RC3 EFFECTS OF ACUTE AND CHRONIC ALCOHOL ON ORBITOFRONTAL CORTEX FUNCTION

酒精中毒的特征是对饮酒失去控制，这表明通常控制强迫行为的高级大脑皮层区域发生了持久的变化。尽管有这种普遍的理解，但人们对酒精对这些皮层回路中的神经元的具体作用知之甚少。在上一个资助周期中，我们解决了这一缺陷，并完成了一系列电生理学研究，研究了乙醇对中膜“持续”活动的影响。 前额叶皮层（PFC）。这种活动的特点是自发的和有节奏的过渡之间的静态下的状态和去极化的状态，产生相关的模式的发射。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电路。这些开创性研究的结果表明，前额叶的上升状态和相关的放电受到与轻度至中度中毒相关的乙醇浓度的抑制。他们还证明，这种效应是由突触NMDA受体的抑制引起的，PFC AMPA受体和GABA{A}受体对行为相关浓度的乙醇基本不敏感。在本申请中，我们扩展了这些研究，并将调查慢性乙醇对前额叶皮层功能的影响。这些研究使用了一种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，CIE暴露的重复周期将产生持久的变化，神经元的兴奋性和可塑性内的眶额区（OFC）的前额叶皮层，一个已知的功能障碍的区域在人类酗酒。将使用四个具体目标来检验该假设，即：i）评估慢性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）监测来自对照和乙醇依赖性小鼠的OFC神经元中谷氨酸能和GABA能突触传递的变化，和确定慢性乙醇暴露对眶额皮层神经元可塑性机制的影响。这些研究的结果将是至关重要的，在推进我们的慢性乙醇对高级皮质功能的影响的理解。

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.