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A matter of timing: harm reduction in learned helplessness.

Richter SH, Sartorius A, Gass P, Vollmayr B - Behav Brain Funct (2014)

Bottom Line: Learned helplessness has excellent validity as an animal model for depression, but problems in reproducibility limit its use and the high degree of stress involved in the paradigm raises ethical concerns.We therefore aimed to identify which and how many trials of the learned helplessness paradigm are necessary to distinguish between helpless and non-helpless rats.A trial-by-trial reanalysis of tests from 163 rats with congenital learned helplessness or congenital non-learned helplessness and comparison of 82 rats exposed to inescapable shock with 38 shock-controls revealed that neither the first test trials, when rats showed unspecific hyperlocomotion, nor trials of the last third of the test, when almost all animals responded quickly to the stressor, contributed to sensitivity and specificity of the test.

View Article: PubMed Central - PubMed

Affiliation: Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, 68159 Mannheim, Germany. barbara.vollmayr@zi-mannheim.de.

ABSTRACT

Background: Learned helplessness has excellent validity as an animal model for depression, but problems in reproducibility limit its use and the high degree of stress involved in the paradigm raises ethical concerns. We therefore aimed to identify which and how many trials of the learned helplessness paradigm are necessary to distinguish between helpless and non-helpless rats.

Findings: A trial-by-trial reanalysis of tests from 163 rats with congenital learned helplessness or congenital non-learned helplessness and comparison of 82 rats exposed to inescapable shock with 38 shock-controls revealed that neither the first test trials, when rats showed unspecific hyperlocomotion, nor trials of the last third of the test, when almost all animals responded quickly to the stressor, contributed to sensitivity and specificity of the test. Considering only trials 3-10 improved the classification of helpless and non-helpless rats.

Conclusions: The refined analysis allows abbreviation of the test for learned helplessness from 15 trials to 10 trials thereby reducing pain and stress of the experimental animals without losing statistical power.

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Related in: MedlinePlus

Reanalysis of data from 163 congenitally helpless (cLH, n = 88) and non-helpless rats (cNLH, n = 75). A: All rats have been tested for learned helplessness at the age of nine or ten weeks to confirm the helpless or non-helpless phenotype in the escape paradigm. The test consisted of 15 trials in which an electric foot shock (0.8 mA, 60 s) could be terminated by the animals pressing a bar. Latency until pressing the lever is given separately for the strains as means ± SEM. As indicated by the red box, the latency difference between cLH and cNLH was most pronounced between trials 3 to 6. B and C: Receiver Operating Characteristic (ROC)-curves: In a ROC-curve the true positive rate (sensitivity) is plotted in function of the false positive rate (100-specificity). A test with perfect discrimination (no overlap between the two distributions) has a ROC-curve that passes through the upper left corner (100% sensitivity, 100% specificity). Therefore the closer the ROC curve is to the upper left corner, the higher the overall accuracy of the test [14]. Latency measurements of trials 3 to 6 classified cLH and cNLH rats with at least the same sensitivity and specificity as being helpless or non-helpless as trials 1 to 15 did.
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Fig1: Reanalysis of data from 163 congenitally helpless (cLH, n = 88) and non-helpless rats (cNLH, n = 75). A: All rats have been tested for learned helplessness at the age of nine or ten weeks to confirm the helpless or non-helpless phenotype in the escape paradigm. The test consisted of 15 trials in which an electric foot shock (0.8 mA, 60 s) could be terminated by the animals pressing a bar. Latency until pressing the lever is given separately for the strains as means ± SEM. As indicated by the red box, the latency difference between cLH and cNLH was most pronounced between trials 3 to 6. B and C: Receiver Operating Characteristic (ROC)-curves: In a ROC-curve the true positive rate (sensitivity) is plotted in function of the false positive rate (100-specificity). A test with perfect discrimination (no overlap between the two distributions) has a ROC-curve that passes through the upper left corner (100% sensitivity, 100% specificity). Therefore the closer the ROC curve is to the upper left corner, the higher the overall accuracy of the test [14]. Latency measurements of trials 3 to 6 classified cLH and cNLH rats with at least the same sensitivity and specificity as being helpless or non-helpless as trials 1 to 15 did.

Mentions: For the present analysis, all LH data from the subsequent generations 72, 73, and 74 of the colonies bred at the Central Institute of Mental Health in Mannheim were pooled and re-analysed with respect to latency measurements (data of males of the generations 72 and 73 have previously been published [14]). Already the descriptive presentation of the latency measures over the time course of the LH-test showed that reactions to shock exposure might be confounded or overlaid by other behavioral processes occurring at the same time (Figure 1A): Upon first exposure to shock all animals reacted with some kind of hyperlocomotive agitation in the box, paralleled by a more or less incidental pressing of the lever. In the subsequent trials, cNLH were characterized by constantly low latencies, showing that they have quickly learned the contingency between bar-pressing and shock termination, while cLH rats showed typical freezing behavior accompanied by higher latencies to terminate the shock. Around trials 6 to 7, latencies started to decrease also in cLH rats, documenting the learning process in these rats. Consequently, the difference between cLH and cNLH rats in the mean latencies to press the lever was most pronounced in the first half of testing, specifically between trials 3 to 6, and then became less apparent in the second half of the trials (Figure 1A). However, to be able to reliably distinguish between helpless and non-helpless animals, it is important to disentangle the specific LH behavior from other behavioral processes, such as hyperlocomotion superimposed during the first trials, or learning, becoming apparent as LH-specific behavior ceases. Therefore, to find out, which trials maximise the discriminative power, we summed up latencies across one to six subsequent trials (bin sizes 1–6), and calculated the area under the ROC-curves (AUC, measure of how well a parameter can distinguish between two groups [15]) for each sliding window (Table 1). As already assumed on the basis of the descriptive analysis (Figure 1A), we found the highest AUC value for trials 3 to 6 (bin size 4, Table 1). Here, the absolute AUC value was even higher (Figure 1B) than the AUC based on all trials (Figure 1C), indicating at least equal sensitivity and specificity using this specific trial window.Figure 1


A matter of timing: harm reduction in learned helplessness.

Richter SH, Sartorius A, Gass P, Vollmayr B - Behav Brain Funct (2014)

Reanalysis of data from 163 congenitally helpless (cLH, n = 88) and non-helpless rats (cNLH, n = 75). A: All rats have been tested for learned helplessness at the age of nine or ten weeks to confirm the helpless or non-helpless phenotype in the escape paradigm. The test consisted of 15 trials in which an electric foot shock (0.8 mA, 60 s) could be terminated by the animals pressing a bar. Latency until pressing the lever is given separately for the strains as means ± SEM. As indicated by the red box, the latency difference between cLH and cNLH was most pronounced between trials 3 to 6. B and C: Receiver Operating Characteristic (ROC)-curves: In a ROC-curve the true positive rate (sensitivity) is plotted in function of the false positive rate (100-specificity). A test with perfect discrimination (no overlap between the two distributions) has a ROC-curve that passes through the upper left corner (100% sensitivity, 100% specificity). Therefore the closer the ROC curve is to the upper left corner, the higher the overall accuracy of the test [14]. Latency measurements of trials 3 to 6 classified cLH and cNLH rats with at least the same sensitivity and specificity as being helpless or non-helpless as trials 1 to 15 did.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4232717&req=5

Fig1: Reanalysis of data from 163 congenitally helpless (cLH, n = 88) and non-helpless rats (cNLH, n = 75). A: All rats have been tested for learned helplessness at the age of nine or ten weeks to confirm the helpless or non-helpless phenotype in the escape paradigm. The test consisted of 15 trials in which an electric foot shock (0.8 mA, 60 s) could be terminated by the animals pressing a bar. Latency until pressing the lever is given separately for the strains as means ± SEM. As indicated by the red box, the latency difference between cLH and cNLH was most pronounced between trials 3 to 6. B and C: Receiver Operating Characteristic (ROC)-curves: In a ROC-curve the true positive rate (sensitivity) is plotted in function of the false positive rate (100-specificity). A test with perfect discrimination (no overlap between the two distributions) has a ROC-curve that passes through the upper left corner (100% sensitivity, 100% specificity). Therefore the closer the ROC curve is to the upper left corner, the higher the overall accuracy of the test [14]. Latency measurements of trials 3 to 6 classified cLH and cNLH rats with at least the same sensitivity and specificity as being helpless or non-helpless as trials 1 to 15 did.
Mentions: For the present analysis, all LH data from the subsequent generations 72, 73, and 74 of the colonies bred at the Central Institute of Mental Health in Mannheim were pooled and re-analysed with respect to latency measurements (data of males of the generations 72 and 73 have previously been published [14]). Already the descriptive presentation of the latency measures over the time course of the LH-test showed that reactions to shock exposure might be confounded or overlaid by other behavioral processes occurring at the same time (Figure 1A): Upon first exposure to shock all animals reacted with some kind of hyperlocomotive agitation in the box, paralleled by a more or less incidental pressing of the lever. In the subsequent trials, cNLH were characterized by constantly low latencies, showing that they have quickly learned the contingency between bar-pressing and shock termination, while cLH rats showed typical freezing behavior accompanied by higher latencies to terminate the shock. Around trials 6 to 7, latencies started to decrease also in cLH rats, documenting the learning process in these rats. Consequently, the difference between cLH and cNLH rats in the mean latencies to press the lever was most pronounced in the first half of testing, specifically between trials 3 to 6, and then became less apparent in the second half of the trials (Figure 1A). However, to be able to reliably distinguish between helpless and non-helpless animals, it is important to disentangle the specific LH behavior from other behavioral processes, such as hyperlocomotion superimposed during the first trials, or learning, becoming apparent as LH-specific behavior ceases. Therefore, to find out, which trials maximise the discriminative power, we summed up latencies across one to six subsequent trials (bin sizes 1–6), and calculated the area under the ROC-curves (AUC, measure of how well a parameter can distinguish between two groups [15]) for each sliding window (Table 1). As already assumed on the basis of the descriptive analysis (Figure 1A), we found the highest AUC value for trials 3 to 6 (bin size 4, Table 1). Here, the absolute AUC value was even higher (Figure 1B) than the AUC based on all trials (Figure 1C), indicating at least equal sensitivity and specificity using this specific trial window.Figure 1

Bottom Line: Learned helplessness has excellent validity as an animal model for depression, but problems in reproducibility limit its use and the high degree of stress involved in the paradigm raises ethical concerns.We therefore aimed to identify which and how many trials of the learned helplessness paradigm are necessary to distinguish between helpless and non-helpless rats.A trial-by-trial reanalysis of tests from 163 rats with congenital learned helplessness or congenital non-learned helplessness and comparison of 82 rats exposed to inescapable shock with 38 shock-controls revealed that neither the first test trials, when rats showed unspecific hyperlocomotion, nor trials of the last third of the test, when almost all animals responded quickly to the stressor, contributed to sensitivity and specificity of the test.

View Article: PubMed Central - PubMed

Affiliation: Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, 68159 Mannheim, Germany. barbara.vollmayr@zi-mannheim.de.

ABSTRACT

Background: Learned helplessness has excellent validity as an animal model for depression, but problems in reproducibility limit its use and the high degree of stress involved in the paradigm raises ethical concerns. We therefore aimed to identify which and how many trials of the learned helplessness paradigm are necessary to distinguish between helpless and non-helpless rats.

Findings: A trial-by-trial reanalysis of tests from 163 rats with congenital learned helplessness or congenital non-learned helplessness and comparison of 82 rats exposed to inescapable shock with 38 shock-controls revealed that neither the first test trials, when rats showed unspecific hyperlocomotion, nor trials of the last third of the test, when almost all animals responded quickly to the stressor, contributed to sensitivity and specificity of the test. Considering only trials 3-10 improved the classification of helpless and non-helpless rats.

Conclusions: The refined analysis allows abbreviation of the test for learned helplessness from 15 trials to 10 trials thereby reducing pain and stress of the experimental animals without losing statistical power.

Show MeSH
Related in: MedlinePlus