Abstract
Negative cognitive bias—the tendency to interpret ambiguous situations pessimistically—is a central feature of stress-related disorders such as depression. The underlying neurobiology of this bias, however, remains unclear, not least because of a lack of translational tools. We established a new ambiguous-cue interpretation paradigm and, with respect to the etiology of depression, evaluated if environmental and genetic factors contribute to a negative bias. Rats were trained to press a lever to receive a food reward contingent to one tone and to press another lever in response to a different tone to avoid punishment by electric foot-shock. In the ambiguous-cue test, the lever-press responses to tones with frequencies intermediate to the trained tones were taken as indicators for the rats' expectation of a positive or negative event. A negative response bias because of decreased positive and increased negative responding was found in congenitally helpless rats, a genetic animal model of depression. Moreover, treatment with a combined noradrenergic-glucocorticoid challenge, mimicking stress-related changes in endogenous neuromodulation, biased rats away from positive responding. This response shift was accompanied by neuronal activation in dentate gyrus and amygdala. Thus, environmental and genetic risk factors for depression induce a response bias, which resembles the pessimistic bias of patients suffering from depression. The behavioral paradigm described constitutes a useful tool to study the neuronal basis of decision making under ambiguous conditions and may promote innovative pharmaco- and psychotherapy for depression.
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Acknowledgements
We thank A Meyer-Lindenberg, B Krumm, and C Hiemke for valuable discussion, the unknown reviewers for helpful comments and H Schamber and C Dormann for technical support. BV, and RH were supported by the German Federal Ministry of Education and Research (BMBF) as a part of the research consortium ‘The neurofunctional basis of emotion-cognition coupling’. In addition, RH was supported by a Starting Independent Researcher Grant provided by the Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia (MIWFT). PG was supported by the Deutsche Forschungsgemeinschaft (SFB 636/B3). CS-S was supported by a contract of the Ramón y Cajal program from the Spanish Ministerio de Ciencia e Innovación.
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Dr Spanagel holds research and consultant contracts with Abbott, GSK, Organon, Solvay and XenoPort. All other authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)
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Enkel, T., Gholizadeh, D., von Bohlen und Halbach, O. et al. Ambiguous-Cue Interpretation is Biased Under Stress- and Depression-Like States in Rats. Neuropsychopharmacol 35, 1008–1015 (2010). https://doi.org/10.1038/npp.2009.204
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DOI: https://doi.org/10.1038/npp.2009.204
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