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

7/8：INIA 压力和慢性酒精相互作用：猴子的压力和乙醇自我管理

基本信息

批准号：
10090536
负责人：
Verginia Carmella Cuzon Carlson
金额：
$ 45.07万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2022-03-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090536
关键词：
Abstinence Address Adrenal Glands Alcohol consumption Alcohols Amygdaloid structure Area Basal Ganglia Behavior Behavior assessment Biological Markers Brain Brain region Chronic Cognitive Corpus striatum structure Development Disease Dissociation Dorsal Endocrine Epigenetic Process Ethanol Female Functional Magnetic Resonance Imaging Gene-Modified Genomics Glucocorticoid Receptor Goals Heavy Drinking Homeostasis Hypothalamic structure Immune system Impairment Individual Differences Intoxication Lateral Link Macaca Macaca mulatta Magnetic Resonance Imaging Measures Methods Modeling Monkeys Morphology Motor Neuroimmune Neurosciences Oregon Output Pathway interactions Pattern Performance Pharmacotherapy Phenotype Pituitary Gland Population Positioning Attribute Prefrontal Cortex Primates Proteomics Recording of previous events Relapse Research Research Personnel Rest Risk Factors Self Administration Severities Slice Social Dominance Stimulus Stress Synapses System Technology Testing Tissues addiction alcohol abstinence alcohol misuse alcohol relapse alcohol use disorder allostasis attenuation biological adaptation to stress brain circuitry caudate nucleus chronic alcohol ingestion cognitive function designer receptors exclusively activated by designer drugs drinking flexibility in vivo in vivo imaging innovation interest locus ceruleus structure longitudinal design male neuroregulation neurotechnology nonhuman primate novel strategies outcome prediction predicting response putamen response sex tool young adult

项目摘要

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.

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。