Ethanol and Persistent Activity in Prefrontal Cortex

酒精中毒的特征是失去对饮酒的控制，这可能是由于长期的酒精中毒 正常情况下控制强迫行为的高级大脑皮层回路。脑成像研究表明，在 酗酒者，前额叶皮质(PFC)在戒酒期间或暴露于酒精后出现功能变化 酒精(乙醇)或与饮酒有关的视觉提示。然而，人们对埃托的行为知之甚少 在细胞水平上的前额叶功能。在这个项目中，我们将调查急性和慢性的影响 乙醇暴露对前额叶皮质兴奋性锥体神经元功能的影响。的一个标志 前额叶皮质神经元是一种“持续活动”，其特征是自发的和有节奏的转换。 在激发被抑制的超极化下态和有利于 用来产生动作电位。上行状态期间的放电活动受多巴胺能神经调节 来自VTA神经元的输入，这些神经元与V层前额叶皮质神经元突触。持续的活动可能会允许 前额叶皮质对成瘾神经回路的高级控制作用 处理来自内部和外部线索的感觉信息。持续活动的中断 由乙醇引起的前额叶皮质内的状态可能是强迫症失去控制的主要事件 饮酒行为。已经在麻醉的整个动物身上进行了持续活动的研究，但没有发生。 在减少的系统中，例如急性分离的皮质切片。绕过与以下内容相关的问题 为了麻醉和精确分析可能的机制，我们采用了切片共培养。 包括前额叶皮质、VTA和海马体的系统。培养2周后，前额叶神经元在 该系统显示了强健和可重现的持续活动模式，可以通过刺激诱发来调节 VTA多巴胺神经元的放电。该项目的主要目标是确定急性呼吸道感染的影响。 使用该共培养系统，慢性乙醇暴露对PFC神经元持续活动的影响。目标1、2 和3将利用膜片钳电生理学来分析急性和慢性乙醇对心肌细胞的影响 V层前额锥体神经元自发和VTA诱发的持续活动。AIM 4将使用 共聚焦成像技术在网络水平评估乙醇对锥体细胞活动的影响。 这些研究的结果将为乙醇对大脑功能的影响提供重要的新信息。

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.