Rodent tests of depression and anxiety: Construct validity and translational relevance

Rodent tests of depression and anxiety: Construct validity and translational relevance

27 February 2024 | Sinem Gencturk, Gunes Unal
This review discusses the validity and relevance of rodent behavioral tests for assessing depression and anxiety. Behavioral testing is a key method for evaluating emotional states in non-human animals, particularly rodents, to understand the complex cognitive and affective symptoms of neuropsychiatric disorders. These tests focus on behavioral patterns resembling the superficial symptoms of these disorders. While they have been used to screen novel antidepressant and anxiolytic drug candidates, their construct validity—relating to underlying mechanisms—has been questioned. The review presents laboratory procedures used to assess depressive- and anxiety-like behaviors in rats and mice, including constructs such as behavioral despair and cognitive affective bias. It discusses the criticisms of these tests and introduces novel, ethologically relevant frameworks that emphasize simple behavioral patterns. The review also explores behavioral monitoring and morphological analysis methods that can enhance the construct validity of these tests. The review begins with constructs associated with clinical depression, including learned helplessness, behavioral despair, anhedonia, and cognitive affective bias. It then explores anxiety-like behaviors, focusing on thigmotaxis and approach-avoidance behavior. The nature and evolution of each construct are discussed in relation to their behavioral tests, followed by standardized protocols for each test. The review addresses major criticisms regarding the construct validity and translational relevance of each procedure and explores the contribution of novel theoretical frameworks, such as the RDoC. In the final part, the use of supplementary behavioral monitoring and morphological assessment methods in assessing affective states of rodents is reviewed, highlighting their potential to enhance the construct validity of conventional methods. Learned helplessness (LH) is a model of depression where animals learn to give up after experiencing inescapable aversive stimuli. It was originally developed to measure hopelessness in non-human animals and later associated with clinical depression. LH is considered a valid construct for depression, but its interpretation using human clinical frameworks has been criticized. The review discusses the generalizability of LH and its role in understanding the cognitive processes underlying human depression. Behavioral despair is elicited and measured using the forced swim test (FST) and the tail suspension test (TST). The FST involves placing the animal in a water-filled cylinder, while the TST suspends the animal by its tail. Both tests are used to assess behavioral despair, with the FST being the original test and the TST being developed for mice. The FST is criticized for not measuring the affective phenomenon of behavioral despair but producing differential results due to other factors. The TST shares many of the criticisms of the FST, including the potential for learned, adaptive strategies or passive coping to an acute stressor. Anhedonia, the inability to experience pleasure, is one of the two decisive symptoms of major depressive disorder. It is assessed using the sucrose preference test (SPT) and the female urine sniffing test (FUST). The SPT measures anhedonia by assessing the preference for sweet solutions, while the FThis review discusses the validity and relevance of rodent behavioral tests for assessing depression and anxiety. Behavioral testing is a key method for evaluating emotional states in non-human animals, particularly rodents, to understand the complex cognitive and affective symptoms of neuropsychiatric disorders. These tests focus on behavioral patterns resembling the superficial symptoms of these disorders. While they have been used to screen novel antidepressant and anxiolytic drug candidates, their construct validity—relating to underlying mechanisms—has been questioned. The review presents laboratory procedures used to assess depressive- and anxiety-like behaviors in rats and mice, including constructs such as behavioral despair and cognitive affective bias. It discusses the criticisms of these tests and introduces novel, ethologically relevant frameworks that emphasize simple behavioral patterns. The review also explores behavioral monitoring and morphological analysis methods that can enhance the construct validity of these tests. The review begins with constructs associated with clinical depression, including learned helplessness, behavioral despair, anhedonia, and cognitive affective bias. It then explores anxiety-like behaviors, focusing on thigmotaxis and approach-avoidance behavior. The nature and evolution of each construct are discussed in relation to their behavioral tests, followed by standardized protocols for each test. The review addresses major criticisms regarding the construct validity and translational relevance of each procedure and explores the contribution of novel theoretical frameworks, such as the RDoC. In the final part, the use of supplementary behavioral monitoring and morphological assessment methods in assessing affective states of rodents is reviewed, highlighting their potential to enhance the construct validity of conventional methods. Learned helplessness (LH) is a model of depression where animals learn to give up after experiencing inescapable aversive stimuli. It was originally developed to measure hopelessness in non-human animals and later associated with clinical depression. LH is considered a valid construct for depression, but its interpretation using human clinical frameworks has been criticized. The review discusses the generalizability of LH and its role in understanding the cognitive processes underlying human depression. Behavioral despair is elicited and measured using the forced swim test (FST) and the tail suspension test (TST). The FST involves placing the animal in a water-filled cylinder, while the TST suspends the animal by its tail. Both tests are used to assess behavioral despair, with the FST being the original test and the TST being developed for mice. The FST is criticized for not measuring the affective phenomenon of behavioral despair but producing differential results due to other factors. The TST shares many of the criticisms of the FST, including the potential for learned, adaptive strategies or passive coping to an acute stressor. Anhedonia, the inability to experience pleasure, is one of the two decisive symptoms of major depressive disorder. It is assessed using the sucrose preference test (SPT) and the female urine sniffing test (FUST). The SPT measures anhedonia by assessing the preference for sweet solutions, while the F
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