The use of the elevated plus maze as an assay of anxiety-related behavior in rodents
TL;DR: The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior.
Abstract: The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an open arm, and entries/duration in each arm are recorded by a video-tracking system and observer simultaneously for 5 min. Other ethological parameters (i.e., rears, head dips and stretched-attend postures) can also be observed. An increase in open arm activity (duration and/or entries) reflects anti-anxiety behavior. In our laboratory, rats or mice are exposed to the plus maze on one occasion; thus, results can be obtained in 5 min per rodent.
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TL;DR: This protocol reduces inter-individual variability with the use of a selection criterion based on a minimal time of exploration for both objects during each session, and describes the three most commonly used variants, containing long (3 d), short (1 d) or no habituation phases.
Abstract: The object recognition test is now among the most commonly used behavioral tests for mice. A mouse is presented with two similar objects during the first session, and then one of the two objects is replaced by a new object during a second session. The amount of time taken to explore the new object provides an index of recognition memory. As more groups have used the protocol, the variability of the procedures used in the object recognition test has increased steadily. This protocol provides a necessary standardization of the procedure. This protocol reduces inter-individual variability with the use of a selection criterion based on a minimal time of exploration for both objects during each session. In this protocol, we describe the three most commonly used variants, containing long (3 d), short (1 d) or no habituation phases. Thus, with a short intersession interval (e.g., 6 h), this procedure can be performed in 4, 2 or 1 d, respectively, according to the duration of the habituation phase. This protocol should allow for the comparison of results from different studies, while permitting adaption of the protocol to the constraints of the experimenter.
770 citations
TL;DR: It is shown that sexually dimorphic neurons can control distinct sex-typical behaviors in both sexes, and the corresponding ablation in males reduces mating and aggression.
496 citations
Cites methods from "The use of the elevated plus maze a..."
...For the elevated plus maze test, mice were placed in the center of an elevated maze facing the open arm at the start of the assay (Walf and Frye, 2007)....
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TL;DR: The hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice is tested and dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.
421 citations
Cites methods from "The use of the elevated plus maze a..."
...Overall anxiety and exploratory behavior were assessed using elevated plus (25) and open field assays (26)....
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TL;DR: In CX3CR1-deficient mice, the clearance of myelin debris by microglia is impaired, affecting the integrity of axon and myelin sheaths, a model of demyelination/remyelination.
Abstract: An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow–derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired.
414 citations
TL;DR: The scototaxis (dark/light preference) protocol is a behavioral model for fish that is being validated to assess the antianxiety effects of pharmacological agents and the behavioral effects of toxic substances, and to investigate the (epi)genetic bases of anxiety-related behavior.
Abstract: The scototaxis (dark/light preference) protocol is a behavioral model for fish that is being validated to assess the antianxiety effects of pharmacological agents and the behavioral effects of toxic substances, and to investigate the (epi)genetic bases of anxiety-related behavior. Briefly, a fish is placed in a central compartment of a half-black, half-white tank; following habituation, the fish is allowed to explore the tank for 15 min; the number and duration of entries in each compartment (white or black) are recorded by the observer for the whole session. Zebrafish, goldfish, guppies and tilapias (all species that are important in behavioral neurosciences and neuroethology) have been shown to demonstrate a marked preference for the dark compartment. An increase in white compartment activity (duration and/or entries) should reflect antianxiety behavior, whereas an increase in dark compartment activity should reflect anxiety-promoting behavior. When individual animals are exposed to the apparatus on only one occasion, results can be obtained in 20 min per fish.
399 citations
Cites background from "The use of the elevated plus maze a..."
...as the extent to which the dependent measure predicts behavior on a related measur...
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TL;DR: A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms, which showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
5,391 citations
TL;DR: The plus-maze appears to be a useful test with which to investigate both anxiolytic and anxiogenic agents.
Abstract: To investigate whether an elevated plus-maze consisting of two open and two closed arms could be used as a model of anxiety in the mouse, NIH Swiss mice were tested in the apparatus immediately after a holeboard test. Factor analysis of data from undrugged animals tested in the holeboard and plus-maze yielded three orthogonal factors interpreted as assessing anxiety, directed exploration and locomotion. Anxiolytic drugs (chlordiazepoxide, sodium pentobarbital and ethanol) increased the proportion of time spent on the open arms, and anxiogenic drugs (FG 7142, caffeine and picrotoxin) reduced this measure. Amphetamine and imipramine failed to alter the indices of anxiety. The anxiolytic effect of chlordiazepoxide was reduced in mice that had previously experienced the plus-maze in an undrugged state. Testing animals in the holeboard immediately before the plus-maze test significantly elevated both the percentage of time spent on the open arms and the total number of arm entries, but did not affect the behavioral response to chlordiazepoxide. The plus-maze appears to be a useful test with which to investigate both anxiolytic and anxiogenic agents.
2,504 citations
TL;DR: The responses from a questionnaire distributed to 65 groups that have published studies using the EPM in the past 3 years has, along with reference to published reports, enabled some conclusions regarding the influencing factors to be drawn.
Abstract: Despite or possibly by virtue of the fact that it is one of the most commonly used animal models of anxiety the Elevated Plus-Maze (EPM) results in a wide range of, often contradictory, results following pharmacological experiments. The responses from a questionnaire distributed to 65 groups that have published studies using the EPM in the past 3 years has, along with reference to published reports, enabled some conclusions regarding the influencing factors to be drawn. Some evidence for differential sensitivities between strains exists, with albino rats being more sensitive to the anxiolytic effects of 5-HT3 receptor antagonists and 5-HT1A receptor agonists than pigmented animals. Most important, however, is the manipulation of the animals prior to testing and the aversiveness of the test conditions themselves. Stressing animals before testing (e.g., by moving from holding to test room) or using more aversive test conditions (e.g., elevated light levels) increases sensitivity to potential anxiolytics. Animals that are habituated to gentle handling or tested in less aversive conditions (e.g., EPM with ledges) show reduced likelihood of anxiolytic responses with administration of 5-HT3 antagonists, 5-HT1A agonists, and benzodiazepines.
1,122 citations
TL;DR: Results provide further evidence for the involvement of noradrenergic systems in ‘fear’-motivated behaviour and a paradoxical fall in open arm entries occurred with these agents at higher doses.
Abstract: An elevated X-maze with alternating open and enclosed arms was investigated as a model for the study of fear-induced behaviour. As predicted, the anxiolytics diazepam and amylobarbitone increased, and the putative anxiogenics ACTH and picrotoxin decreased the proportion of open arm entries. The alpha 1-adrenoceptor agonists phenylephrine and ST587, and the alpha 2-adrenoceptor antagonists idazoxan, piperoxane, RS-21361 and yohimbine decreased relative open-arm entries, thus resembling the putative anxiogenics. On the other hand, azepexole, clonidine and guanabenz, agonists at alpha 2-adrenoceptors, and the alpha 1-adrenoceptor antagonists prazosin and thymoxamine, enhanced the proportion of open arm entries at low doses, suggesting anxiolytic-like properties. A paradoxical fall in open arm entries occurred with these agents at higher doses. These results provide further evidence for the involvement of noradrenergic systems in 'fear'-motivated behaviour.
928 citations