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Models Stress-induced Anxiety



  • Models Stress-induced Anxiety
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  • Opinion ARTICLE
  • The development of animal models of anxiety and stress has helped to identify the pharmacological mechanisms and potential clinical effects of several drugs. Braz J Psychiatry. ;35 Suppl 2:S doi: / . Animal models of anxiety disorders and stress. Campos AC(1), Fogaça MV. Some of the other issues that we would like to discuss here are the following: (i) How does anxiety relate to individual stress/fear coping strategies, and how are.

    Models Stress-induced Anxiety

    After the 1-hour period, the litters are placed back with their dams in their home cages. This model has been used extensively to demonstrate the effect of early lifetime stress on vulnerability to addiction and in the generation of anxiety-like behaviors, which are usually observed in the adult rodents subjected to the contextual fear conditioning, EPM, or social interaction tests. Alterations in circadian rhythm have a profound impact on the physical and psychological homeostasis of an individual.

    Another possibility is to promote four or five cycles of dark-light phases minutes during the circadian cycle. This is a good method for induction of short-term stress responses, but repeated exposure may lead to adaptation. Responses to this stressor can be evaluated by measuring biochemical parameters associated with stress response and using the previously described animal models of anxiety. Humans are constantly exposed to potentially hazardous levels of noise in modern daily life.

    In model animals, noise stress can be induced by using loudspeakers 15 W connected to a white noise generator kHz located 30 cm above the cage. The noise can be set at a certain level e. Changes in body temperature lead to stressful responses due to activation of the thermoregulatory center and, subsequently, of the HPA axis. This procedure can be used in acute or chronic protocols days.

    Restraint stress and immobilization protocols are one of the most commonly employed procedures to induce stress-related behavioral, biochemical and physiological changes in laboratory animals. The procedure can be used to induce either acute or chronic stress days. Immobilization models produce an inescapable physical and mental stress with a low rate of adaptation.

    This protocol is very similar to the pre-test session described in fear conditioning-based models. Rodents are very susceptible to mild shocks, exhibiting a remarkable stress response after foot shock delivery.

    The protocol consists of placing rodents in a chamber with a metal grid floor connect to a shock generator. After a habituation period, animals receive mild mA , brief s duration foot shocks. Like other stress protocols, electric foot shocks can be combined with anxiety tests.

    The time spent by an intruder mouse in social defeat posture induced by the presence of an aggressor is computed throughout five trials by a blind observer.

    Defeat posture is identified by the followed criteria: The chronic unpredictable stress CUS model has been widely used to induce persisting stress-related behavioral changes in rodents. This scheme prevents the stress adaptation process observed in other models of chronic stress.

    After several days of exposure to this regimen, the animals exhibit a gradually increased HPA axis sensitivity and a decrease in responses to pleasant stimuli, without, however, any change in exploratory activity. This protocol has good face validity and seems to represent the stressors faced by humans in everyday life more realistically. Moreover, it has excellent predictive validity, since repeated treatment with antidepressants fluoxetine, desipramine, or imipramine is able to reverse the behavioral effects induced by this model.

    The number of stress and anxiety animal models currently available is significantly greater then when these models first entered research use 50 years ago. This means the choice of the most appropriate model for a specific experiment is not always a straightforward task. Ideally, this choice should be based on the hypothesis being tested, the design of the experiment, the experience of the investigator, and knowledge of the limitations of the model.

    Particular attention should be paid to procedures that can control for false-positive or false-negative results and bias induced by local laboratory conditions. Some of these aspects have been addressed in the current review.

    Despite their drawbacks, animal models are invaluable tools for investigation of the neurobiology of anxiety- and stress-related disorders. American Psychiatric Publishing; Prevalence and treatment of mental disorders, to N Engl J Med.

    Longitudinal trajectories of depression and anxiety in a prospective community study: The expression of the emotions in man and animals.

    Animal models of anxiety in mice. Ethologically-based animal models of anxiety disorders. Ethological evaluation of the effects of acute and chronic buspirone treatment in the murine elevated plus-maze test: The relation between fear induced by novel stimulation and exploratory behavior. J Comp Physiol Psychol. The arousal and satiation of perceptual curiosity in the rat. File SE, Day S. Effects of time of day and food deprivation on exploratory activity in the rat.

    Relationships between exploratory behaviour and fear: Differential behavioral and neurochemical effects following lesions of the dorsal or median raphe nuclei in rats. Handley SL, Mithani S. Naunyn Schmiedebergs Arch Pharmacol. Pellow S, File SE. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: The use of a plus-maze to measure anxiety in the mouse.

    Behavioural detection of anxiolytic action. Experimental approaches to anxiety and depression. Attack and defense in rodents as ethoexperimental models for the study of emotion. Prog Neuropsychopharmacol Biol Psychiatry. Behavioral effects of acute and chronic imipramine in the elevated T-maze model of anxiety. Crawley J, Goodwin FK. Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines.

    Interaction between purine and benzodiazepine: Inosine reverses diazepam-induced stimulation of mouse exploratory behavior. Validity of head-dipping as a measure of exploration in a modified hole-board. Some doubts about the basic concept of hole-board test. Effects of chlorpromazine on exploration and habituation in the rat.

    The effects of benzodiazepines on the behaviour of mice on a hole-board. Can social interaction be used to measure anxiety? The age of anxiety: The effects of chronic antidepressant treatment in an animal model of anxiety.

    Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety.

    The acquisition and extinction of conditioned suppression as a function of the base-line reinforcer. J Exp Anal Behav. A simple and reliable conflict procedure for testing anti-anxiety agents. Millan MJ, Brocco M. The Vogel conflict test: Simple method for CER conditioning and measurement. Anti-conflict efficacy of buspirone following acute versus chronic treatment. Effects of acute and chronic imipramine administration on conflict behavior in the rat: Comparison of the anticonflict effect of buspirone and its major metabolite 1- 2-pyrimidinyl -piperazine 1-PP in rats.

    Acute and chronic administration of buspirone fails to yield anxiolytic-like effects in a mouse operant punishment paradigm. Pearce JM, Hall G. A model for Pavlovian learning: Neural circuits and mechanisms involved in Pavlovian fear conditioning: Neurobiology of Pavlovian fear conditioning. Emotion circuits in the brain. Conditioned and unconditional components of post-shock freezing.

    Pavlov J Biol Sci. Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex. Understanding contextual fear conditioning: Effects of acute citalopram on the expression of conditioned freezing in naive versus chronic citalopram-treated rats.

    Molecular mechanisms of fear learning and memory. Mineka S, Oehlberg K. The relevance of recent developments in classical conditioning to understanding the etiology and maintenance of anxiety disorders. SSRIs and conditioned fear. Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats. Effect of citalopram, a selective serotonin reuptake inhibitor, on the acquisition of conditioned freezing.

    Effect of a serotonin and noradrenaline uptake inhibitor in panic disorder; a double-blind comparative study with fluvoxamine and maprotiline. Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled study. Effect of chronic administration of flesinoxan and fluvoxamine on freezing behavior induced by conditioned fear. Contextual conditioning in rats as an animal model for generalized anxiety disorder.

    Cogn Affect Behav Neurosci. The characterization and modelling of antipredator defensive behavior. Ethoexperimental approaches to the biology of emotion. Exploration and predation models of anxiety: Conditioning and residual emotionality effects of predator stimuli: Kavaliers M, Choleris E. Antipredator responses and defensive behavior: Neural correlates of cat odor-induced anxiety in rats: The effects of predator odors in mammalian prey species: NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure--implications for anxiety associated with posttraumatic stress disorder.

    Predator threat stress promotes long lasting anxiety-like behaviors and modulates synaptophysin and CB1 receptors expression in brain areas associated with PTSD symptoms.

    Differentiation of anxiolytic and panicolytic drugs by effects on rat and mouse defense test batteries. Further evidence that the mouse defense test battery is useful for screening anxiolytic and panicolytic drugs: Chlordiazepoxide reduces the generalised anxiety, but not the direct responses, of rats exposed to cat odor. Sensations evoked by stimulation in the midbrain of man. Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors.

    Heim C, Nemeroff CB. The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Role of corticotropin releasing factor in anxiety disorders: Recent advances in the neurobiology of anxiety disorders: Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress.

    Psychosocial support and change in the health status of physically disabled people. Life stress and symptom pattern in out-patient depression. Stress factors in affective diseases. Kandler K, Katz LC. Neuronal coupling and uncoupling in the developing nervous system. Savoia MG, Bernik M. Adverse life events and coping skills in panic disorder. Life events and social support in a 1-year preceding panic disorder.

    The burn as a continuous traumatic stress: J Burn Care Rehabil. Why stress is bad for your brain. Cortisol regulation in posttraumatic stress disorder and major depression: Integr Physiol Behav Sci.

    Overview of biological themes in PTSD. Ann N Y Acad Sci. Adamec RE, Shallow T. Lasting effects on rodent anxiety of a single exposure to a cat. Transmitter systems involved in neural plasticity underlying increased anxiety and defense--implications for understanding anxiety following traumatic stress.

    The effect of early poststressor intervention with sertraline on behavioral responses in an animal model of post-traumatic stress disorder. Long-lasting, selective, anxiogenic effects of feline predator stress in mice. Fos expression following regimens of predator stress versus footshock that differentially affect prepulse inhibition in rats. Maternal care and the development of stress responses. Enhanced acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience.

    Kosten TA, Ambrosio E. HPA axis function and drug addictive behaviors: Kosten TA, Kehoe P. Neonatal isolation is a relevant model for studying the contributions of early life stress to vulnerability to drug abuse: Affiliative behavior attenuates stress responses of GI tract via up-regulating hypothalamic oxytocin expression.

    Maniam J, Morris MJ. Long-term postpartum anxiety and depression-like behavior in mother rats subjected to maternal separation are ameliorated by palatable high fat diet. Neonatal isolation enhances anxiety-like behavior following early-life seizure in rats. American Physiological Society, Diurnal variations in responsiveness of the hypothalamo-pituitary-adrenocortical axis of the rat.

    Comparative study of perturbations of peripheral markers in different stressors in rats. Can J Physiol Pharmacol. Influence of light at night on murine anxiety- and depressive-like responses.

    Effects of long-term continuous exposure to light on memory and anxiety in mice. Noise-stress-induced brain neurotransmitter changes and the effect of Ocimum sanctum Linn treatment in albino rats. Manikandan S, Devi RS. Thus, when an animal faces a predator, freezing is preferentially activated when the source of known danger is still far away. Coping strategies provide a new, interesting theoretical framework for models investigating the role of individual differences in vulnerability to anxiety disorders, and their genetic and epigenetic determinants.

    Learning the relationships between aversive events and environmental stimuli which predict these events is essential for survival. The neurobiological bases of fear conditioning have been extensively investigated during the last decades. The critical stage appears to be not the training conditioning phase, when the conditional CS and unconditional US stimuli are presented in a meaningful temporal relationship, but the extinction phase, when the CS is presented alone without the reinforcement stimulus , during the time necessary for extinction to occur; some individuals fail to repress the memory of fear and show all the behavioral and physiological signs normally triggered in the presence of an actual threat.

    Thus, fear conditioning provides another relevant theoretical framework for translational studies on anxiety disorders. This can be a major source of anxiety.

    In any case, making a decision when the consequences are unpredictable is a source of stress. Frustration can also be a source of anxiety, could be considered as a particular form of conflict. Frustration occurs when there is a discrepancy between the expected and actual outcome of an action.

    For instance, if you train animals to reach a goal by obeying certain rules, and then change the rules, they get very upset and enter a motivational conflict. This situation is very frequent in humans, and can lead not only to various anxiety disorders, but also to depression. Conflict situations are present, directly or indirectly, in most animal models of anxiety.

    Thus, during exploration of a novel environment a situation encountered in many of the tests , there is always a conflict between curiosity knowing more about it and fear how risky is it? In rats, this conflict may be displayed in the form of a displacement activity such as self-grooming.

    The capacity to remember past events and situations particularly frightful or traumatic ones , and to anticipate them, parallels the development of the corticolimbic system during evolution. Generalized Anxiety Disorder GAD is probably linked to a bias in anticipating adverse circumstances often without any obvious threat , whereas PTSD certainly results from a deficit in repressing traumatic memories.

    This is also the case, on a more elementary level, lor various kinds of phobic disorders, although some of these may be associated with more primitive, species-related fear memories. Individual differences in coping styles, and in the capacity to deal with learned fear, conflict, fear memories, and anticipation of adverse events are thus the most important factors determining vulnerability to anxiety disorders.

    Genetic and epigenetic predisposition factors do also play an important role, either per se or in combination with the above. In the following sections, we will see how and to what extent these concepts are applied in various animal models of anxiety disorders. Reference is sometime made to two sorts of anxiety: Trait anxiety is supposed to be a predisposing factor for anxiety disorders. The mismatch hypothesis and the concept of adaptive phenotypic plasticity have been recently proposed in the context of animal models of depression in order to explain why some individuals may develop depression-like symptoms in adulthood when exposed to chronic stress in early life, while others do well or even better.

    Thus, rat pups born from mothers having been stressed during pregnancy tend to be more anxious than their counterparts raised by non-stressed mothers. For this reason, it has been recently proposed that the basis for vulnerability to disease could involve genes yet to be discovered that would be responsible for different forms of brain and behavioral plasticity.

    Animal models of psychiatric disorders can belong to both categories. The only variables that can be observed and measured in animals are the behavioral and physiological responses elicited when they are exposed to more or less naturalistic, potentially anxiogenic situations under controlled laboratory conditions. This usage should be avoided, because it is misleading: In the following section, we will mention a few examples of mainly ethological anxiety tests for rodents, which are by far the most common species used as animals models nowadays.

    There are over 30 different procedures and many variations described in the literature, with two main categories: More information regarding practical aspects of testing can be found in the literature 55 - 58 and in the references in Table I.

    In the mid s, Willner proposed three sets of criteria for assessing animal models of human mental disorders: Thus, risk factors such as adverse early life events should only affect a subpopulation of more vulnerable individuals.

    Application of this criterion poses a number of problems, notably regarding the number of animals which have to be used. In our views, the obvious answer to that question is: First, the classifications of psychiatric diseases either with the DSM-IV or ICD systems remain essentially syndromic and is constantly being revised.

    And third, some important aspects of human pathology will probably never be accessible in animal models eg, sadness or suicidal ideation in depression.

    However, some symptoms found in anxiety disorders can probably be modeled quite accurately in rats or mice. Development of animal partial-models in psychiatry relies on identifying critical components of behavior or other neurobiological traits that are representative of more complex phenomena.

    Animals will never have guilty ruminations, suicidal thoughts, or rapid speech. Thus, animal models based on endophenotypes that represent, evolutionarily selected and quantifiable traits may better lend themselves to investigation of psychiatric phenomena than models based on face-valid diagnostic phenotypes. As compared with other psychiatric disorders eg, schizophrenia , only a few endophenotypes for anxiety have been proposed so far.

    One is HPA axis activation and other parameters associated with an inhibited fearful temperament. Other, more psychophysiological endophenotypes that have been suggested are C0 2 sensitivity for panic disorder, 78 stress-induced hyperthermia SIH , which is found across numerous species, including humans, and reflects SAM activation, 79 and the startle response, which is also found in humans and various species. Further progress in the field of animal models of anxiety will certainly rely heavily on discovering and validating more endophenotypes, in particular those related to individual brain and behavioral plasticity, and the capacity to adapt to stressful experiences.

    A number of rat lines have been proposed as models of trait anxiety: As regards the genetic bases of vulnerability to anxiety disorders, many different approaches are being used, apart from using selected lines. These include targeted manipulation of candidate genes eg, generation of knockout or transgenic animals , siRNA and viral transfection, quantitative trait loci QTL analysis, and the use of gene expression arrays, among others.

    In , the National Institute of Mental Health NIMH organized a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders.

    The conclusions were not too optimistic:. The probability of developing comprehensive animal models that, accurately reflect the relative influences of factors contributing to anxiety disorder syndromes is quite low. However, ample opportunity remains to better define and extend existing models and behavioral measures related to specific processes that may be disrupted in anxiety disorders, and to develop new models that consider the impact of combined factors in determining anxious behaviors.

    Indeed, the last decade has seen some major conceptual progress. First, the primary importance of individual differences in personality, temperament, or coping style as regards vulnerability to various anxiety disorders has been recognized, not only in psychiatry, but also in animal models.

    Second, some recent discoveries have also indicated an important role for behavioral flexibility and adaptive neural plasticity. This suggests that some disorders may result from a deficit in various forms of brain and behavioral plasticity and perhaps depend, at least in part, on altered neurodevelopmental processes. One issue that remains unsettled is the following: It is likely that the answer will depend not only on the intrinsic validity of the models, but also on refining diagnostic criteria for anxiety disorders, which will have to be based at least in part on the description of relevant endophenotypes.

    This implies a bidirectional exchange of information and hypotheses between clinicians and neurobiologists, which is after all the true essence of translational research. National Center for Biotechnology Information , U. Journal List Dialogues Clin Neurosci v. Author information Copyright and License information Disclaimer. This is an open-access article distributed under the terms of the Creative Commons Attribution License http: This article has been cited by other articles in PMC.

    Introduction This brief review will focus on rodent rat and mouse models of anxiety disorders. Open in a separate window. Alternative defense coping strategies in response to threat.

    See text for details. Fear conditioning Learning the relationships between aversive events and environmental stimuli which predict these events is essential for survival. Conflict Motivational conflict This can be a major source of anxiety. Frustration Frustration can also be a source of anxiety, could be considered as a particular form of conflict.

    Memories and anticipation The capacity to remember past events and situations particularly frightful or traumatic ones , and to anticipate them, parallels the development of the corticolimbic system during evolution. Trait vs state anxiety Reference is sometime made to two sorts of anxiety: Animal models and tests What is a model? How do we measure anxiety in animals? Models or tests of anxiety in rodents. For a definition of tests vs models, see text.

    See also refs 95, Adapted from ref Animal models of 'anxiety': How can we assess the validity of models? Should models be based on clinical symptom classification? How can we define endophenotypes for anxiety? What are the current trends in animal models? Summary and conclusions In , the National Institute of Mental Health NIMH organized a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders.

    The conclusions were not too optimistic: Non-human primate models for investigating fear and anxiety. Penser comme un rat. A neuro-evolutionary approach to the anxiety disorders. Threat detection, precautionary responses, and anxiety disorders. Adult zebrafish as a model organism for behavioural genetics. Use of zebrafish as a model to understand mechanisms of addiction and complex neurobehavioral phenotypes.

    Measuring anxiety in zebrafish: Anxiety from a phylogenetic perspective: The biology of fear - and anxiety - related behaviors. Coping styles in animals: Human defensive behaviors to threat scenarios show parallels to fear - and anxiety - related defense patterns of non-human mammals. Evolutionary background for stress-coping styles: Relationships between physiological, behavioral, and cognitive traits in non-mammalian vertebrates.

    Some guidelines for defining personality differences in rats. Handbook of Behavior Genetics. Coping styles and behavioural flexibility: Health and the Social Environment: Physiology, Emotions and Psychosomatic Illness.

    Effects of early stress on adult affiliative behavior. The role of defeat and entrapment in depression, anxiety, and suicide. Ethological strategies for defence in animals and humans: Br J Med Psychol. Biting suppresses stress-induced expression of corticotropin-releasing factor CRF in the rat hypothalamus. Behavioral and neuroendocrine correlates of displaced aggression in trout. A call to action: The structure of the emotions and the limbic system.

    Gray's Reinforcement Sensitivity Theory as a framework for research on personality-psychopathology associations. The role of theory in the psychophysiology of personality: Interdisciplinary approach to its mechanisms and physiopathology. Emotion, Inhibition and Health. The Stress of Life. The Foundations of Human and Animal Emotions.

    The psychoneurology of fear: Handbook of Anxiety Vol. Elsevier Science Publishers BV. Neurobiology of Pavlovian fear conditioning. Fear and the brain:

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    Naturalistic models of survival threat Fear-and anxiety-based paradigms. Exposure to a predator is. Review Article. Describing some behavioural animal models of anxiety and their mechanistics with special reference to oxidative stress and oxytocin relevance. More promising are models that make use of the anxiogenic potential of stress. Stress is among the aetiological factors of anxiety and human patients are.

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