4/8: INIA Stress and Chronic Alcohol Interactions: Impact of stress mediated locus coeruleus dysregulation on cognitive control and excessive drinking

4/8：INIA 压力和慢性酒精相互作用：压力介导的蓝斑失调对认知控制和过度饮酒的影响

• 批准号: 9241795
• 负责人: DAVID E MOORMAN
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241795
• 关键词: Acute; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Attention; Behavior; Behavioral; Brain; Cell Nucleus; Cells; Characteristics; Chronic; Chronic stress; Cognition; Cognitive; Comorbidity; Complement; Corticotropin-Releasing Hormone Receptors; Dependence; Development; Down-Regulation; Economics; Emotional; Ethanol; Executive Dysfunction; Exposure to; Female; Functional disorder; Goals; Health; Heavy Drinking; Hyperactive behavior; Impaired cognition; Lead; Marble; Mediating; Mediator of activation protein; Methods; Microdialysis; Microinjections; Modeling; Mus; Neurons; Norepinephrine; Pathologic; Phenotype; Physiological; Play; Prefrontal Cortex; Recording of previous events; Regulation; Role; Stress; Structure; Swimming; Testing; Up-Regulation; Work; alcohol exposure; alcohol use disorder; cognitive control; cognitive function; cognitive reappraisal; cognitive testing; designer receptors exclusively activated by designer drugs; drinking; emotion regulation; excessive anxiety; executive function; feeding; flexibility; in vivo; insight; locus ceruleus structure; memory recognition; noradrenergic; norepinephrine system; novel; postsynaptic; prevent; receptor function; relating to nervous system; response; selective expression; targeted treatment; tool; treatment strategy

PROJECT SUMMARY/ABSTRACT There is strong comorbidity between alcohol use disorders and chronic stress and anxiety. Dysfunction within overlapping neural targets of alcohol and stress may facilitate the development of this comorbid phenotype. The locus coeruleus norepinephrine (LC-NE) system is sensitive to both alcohol and stress and plays an important role in cognitive and emotional regulation of behavior. Plasticity within LC-NE circuits after chronic stress and alcohol can produce feed-forward effects, elevating stress and anxiety via the HPA axis and decreasing cognitive control by disrupting prefrontal cortex (PFC) function. The consequence of this stress- cognition “double-hit” is an increased need to drink and a decreased control over drinking. Our preliminary evidence demonstrates that chronic intermittent ethanol exposure in addition to repeated swim stress, disrupts PFC dependent cognition and increases excessive drinking more than either ethanol or stress alone. In these studies we will investigate the LC as a key target of stress/ethanol maladaptations and the potential for LC-NE targeted therapeutics to ameliorate stress/ethanol induced executive dysfunction, elevated anxiety, and excessive drinking. This project will provide new insights into the role of LC-NE dysfunction after chronic stress and alcohol. Our results will identify novel circuit changes underlying excessive alcohol consumption and the potential for NE targeted therapies in treating cognitive and emotional dysfunction in alcohol use disorders.

项目总结/文摘