Alcoholism and other addictive disorders have been categorized as brain diseases, implying that the brain is dysfunctional in addicted individuals. However, the extent to which the brains of people with alcohol use disorders (AUDs) were dysfunctional prior to being introduced to alcohol or became dysfunctional as a result of acquiring an AUD is not clear. Non human primates (NHPs) are particularly useful in linking brain circuitry to risk factors for and consequences of AUD because 1) in vivo imaging techniques used in humans can be applied to NHPs and are informative of circuitry involving different cortical fields (Kroenke et al., 2014; Miranda- Dominguez et al., 2014 a, b) (2) macaque monkeys show stable individual differences in the amount of alcohol they will self-administer over extended access (Grant et al, 2008a; Baker et al. 2014) (3) their genetic composition is highly similar to humans (Ferguson et al. 2012). Translational risk factors between NHP and humans that lead to excessive alcohol drinking have been identified, including drinking topography (Grant et al., 2008b), endocrine factors (Helms, Park and Grant, 2014) and age at the onset of drinking (Helms et al. 2014), but these risk factors have not been linked to brain circuitry. We propose to structural and functional connectivity between subcortical and cortical fields as potential biomarkers for risk and consequence of chronic binge drinking in both male and female cynomolgus monkeys. To our knowledge, the proposed studies will be the first to assess both structural diffusion tensor imaging (DTI) as well as functional brain aspects of resting state connectivity MRI in monkeys; the first to examine individual differences in resting state connectivity with the risk for heavy drinking; the first to quantify chronic ethanol intake on measures of resting state connectivity; the first to examine potential sex differences in these correlates of risk for and consequences of chronic ethanol drinking and the first to accumulate an informative dataset of within-subject genomic changes in the pre-frontal cortex of primates as a result of chronic ethanol self-administration. Collectively for the PARC, the studies will provide a translational bridge to the human subject project (P001: Nagel) and mouse project (P003: Hitzemann) while providing tissue to explore epigenetic changes across the brain and link them to changes in brain circuitry (P004: Carbone). Finally, because the brain imaging techniques proposed here are translational, the studies have the potential to inform prevention as well treatment for alcoholism and AUDs.
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