute shock stress. The data were related to the effects of uncontrollable stressors on escape performance, and with respect to the use of this preparation as an animal model of human depression.     

Cognitive vulnerability to depression: a comparison of the weakest link, keystone and additive models

Multiple theories of cognitive vulnerability to depression have been proposed, each focusing on different aspects of negative cognition and utilising different measures of risk. Various methods of integrating such multiple indices of risk have been examined in the literature, and each demonstrates some promise. Yet little is known about the interrelations among these methods, or their incremental validity in predicting changes in depression. The present study compared three integrative models of cognitive vulnerability: the additive, weakest link, and keystone models. Support was found for each model as predictive of depression over time, but only the weakest link model demonstrated incremental utility in predicting changes in depression over the other models. We also explore the correlation between these models and each model's unique contribution to predicting onset of depressive symptoms.     

Poly I:C母体免疫刺激诱导的子代精神分裂症神经发育动物模型研究

精神分裂症是一组病因未明的重性精神障碍,其病理生理学机制极其复杂,建立能够确切模拟精神分裂症的动物模型对于其发病机制的研究及抗精神分裂症药物的研发具有十分重要的意义。本文意在介绍产前母体免疫刺激（聚肌胞苷酸聚肌苷酸-聚胞苷酸,poly-I:C）诱导子代出现精神分裂症样的神经发育动物模型,以及该模型对精神分裂症的病因研究、生物学机制及其治疗和药物研发的重要意义。     

Toward a biopsychosocial model for 21st-century genetics

Advances in genomic research are increasingly identifying genetic components in major health and mental health disorders. This article presents a Family System Genetic Illness model to address the psychosocial challenges of genomic conditions for patients and their families, and to help organize this complex biopsychosocial landscape for clinical practice and research. This model clusters genomic disorders based on key characteristics that define types of disorders with similar patterns of psychosocial demands over time. Key disease variables include the likelihood of developing a disorder based on specific genetic mutations, overall clinical severity, timing of clinical onset in the life cycle, and whether effective treatment interventions exist to alter disease onset and/or progression. For disorders in which carrier, predictive, or presymptomatic testing is available, core nonsymptomatic time phases with salient developmental challenges are described pre- and post-testing, including a long-term adaptation phase. The FSGI model builds on Rolland's Family System Illness model, which identifies psychosocial types and phases of chronic disorders after clinical onset. The FSGI model is designed to be flexible and responsive to future discoveries in genomic research. Its utility is discussed for research, preventive screening, family assessment, treatment planning, and service delivery in a wide range of healthcare settings.