The stress response is an adaptive mechanism for the organism to cope with challenging situations (stressors). By increasing circulating levels of glucocorticoids and adrenaline and by activating the sympathetic nervous system animals enter a transient emergency life-history mode that helps them to deal with the event/stimuli that is threatening their homeostasis. Thus an acute response to a stressor is considered to be adaptive. On the other hand, a sustained or very frequent activation of the stress response (chronic stress) is considered to be maladaptive since the costs in terms of its impact on growth, reproduction and immune function out weight the short-term benefits of the response. Therefore, chronic stress has a major impact on the health of both humans and animals and the understanding of the mechanisms that activate the stress response (i.e., that translate the perception of the stress-eliciting event into a response) is crucial to develop ways to mitigate it. Since the 1970’s it became clear that the cognitive appraisal of stressors is a key mechanisms in the activation of the stress response, so that it is not only the intrinsic characteristics of the stressor that trigger a response but rather the evaluation of what that stimuli or event means to that organism at that moment in time. Therefore, the exactly same stressor may elicit different stress responses, depending on the way it is appraised by different individuals or by the same individual at different moments in time (e.g., in different social contexts). The involvement of appraisal in the activation of the stress response also opens the possibility for evaluation biases to occur (i.e., some individuals will consistently evaluate ambiguous stimuli as negative, and others as positive). Thus, cognitive bias in the appraisal process can be a major factor in individual variation in the susceptibility to stress and stress-related diseases. In this project we aim to uncover the genetic pathways and neural circuits involved in cognitive appraisal and in the response to stressors, using zebrafish (Danio rerio) as a model organism. The broader goals of the project are:
1) To develop a behavioural assay to test cognitive bias in zebrafish, and to characterize the behavioural and neuroendocrine profiles of “optimistic” and “pessimistic” individuals. Immediate early genes (IEG) will be used to map brain activation, since they constitute the first gene expression response to the stimulation of a neuron. Therefore, the accumulation of IEG mRNA or protein will be used as a marker of functional neural activity. (TASK 1)
2) To assess if cognitive bias (e.g. pessimistic bias) is mediating the inter-individual variation in the susceptibility to the detrimental effects of stress, using behavioural, systemic (stress axis activity and adult neurogenesis) and cellular (telomere dynamics) read-outs. (TASK 2)
3) To manipulate genetically the neural circuits involved in the cognitive appraisal of stressors (identified in TASK 1) and check its effects on the activation of the stress response. Taking advantage of the large number of GAL4-UAS enhancer trap lines available in zebrafish that have restricted expression in different brain areas (e.g., dorsomedial telencephalon = amygdala; dorsolateral telencephalon = hippocampus), once the area of interest has been identified gain and loss of function can be triggered genetically, and its impact on the stress response assessed. (TASK 3) Although this project is focused on basic biological mechanisms of stress, its outcomes have the potential to have a significant impact in stress management and open the way for the use of zebrafish as a stress model organism in translational biomedical research.