RC3 EFFECTS OF ACUTE AND CHRONIC ALCOHOL ON ORBITOFRONTAL CORTEX FUNCTION

RC3 急性和慢性酒精对眶额皮层功能的影响

• 批准号: 8128132
• 负责人: JOHN J. WOODWARD
• 金额: $ 22.41万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128132
• 关键词: AMPA Receptors; Acute; Address; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Animals; Area; Behavior; Behavioral; Biological Assay; Brain; Choice Behavior; Chronic; Cognition; Complex; Cues; Decision Making; Dependence; Disease; Dopamine; Electrophysiology (science); Environmental Risk Factor; Ethanol; Ethanol dependence; Funding; GABA-A Receptor; Genetic; Glutamates; Heart; Heavy Drinking; Human; Hypothalamic structure; Impaired cognition; Individual; Intoxication; Judgment; Lead; Medial; Modeling; Molecular; Monitor; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Obsessive compulsive behavior; Outcome; Pathway interactions; Pattern; Predisposition; Prefrontal Cortex; Process; Property; Research; Rewards; Sensory; Sensory Process; Series; Short-Term Memory; Signal Transduction; Site; Slice; Smell Perception; Synapses; Synaptic Transmission; Synaptic plasticity; Taste Perception; Testing; Time; Ventral Tegmental Area; Visual Cortex; addiction; alcohol effect; alcohol exposure; alcohol related problem; alcohol research; alcohol sensitivity; base; cognitive control; drinking; drinking behavior; executive function; functional status; in vivo; mouse model; patch clamp; problem drinker; synaptic inhibition; transmission process; treatment center

Alcoholism is characterized by a loss of control over drinking, suggesting that there are long-lasting changes in higher cortical brain areas that normally control compulsive behaviors. Despite this general understanding, there is little known about the specific actions of alcohol on neurons within these cortical circuits. During the last funding cycle, we addressed this shortcoming and completed a series of electrophysiological studies that examined the effects of ethanol on "persistent" activity in the medial prefrontal cortex (PFC). This activity is characterized by spontaneous and rhythmic transitions between quiescent down-states and depolarized up-states that generate relevant patterns of firing. Persistent activity may allow PFC neurons to integrate and process sensory information derived from internal and external cues and to use this information to control sub-cortical circuits. The results from these pioneering studies showed that prefrontal up-states and associated firing are inhibited by concentrations of ethanol associated with mild to moderate intoxication. They also demonstrated that this effect resulted from inhibition of synaptic NMDA receptors and that PFC AMPA receptors and GABA{A} receptors are largely insensitive to behaviorally relevant concentrations of ethanol. In this application, we extend these studies and will investigate the effects of chronic ethanol on prefrontal cortex function. These studies use a well-established mouse model of chronic intermittent ethanol (CIE) exposure that increases levels of drinking as compared to non-dependent animals. We hypothesize that repeated cycles of CIE exposure will produce long-lasting changes in the excitability and plasticity of neurons within the orbitofrontal region (OFC) of the prefrontal cortex, an area known to be dysfunctional in human alcoholics. This hypothesis will be tested using four specific aims that will i) Assess the effect of chronic ethanol exposure on behaviors that require a functional OFC network; ii) Determine the acute ethanol sensitivity of glutamatergic and GABAergic transmission in OFC neurons; iii) Monitor changes in glutamatergic and GABAergic synaptic transmission in OFC neurons from control and ethanol dependent mice and iv) Determine the effects of chronic ethanol exposure on plasticity mechanisms of OFC neurons. The results from these studies will be critical in advancing our understanding of the effects of chronic ethanol on higher cortical function.

酗酒的特点是对饮酒失去控制，这表明通常控制强迫行为的高级皮质大脑区域发生了长期的变化。尽管有这样的普遍认识，但人们对酒精对这些皮质回路内神经元的具体作用知之甚少。在上一个资助周期中，我们解决了这个缺点并完成了一系列电生理学研究，检查乙醇对内侧中枢神经系统“持续”活动的影响 前额皮质（PFC）。这种活动的特点是静态下状态和去极化上状态之间自发且有节奏的转变，从而产生相关的放电模式。持续的活动可能允许 PFC 神经元整合和处理来自内部和外部线索的感觉信息，并使用这些信息来控制皮层下回路。这些开创性研究的结果表明，与轻度至中度中毒相关的乙醇浓度会抑制前额叶的上调状态和相关的放电。他们还证明，这种效应是由突触 NMDA 受体的抑制引起的，并且 PFC AMPA 受体和 GABA{A} 受体在很大程度上对行为相关的乙醇浓度不敏感。在本申请中，我们扩展了这些研究，并将研究长期乙醇对前额皮质功能的影响。这些研究使用了成熟的慢性间歇性乙醇（CIE）暴露小鼠模型，与非依赖性动物相比，该模型增加了饮酒水平。我们假设，重复周期的 CIE 暴露会对前额皮质眶额区 (OFC) 内神经元的兴奋性和可塑性产生持久的变化，该区域已知在人类酗酒者中存在功能障碍。该假设将使用四个具体目标进行测试，这些目标将 i) 评估长期乙醇暴露对需要功能性 OFC 网络的行为的影响； ii) 确定 OFC 神经元中谷氨酸能和 GABA 能传递的急性乙醇敏感性； iii) 监测对照小鼠和乙醇依赖小鼠的 OFC 神经元中谷氨酸能和 GABA 能突触传递的变化，以及 iv) 确定长期乙醇暴露对 OFC 神经元可塑性机制的影响。这些研究的结果对于增进我们对长期乙醇对高级皮质功能的影响的理解至关重要。