Negative cognitive biasFthe tendency to interpret ambiguous situations pessimisticallyFis 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 leverpress 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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The time course of central and peripheral BDNF changes may significantly differ. However, we demonstrate substantial evidence that it can be justified to measure serum BDNF levels with a time delay to monitor brain tissue neurotrophin alterations.

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Investigations of cognitive biases in animals are conceptually and translationally valuable because they contribute to animal welfare research and help to extend and refine our understanding of human emotional disorders, where biased information processing is a critical causal and maintenance factor. We employed the "learned helplessness" genetic rat model of depression in studying cognitive bias and its modification by environmental manipulations. Using a spatial judgment task, responses to ambiguous spatial cues were assessed before and after environmental enrichment to test whether this manipulation would cause an optimistic shift in emotional state. Twenty-four congenitally helpless and nonhelpless male rats were trained to discriminate two different locations, "rewarded" versus "aversive." After successful acquisition of this spatial discrimination, cognitive bias was probed by measuring responses to three ambiguous locations. Latencies to "reach" and to actively "choose" a goal pot were recorded alongside exploratory behaviors. An overall strain difference was observed, with helpless rats displaying longer "reach" latencies than nonhelpless rats. This implies a "pessimistic" response bias in helpless rats, underscoring their depressive-like phenotype. No strain differences were observed regarding other behavioral measures. Half of the animals were then transferred to enriched cages and retested. Environmental enrichment resulted in reduced "choose" latencies in both rat strains, associating enrichment with more optimistic interpretations of ambiguous cues. Our results emphasize the suitability of cognitive bias measurement for animal emotion assessment. They extend the methodological repertoire for characterizing complex phenotypes and bear implications for animal welfare research and for the use of animal models in preclinical research.