Final Activity Report Summary - GHIRP (Genetic and hormonal influences on reward processing: insights from brain imaging in humans) Advances in molecular genetics, endocrinology and neuro-imaging start to unravel the relationships between genes, hormonal status, cognition and functional brain regions and to build new bridges between molecular, cellular and neuroscience systems levels in humans. This approach is fruitful to understand the genetic / hormonal influences contributing to individual differences in normal and pathological conditions. Reward processing plays a fundamental role in a number of behavioural processes such as motivation, learning and social cognition. Studies of the neurobiology of reward are important because they provide insights into the vulnerability of the dopaminergic system, which is a critical in the neuropathophysiology of disorders such as Parkinson's disease or schizophrenia. The goal of this project was to study how genetic polymorphisms of genes involved in dopamine transmission and various hormonal differences modulate the reward system in humans. To achieve this goal, we used an original fMRI experimental paradigm in which subjects were paid for respond to different 'slot machines' that systematically varied monetary reward probability, magnitude, and expected reward value. We first tested subjects presenting genetic polymorphisms of the catechol-O-methyltransferase (COMT), an enzyme that catabolises released dopamine in order to investigate how these polymorphisms of the COMT could influence brain activation related to reward signals in humans. We then studied the relationship between gonadal steroids and the reward system by testing women in a counterbalanced repeated-measure design during follicular and luteal phases, using our monetary reward task. These studies demonstrated that responsivity of a prefronto-striatal reward-related network is directly influenced by heritable variation in dopamine neurotransmission associated with the COMT polymorphism. We also showed an augmented reactivity of the reward system, including the midbrain, striatum and left frontopolar cortex, in women during the midfollicular phase when estrogen is unopposed by progesterone. Taken together, our results indicate that reward system function may be modulated by gonadal steroids, as well as by COMT activity through their actions on dopaminergic function. Such genetically and hormonally driven variations in dopamine function and consequent reactivity of the reward system have important implications for clinical manifestations of diseases involving disordered catecholamine regulation, and therefore clarify biological mechanisms underlying individual and/or gender differences in neuropsychiatric disorders affecting the reward system.