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

项目摘要 我们在非人类灵长类动物中进行的纵向酒精自我给药设计已经产生了压力的证据 轴危险因素与重度饮酒的发展以及脑损伤相关 参与控制自愿行动的区域。在本提案中，我们将研究操纵 通过抑制糖皮质激素受体来减少大量饮酒和复发。我们将 还测试了大量饮酒会导致自愿神经控制受损的假设。 涉及皮质基底神经节回路激活在联合和 感觉运动子回路对情境、意外事件和行动的预期结果做出反应。的 联想回路，涉及前额叶皮质投射到尾状核，涉及灵活的 行为的调整。另一方面，感觉运动回路涉及感觉运动和运动 皮质投射到壳核并控制习惯性行为。我们将使用基线静息状态 功能连接与MRI，以调查是否皮质基底神经节连接的个体差异， 与自我调节的固定转换任务的表现以及大量饮酒有关。设计师 受体专门激活的设计师药物（DREADD）将实施改变皮质基底神经节 电路，并检查对认知灵活性和大量饮酒的影响。静息状态的功能磁共振成像将 用于通过激活DREADD来验证连接强度的变化， 方法可以定位为识别皮质基底神经节子回路的异常功能。这种高度 猕猴的创新研究将推动神经技术的应用， 调节成瘾，一种适应不良的行为。

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.