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.
Anxiety Models Stress-induced
Fear conditioning models involve the encoding of traumatic memories, representing a psychological stress without physical stimuli. In this model, administration of anxiolytic drugs immediately before the pairing of CS and US during the memory acquisition process affects the formation of conditioned learning. If administration occurs before the re-exposure to CS, it will affect fear and anxiety expression acquired during the conditioning.
The drug could also affect extinction of the conditioned response, where a new learning process that the CS no longer predicts the occurrence of the UCS occurs after repeated exposure to a CS in the absence of the US. Systemic administration of benzodiazepines or SSRIs reduces the freezing behavior observed during the expression of conditioned fear. Defensive behaviors are observed in all mammalian species and occur in response to threatening cues, such as the presence of live predators and environmental hazards.
In rats, exposure to a live cat or to its odor elicits specific behaviors, such as fight, freezing, risk-assessment, and autonomic activation. These responses are accompanied by a reduction in locomotor activity and in non-defensive behaviors, such as grooming and reproduction. Furthermore, live cat exposure is usually resistant to habituation, has a strong contextual conditioning component, and induces anxiogenic-like effects in animals that are subsequently exposed to other anxiety models, such as the EPM see below.
This model was pharmacologically validated with the observation that chronic administration of panicolytic drugs decreases the fight reactions induced by the presence of the predator, whereas benzodiazepines preferentially inhibit the avoidance behavior. However, acute treatment with benzodiazepines did not reduce the defensive behaviors elicited by odor itself. The periaqueductal grey matter PAG is a midbrain structure that, among other functions, integrates defensive behavior. In humans, electrical stimulation of this structure evokes strong feelings of fear, impending death, non-localized pain, and marked autonomic changes.
Stimulation of the dPAG is usually performed in a circular arena 40 cm in diameter with 40 cm-high walls made of transparent Plexiglas.
For electrical stimulation, a brain electrode is connected to the stimulator by means of an electromechanical swivel and a flexible cable, allowing ample movement of the animal inside the experimental cage. The current is generated by a sine-wave stimulator and monitored on the screen of an oscilloscope. The influence of stressful situations on anxiety-like behavior: Several studies conducted on animals and volunteers have suggested that stressful experiences occurring throughout life may contribute crucially to the development and pathogenesis of several psychiatric disorders, including mood disorders, schizophrenia, and anxiety.
Several studies have reported the association between exposure to stressful situations and subsequent episodes of major depression. For example, patients who apparently experienced some stressful situation in the course of their lives have more intense episodes of panic attacks 89 , 90 and are more vulnerable to the development of PTSD, a disorder that involves an individual overreaction to an initial exposure to traumatic event. It was only in the last three decades that the relationship between somatic and psychological consequences promoted by exposure to extreme stressors and the neurobiological substrate involved in these processes started to be better understood.
This advance was made possible by the development of models that aim to evaluate behavioral changes induced by acute or chronic exposure to stressors predators, shocks, movement restriction , which respond to clinically effective drugs.
The main differences among these models relate to the duration chronic vs. PTSD is a debilitating chronic condition that reflects emotional and physiological modifications following an initial reaction to a traumatic experience. PTSD modeling in laboratory animals has been a particular challenge, since some of the symptoms of this disorder nightmares, invasive thoughts cannot be evaluated. Essentially, these models induce stress by exposing the animals to psychological or physical challenges.
These procedures may be used in acute or chronic studies depending on the objectives and parameter chosen by the experimenter to evaluate the impact of stress on anxiety. The main protocols used are presented in Table 2 and briefly described below. Early-life stressful experiences, such as maternal separation or neonatal isolation, promote long-lasting neural and behavioral effects and have profound consequences on subsequent quality of life.
White noise is played in the background to mask the vocalizations of other pups. 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.
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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. 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.
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Animal models of anxiety disorders in rats and mice: some conceptual issues
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.