Humans and animals often make decisions under uncertainty, whereby each decision affects not only the immediate reward gain but also longer-term information gain. While important advances have been made in understanding human learning and decision-making, there is still a lack of understanding of the different motivational factors that come into play when the behavioral context confers systematically varying amounts of reward and information gain. This project tackles this problem using a combination of sophisticated cognitive modeling, innovative behavioral experiments, fMRI data, physiological (pupillometry, cardiac, and respiratory) data, and psychiatric measures (questionnaires addressing depressiveness, anxiety, anhedonia, locus of control, pessimism, and substance abuse). The objectives are (1) to develop a statistically grounded and neurobiologically informed theory for how different motivational factors (immediate reward, long-term reward, reduction of uncertainties, and random stochasticity) jointly influence human decision making; (2) use this theoretical framework to guide the understanding of how different brain regions, in particular neuromodulatory systems, work separately and conjointly to implement behavioral choices in response to the reward and informational structure of the environment; (3) characterize individual differences in terms of motivations, subjective monitoring of uncertainties, neural and physiological responses, and psychiatric profile. This work builds on multiple theoretic approaches: Bayesian ideal observer, reinforcement learning, Markov decision process, and control theory; and multiple neuroscientific research areas: learning, information seeking, confidence, decision making, change-point detection. It will advance an integrated understanding of computational theory, neuro-cognitive processes, behavioral manifestations, physiological signals, and psychiatric traits in choice behavior under uncertainty. It will help to clarify how different cortical and subcortical (especially neuromodulatory) brain regions differentially and cooperatively contribute to reward- and information-based learning, decision making, and exploration. These outcomes can be expected to contribute to advancements in basic scientific understanding of brain circuits, mechanisms, and functions related to the use and abuse of addictive substances, as well as their prevention and treatment. RELEVANCE (See instructions): Drug use and abuse often involve alterations in reward learning, decision-making, and uncertainty-related processing. This project contributes to basic computational and neurobiological understanding of these processes in the healthy brain, and may help to elucidate how these processes go awry in substance use and addiction disorders.