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.

酒精中毒的特征是失去了对饮酒的控制，这表明较高的皮质大脑区域的持久变化通常会控制强迫行为。尽管有这种一般的理解，但对这些皮质回路中酒精对神经元的特定作用鲜为人知。在上一个融资周期中，我们解决了这一缺点并完成了一系列电生理研究，这些研究检查了乙醇对内侧“持续”活性的影响 前额叶皮层（PFC）。该活动的特征是静止下降阶段的自发和节奏转变，以及产生相关射击模式的去极化的向上状态。持续的活动可能使PFC神经元可以整合和处理从内部和外部提示得出的感觉信息，并使用此信息来控制亚皮质电路。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抑制了前额叶上的状态和相关的射击。他们还证明，这种作用是由于抑制突触NMDA受体而引起的，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。在此应用中，我们扩展了这些研究，并将研究慢性乙醇对前额叶皮层功能的影响。这些研究使用了公认的慢性间歇性乙醇（CIE）暴露的小鼠模型，该模型与非依赖动物相比增加了饮酒水平。我们假设CIE暴露的重复循环将导致前额叶皮层（OFC）内神经元（OFC）内神经元的兴奋性和可塑性的持久变化，该区域已知在人类酒精中毒中功能障碍。该假设将使用四个特定目的进行检验。 ii）确定OFC神经元中谷氨酸能和GABA能传播的急性乙醇敏感性； iii）监测来自对照和乙醇依赖小鼠的OFC神经元中谷氨酸能和GABA能突触传播的变化，并确定慢性乙醇暴露对OFC神经元可塑性机制的影响。这些研究的结果对于促进我们对慢性乙醇对较高皮质功能的影响的理解至关重要。