The Section on Integrative Neuroimaging continues to make advances toward our goals of elucidating systems-level neurobiological mechanisms underlying genetic predisposition to neuropsychiatric disease. To this end, recent progress has taken the form of key investigations of two central neural systems broadly implicated in neuropsychiatric illness: reward and mnemonic circuitry. With regard to the first, we have used a gambling fMRI paradigm we developed to demonstrate that variation in dopamine-related genes affect reward system functioning, for the first time evidencing an interaction between catechol-O-methyltransferase and dopamine transporter gene variants on frontostriatal activation during reward anticipation. These data are critical not only for understanding molecular underpinnings of core reward circuits, but also for developing approaches to delineate how particular dopamine-related genes might confer risk for neuropsychiatric disorders (Dreher et al., PNAS, 2009). We have further elaborated on this theme to validate the notion that reward-related activation in the striatum is not only sensitive to genetically-determined factors impacting the dopamine system, but also to gonadal steroid hormone status, a variable well-associated with differential expression of mental illness. Specifically, we demonstrated that in healthy women, the anticipatory reward system operates differently depending upon the menstrual phase, with greatest activation occurring post-ovulation. Additionally, men show greater striatal activation during anticipation compared to women. These sample findings represent the first examination of how sex hormones influence reward-evoked brain activity, and provide insights into menstrual-related mood disorders and differential prevalence and course of various mood, anxiety and psychotic disorders. This study also sheds light on potential neural mechanisms that render women more vulnerable to addictive drugs during the pre-ovulation phase of the cycle. Dovetailing our progress examining reward systems, our lab has made notable achievements in understanding the neural foundations of verbal recognition mnemonic processes. Though distinct brain systems underlying short- and long-term memory have been well-defined, neural mechanics of the crucial transition between these two systems remain a fundamental gap in our knowledge despite its relevance for understanding the wide range of pathological conditions affecting memory systems. To address this gap, we have published work this year (Buchsbaum et al., Journal of Cognitive Neuroscience, 2010) revealing with relatively high temporal resolution a shift in the distribution of memory-related activity from posterior temporo-parietal cortical networks in the first 10 seconds after stimulus presentation to inferior frontal regions thereafter. This indicates that as time advances the burden of recognition memory is increasingly placed on top-down retrieval mechanisms that are mediated by structures in the inferior frontal cortex. Perhaps the greatest development toward accelerating the Sections research agenda in the past year has been the expansion of our assays of in vivo human central dopamine system function by the addition of new radioligands for measuring D1 and D2/3 receptors, which will permit examination of direct neurochemical correlates of the reward and mnemonic/cognitive neural systems and better characterization of genetic influences on these relationships.
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