br Experimental Procedures br Author Contributions
Acknowledgments Research in the Davis laboratory was supported by grants 4R37NS019904, 5R01NS052351, and 1R35NS097224 from NINDS. Research in the Martemyanov laboratory was supported by grants DA036596 and DA026405 from NIDA, and MH105482 from NIMH. We thank TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947) and Janelia Farms for providing transgenic fly stocks used in this study.
Introduction Individual variation in coping with environmental challenges is a well-known phenomenon across vertebrates, including teleost fish [1,2]. Depending on how individuals react to and deal with challenges, they can be categorized into distinct behavioral phenotypes, often called behavioral syndromes or coping styles [1,3,4]. A genetic component is involved but the adult phenotype is also shaped by environmental factors, primarily social interaction . Behavioral syndromes are commonly defined as individual differences in behavior that are consistent over time and/or across context , where bold and shy mainly refer to the willingness among individuals in taking risks, especially in novel environments . Shy individuals are characterized by a passive response combined with low exploration, while bold individuals are explorative and risk taking . A coping style is typically defined as a set of correlated behavioral and physiological responses to stressful stimuli that are consistent over time [1,3]. Thus, although similarities between behavioral syndromes and coping styles exist, physiological measures are rarely included in descriptions of behavioral syndromes , and a recent study demonstrated that traits underlying behavioral syndromes were not synonymous to traits underlying coping styles . The zebrafish (Danio rerio), long restricted to the field of developmental biology, is rapidly becoming a popular model α-Naphthoflavone within neuroscience [7,8]. The fact that at least 70% of human protein coding genes, including disease-associated genes, have orthologs in zebrafish  has contributed to the use of this species for studies of human pathogenesis. The basic structure of the central nervous system in zebrafish, and other teleosts, has all the major domains found in the mammalian brain with the same modulatory neurotransmitters [10,11], including serotonergic [12,13], dopaminergic [14,15] and opioidergic  systems. The behavioral repertoire of the zebrafish is complex, and the number of tests for behavioral assessment is increasing [7,17]. The novel tank diving test was developed to study risk-taking behavior , and is now one of the most widely used behavioral tests in zebrafish . When a zebrafish is placed in a novel tank, the natural tendency is to initially dive to the bottom, with a gradual increase in vertical activity over time. This initial preference for the bottom of the novel tank has been compared to thigmotaxis in rodents , and the degree of ‘bottom dwelling’ can therefore be used as a measure of risk-taking behavior. Dopamine is known to have multiple behavioral effects, e.g. stimulate aggression, impulsivity and active behavioral responses [20,21]. Moreover, the brain dopaminergic system is well known for its role in reward and reinforcement  but it is also activated by stress . For instance, the dopaminergic system is activated in both winners and losers during dyadic fights for social dominance in rainbow trout (Oncorhynchus mykiss) . In mammals, enhanced nucleus accumbens release of dopamine is observed in response to acute, controllable stress, whereas chronic uncontrollable stressors, associated with behavioral inhibition, have the opposite effect on dopamine release in this brain area . It has been suggested that elevated dopamine release is typical of active stress coping shown by bold, proactive animals, whereas the passive stress response displayed by shy, reactive animals, appear more associated with an inhibition of dopamine release . Thus, the dopaminergic system could form an important part of the mechanisms controlling intra-specific divergence in stress coping styles and behavior.