Orbitofrontal Cortex Dysfunction After Chronic Ethanol Exposure

慢性乙醇暴露后眶额皮质功能障碍

• 批准号: 8003435
• 负责人: Kimberly A Badanich
• 金额: $ 4.76万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-05 至 2012-01-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003435
• 关键词: Acute; Address; Adult; Air; Alcohol consumption; Alcohol dependence; Attention; Behavior; Behavioral; Biological Assay; Brain; Breathing; Cells; Chronic; Dose; Electrophysiology (science); Ethanol dependence; Event; Exhibits; Functional disorder; Glutamates; Human; Impulsivity; Inhalation Exposure; Injection of therapeutic agent; Intoxication; Investigation; Judgment; Knowledge; Lateral; Lesion; Long-Term Effects; Measures; Mediating; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Property; Reversal Learning; Rodent; Saline; Slice; Synapses; Synaptic Transmission; Testing; Time; Training; alcohol effect; alcohol exposure; cognitive function; flexibility; gamma-Aminobutyric Acid; male; neuronal excitability; patch clamp; problem drinker; public health relevance; response; vapor

DESCRIPTION (provided by applicant): In humans, damage to the orbitofrontal cortex (OFC) often results in poor judgment that is characterized by behavioral inflexibility and an inability to anticipate consequences of one's actions. Human alcoholics also exhibit a similar behavioral profile characterized by deficits in inhibition and measures of impulsivity/perseverations. In rodents, lesions of the lateral and ventral portions of the OFC disrupt attentional set-shifting by slowing acquisition rates and increasing the number of errors made during a reversal learning task (Bissonette et al, 2008). These observations suggest that chronic exposure to alcohol produces alterations in OFC function that reduces behavioral flexibility. To date, few studies have investigated the direct effects of ethanol (EtOH) on OFC neuron function and related behavioral consequences. The present proposal will address this issue. Aim 1 will test the hypothesis that acute and chronic alcohol exposure disrupts OFC- dependent cognitive function in adult mice. These studies will use a well-established model of alcohol dependence and a behavioral set-shifting assay recently shown to require an intact OFC. A baseline of set- shifting behavior and reversal learning will be established in all mice prior to alcohol exposure and the effects of an acute injection of EtOH (0.5, 1.0, 1.75 g/kg, ip) or saline will be determined. Mice will then be exposed to chronic intermittent EtOH exposure [multiple cycles of voluntary EtOH drinking and EtOH (or air) vapor inhalation] to induce alcohol dependence. To determine how long effects of EtOH dependence on set-shifting persist, testing will be conducted during the first (days 4-9) or second (days 11-16) week following the last bout of EtOH (or air) inhalation exposure. It is expected that alcohol dependent mice will show dose-dependent deficits in set-shifting and reversal learning. Aim 2 will test the hypothesis that deficits in behavioral flexibility in EtOH dependent mice are associated with changes in the excitability and synaptic properties of OFC neurons. These studies will use acute brain slices and whole-cell patch clamp electrophysiology to investigate changes in OFC neuron function in EtOH-dependent mice. To determine how long effects of EtOH dependence on OFC neuronal excitability and synaptic transmission persist, OFC neurons will be recorded at 0, 5 or 12 days post alcohol exposure with the later two time points corresponding to reversal learning training days. Synaptic efficacy will be determined by measuring evoked synaptic responses in the presence of selective pharmacological agents in order to isolate NMDA, AMPA, and GABA mediated events. We will also determine the effects of acute EtOH on glutamatergic and GABAergic synaptic events in alcohol dependent and non- dependent mice. It is expected that NMDA receptors will be inhibited by concentrations of EtOH (22, 44 or 66 mM) that are associated with behavioral signs of intoxication. These results will address an important gap in our knowledge regarding the effects of alcohol on cognitive function in the OFC and will provide an avenue for the further investigation of mechanisms underlying behavioral inflexibility in alcohol dependent subjects. PUBLIC HEALTH RELEVANCE: These studies will examine the long term effects of alcohol dependency on the adult male mouse brain (orbitofrontal cortex) and their ability to alter attention.

描述（由申请人提供）：在人类中，眶额皮质（OFC）的损伤通常会导致判断力差，其特点是行为不灵活并且无法预测一个人行为的后果。人类酗酒者也表现出类似的行为特征，其特征是抑制和冲动/坚持措施的缺陷。在啮齿类动物中，OFC 外侧和腹侧部分的损伤会减慢习得速度并增加逆转学习任务中的错误数量，从而扰乱注意力转移（Bissonette et al, 2008）。这些观察结果表明，长期接触酒精会导致 OFC 功能发生改变，从而降低行为灵活性。迄今为止，很少有研究调查乙醇 (EtOH) 对 OFC 神经元功能和相关行为后果的直接影响。本提案将解决这个问题。目标 1 将检验以下假设：急性和慢性酒精暴露会破坏成年小鼠依赖 OFC 的认知功能。这些研究将使用一个完善的酒精依赖模型和最近证明需要完整的 OFC 的行为定势转移测定。在酒精暴露之前，将在所有小鼠中建立设定转移行为和逆转学习的基线，并且将确定急性注射EtOH（0.5、1.0、1.75g/kg，腹膜内）或盐水的效果。然后，小鼠将接受慢性间歇性乙醇暴露[自愿饮用乙醇和吸入乙醇（或空气）蒸气的多个周期]以诱导酒精依赖。为了确定乙醇依赖性对设定转变的影响持续多久，将在最后一次吸入乙醇（或空气）后的第一周（第 4-9 天）或第二周（第 11-16 天）进行测试。预计酒精依赖小鼠将在设定转移和逆转学习中表现出剂量依赖性缺陷。目标 2 将检验以下假设：EtOH 依赖小鼠的行为灵活性缺陷与 OFC 神经元的兴奋性和突触特性的变化有关。这些研究将使用急性脑切片和全细胞膜片钳电生理学来研究 EtOH 依赖性小鼠 OFC 神经元功能的变化。为了确定 EtOH 依赖对 OFC 神经元兴奋性和突触传递的影响持续多久，将在酒精暴露后 0、5 或 12 天记录 OFC 神经元，后两个时间点对应于逆转学习训练日。突触功效将通过测量选择性药理学试剂存在下诱发的突触反应来确定，以便分离 NMDA、AMPA 和 GABA 介导的事件。我们还将确定急性乙醇对酒精依赖和非酒精依赖小鼠中谷氨酸能和 GABA 能突触事件的影响。预计 NMDA 受体将受到与中毒行为迹象相关的 EtOH 浓度（22、44 或 66 mM）的抑制。这些结果将弥补我们关于酒精对 OFC 认知功能影响的知识中的一个重要空白，并将为进一步研究酒精依赖受试者行为僵化的机制提供途径。 公共健康相关性：这些研究将研究酒精依赖对成年雄性小鼠大脑（眶额皮质）的长期影响及其改变注意力的能力。