Ethanol and Persistent Activity in Prefrontal Cortex

乙醇与前额皮质的持续活动

• 批准号: 7226878
• 负责人: JOHN J. WOODWARD
• 金额: $ 15.93万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226878
• 关键词: AMPA receptors; GABA receptor; NMDA receptors; alcoholism /alcohol abuse; alcoholism /alcohol abuse chemotherapy; confocal scanning microscopy; dopamine; drug withdrawal; ethanol; fluorescent dye /probe; hippocampus; laboratory rat; mixed tissue /cell culture; neurochemistry; neurophysiology; neuroregulation; neurotransmitter transport; prefrontal lobe /cortex; pyramidal cells; receptor expression; tegmentum; voltage /patch clamp

Alcoholism is characterized by a loss of control over drinking that may result from long-lasting alterations in higher cortical circuits that normally control compulsive behaviors. Brain imaging studies show that, in alcoholics, the prefrontal cortex (PFC) displays functional alterations during abstinence or after exposure to ethanol (EtOH) or visual cues associated with drinking. Little, however, is known about the actions of EtOH on prefrontal function at the cellular level. In this project, we will investigate the effects of acute and chronic EtOH exposure on the function of excitatory pyramidal neurons of the prefrontal cortex. A hallmark of prefrontal cortical neurons is "persistent activity" characterized by spontaneous and rhythmic transitions between a hyperpolarized down-state in which firing is inhibited and a depolarized up-state that is conducive for generating action potentials. The firing activity during up-state periods is modulated by dopaminergic input from VTA neurons that synapse on layer V prefrontal cortical neurons. Persistent activity may allow the prefrontal cortex to exert higher-order control over the addiction neurocircuitry by integrating and processing sensory information derived from internal and external cues. Disruption of persistent activity states within the prefrontal cortex by EtOH may be a primary event in the loss of control over compulsive drinking behaviors. Persistent activity has been studied in anesthetized whole animals but it does not occur in reduced systems such as acutely isolated slices of cortex. To circumvent problems associated with anesthesia and to allow for precise analysis of putative mechanisms, we have adapted a slice co-culture system containing prefrontal cortex, VTA, and hippocampus. After 2 weeks in culture, prefrontal neurons in this system display robust and reproducible patterns of persistent activity that can modulated by stimulusevoked firing of VTA dopamine neurons. The major goal of this project is to determine the effects of acute and chronic ethanol exposure on persistent activity of PFC neurons using this co-culture system. Aims 1, 2 and 3 will use patch-clamp electrophysiology to analyze the effects of acute and chronic ethanol on spontaneous and VTA-evoked persistent activity in layer V prefrontal pyramidal neurons. Aim 4 will use confocal imaging techniques to assess the effects of ethanol on pyramidal cell activity at the network level. The results of these studies will yield important new information regarding ethanol's effects on brain function.

酒精中毒的特征是失去了对饮酒的控制，这可能是由于长期改变而导致的 通常控制强迫行为的较高皮层电路。脑成像研究表明，在 酗酒者，前额叶皮层（PFC）在禁欲期间或暴露后显示功能改变 乙醇（ETOH）或与饮酒相关的视觉提示。然而，对EtOH的作用知之甚少 在细胞水平的前额叶功能上。在这个项目中，我们将研究急性和慢性的影响 ETOH暴露于前额叶皮层的兴奋性锥体神经元功能。一个标志 前额叶皮质神经元是“持续活动”，其特征是自发和有节奏的转变 在抑制发射的超极化下降状态和有益的去极化的向上状态 用于产生行动电位。在上州期间的发射活动受多巴胺能调节 来自VTA神经元的输入，这些神经元在V层前额叶皮质神经元上突触。持续活动可能允许 通过整合和 处理从内部和外部提示得出的感官信息。持续活动的破坏 ETOH前额叶皮层内的状态可能是失去强迫性控制的主要事件 饮酒行为。持续的活动已在麻醉的整体动物中进行了研究，但没有发生 在还原的系统中，例如急性分离的皮层切片。避免与之相关的问题 麻醉并允许对推定机制进行精确分析，我们已经改编了片共培养 包含前额叶皮层，VTA和海马的系统。在培养2周后，前额叶神经元 该系统显示持久活动的强大而可重复的模式，可以通过刺激范围调节 触发VTA多巴胺神经元。该项目的主要目标是确定急性的影响 使用此共培养系统对PFC神经元持续活性的慢性乙醇暴露。目标1，2 3将使用斑板钳电生理学分析急性和慢性乙醇对 V前额叶锥体神经元中自发和VTA引起的持续活动。 AIM 4将使用 共聚焦成像技术评估乙醇对网络水平上锥体细胞活性的影响。 这些研究的结果将产生有关乙醇对脑功能的影响的重要新信息。