7/8: INIA Stress and Chronic Alcohol Interactions: Stress and Ethanol Self Administration in Monkeys

项目总结 我们在非人类灵长类动物中酒精自我给药的纵向设计已经产生了应激的证据 与酗酒和脑损伤相关的轴心危险因素 参与控制自愿行动的地区。在这项提案中，我们将检查操纵 通过抑制糖皮质激素受体的应激回路来减少大量饮酒和复发。我们会 也要检验这样的假设，即大量饮酒会导致自愿行为神经控制的损害 涉及皮层-基底神经节回路激活在联合和 感觉运动子回路对环境、意外情况和行动的预测结果作出反应。这个 牵涉到前额叶皮质投射到尾状核的联合回路，牵涉到 对行为的调整。另一方面，感觉运动电路包括感觉运动和马达。 皮质投射到壳核，控制习惯性行为。我们将使用基线休眠状态 用MRI研究皮质-基底节连接性的个体差异 与自我调整节奏的移位任务的表现以及大量饮酒有关。设计师 专门由特制药物(DREADDS)激活的受体将用于改变皮质-基底节 并检查对认知灵活性和大量饮酒的影响。然后静息状态的功能磁共振成像将 用于验证激活DREADD后连接强度的变化，从而降低侵入性 该方法可以定位于识别皮质-基底节亚回路的异常功能。如此之高 对猕猴的创新研究将推动神经技术的应用，以了解和 调节成瘾，一种不适应的行为。

PROJECT SUMMARY Our longitudinal design of alcohol self-administration in the non-human primate has yielded evidence of stress axis risk factors associated in the development of heavy alcohol drinking as well as an impairment in brain regions involved in the control of voluntary actions. In this proposal, we will examine the ability of manipulating stress circuitry by inhibiting glucocorticoid receptors to decrease heavy ethanol drinking and relapse. We will also test the hypothesis that heavy alcohol drinking leads to impairments of the neural control of voluntary actions that involves a relative shift in activation of cortico-basal ganglia circuitry between the associative and sensorimotor subcircuits in response to context, contingencies and the predicted outcome of the action. The associative circuitry, involving prefrontal cortical projections to the caudate nucleus, is implicated in flexible adjustments to behavior. The sensorimotor circuitry, on the other hand, involves sensorimotor and motor cortical projections to the putamen and controls habitual behaviors. We will use baseline resting-state functional connectivity with MRI to investigate if individual differences in cortico-basal ganglia connectivity are associated with performance on a self-paced set shifting task as well as heavy alcohol consumption. Designer receptors exclusively activated by designer drug (DREADDs) will be implemented to alter cortico-basal ganglia circuits and examine effects on cognitive flexibility and heavy ethanol drinking. Resting-state fMRI will then be used to verify the changes in connectivity strength by the activation of DREADDs, so that this less invasive method can be positioned to identify abnormal functioning of cortico-basal ganglia subcircuits. This highly innovative research in macaque monkeys will advance the application of neurotechnologies to understand and modulate addiction, a maladaptive behavior.