The risk for alcohol dependence runs in families. A component of this heritable risk for alcoholism is common to other addictions, sociopathy, and impulsive behavior. CTNA will explore the hypothesis that these Alcoholism """"""""Common"""""""" Risk Factors (ACRF) involve synaptic pathology related to the convergence of glutamate and dopamine inputs to the ventral striatum and associated """"""""motivation"""""""" circuitry. From a cognitive/behavioral neuroscience perspective, evidence for this vulnerability is expressed as general impairments in the normal ability to engage motivational circuitry by delayed rewards and punishments, biasing individuals toward immediate rewards, (exemplified by alcohol), and impulsive behavior. An aspect of this transmitted vulnerability is hypothesized to involve problems in the brain circuitry for reward and punishment expectation- a """"""""Reward Deficit Hypothesis."""""""" We will use two distinct but complementary behavioral tasks, in combination with functional MRI, to quantify responses in motivational circuitry to situations involving both expectation of and receipt of rewards and punishments, as well as the propensity to take risks on one of the tasks. We will study 80 adult male and female subjects in equal numbers who are either offspring of an alcoholic parent or are family history negative matched controls. Use of two complementary cognitive tasks during functional MRI (fMRI), will dissect functional abnormalities in the circuits converging on the ventral striatum that may contribute to the vulnerability to alcoholism and other risky or impulsive behaviors. The 2 paradigms are: 1) a Monetary Incentive Delay Task, that distinguishes networks engaged in motivational (anticipation) and consummatory (outcome) components of reward processing;2) a Domino Task, that explores anticipatory and consummatory phases of reward processing under contextual manipulations (uncertainty, social interaction) that promote risk-taking. Subjective responses to tasks will be quantified as an important dependent measure. In synergy within CTNA, we will explore: (Genetics Core) whether variation in genes that influence dopaminergic and glutamatergic function moderate the integrity of motivation circuitry;(Project 3) whether increases in NMDA receptor function contribute to functional abnormalities in motivation circuitry;(Project 5) the clinical relevance of the functional integrity of motivation circuitry in alcohol dependent subjects.
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