DEFICIENT RESPONSE INHIBITION AND CORTICAL ALTERATIONS AFTER PRENATAL ALCOHOL EXPOSURE IN THE MOUSE

小鼠产前酒精暴露后反应抑制不足和皮质变化

• 批准号: 10674496
• 负责人: Jonathan L Brigman
• 金额: $ 23.65万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674496
• 关键词: Abnormal coordination; Animals; Attention; Behavioral; Behavioral Assay; Brain; Clinical; Coupling; Data; Diagnosis; Dura Mater; Electroencephalography; Electrophysiology (science); Ethanol; Event-Related Potentials; Executive Dysfunction; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; First Pregnancy Trimester; Human; Immunohistochemistry; Impaired cognition; Impairment; Individual; Interneuron function; Interneurons; Intervention; Lead; Learning; Measures; Mediating; Memory; Modeling; Mus; Neurons; Outcome; Parietal; Parietal Lobe; Parvalbumins; Pattern; Population; Process; Property; Rattus; Rest; Rewards; Rodent; Rodent Model; Role; Second Pregnancy Trimester; Signal Transduction; Slice; Social Behavior; Stimulus; Synaptic Transmission; Task Performances; Testing; Variant; alcohol exposure; analog; awake; clinically relevant; cognitive control; effective therapy; executive function; fetal; frontal lobe; human subject; in vivo; male; migration; neurodevelopment; pharmacologic; preclinical study; recruit; response; sustained attention; touchscreen

Abstract A common feature in Fetal Alcohol Spectrum Disorders (FASD) is an inability to focus attention appropriately and inhibit responding to stimuli that are similar to, but distinct from, those that reliably lead to positive outcomes. Continuous performance tasks have been used to measure both attention and response inhibition in human subjects and the Five Choice Continuous Performance task (5C-CPT) was developed to examine these processes in an analogous manner in rodents. Together with our collaborators, we have recently validated this task behaviorally in mice and human subjects and our current data shows that the 5C-CPT recruits similar EEG signal from frontal and parietal cortex in rodents and healthy human subjects. Here, we propose to test whether moderate ethanol exposure during the first and second trimester equivalents impairs attention and response inhibition on the touch-screen 5C-CPT. Next, we will perform simultaneous EEG-like dura-resting local field potential (LFP) and depth recording of frontal and parietal cortex to examine whether moderate PAE significantly alters frontal and parietal signaling, and if this signaling is related to alteration in neuronal firing pattern or timing. The combination of these approaches will allow us to look at both individual unit firing and regional activity and compare it to a clinically relevant measure of brain activity. Finally, given evidence that LFP oscillatory signaling is controlled by the activity of fast-spiking parvalbumin positive (FS-PV+) interneurons, we will perform targeted in vivo recording of FS-PV+ neurons, immunohistochemistry and ex vivo electrophysiology to examine whether deficits in cognitive control are mediated by alterations in interneuron number and excitatory tone. Our hypothesis is that PAE leads to inappropriate parietal oscillatory tone via loss of interneuron signaling, with the overall outcome being impaired cognitive control. Taken together, the completion of these aims will allow us to better understand the mechanisms of the long-lasting impairments in cognitive control seen in FASD and provide targets for more effective therapies for executive dysfunction.

抽象的 胎儿酒精谱系障碍 (FASD) 的一个常见特征是无法适当集中注意力 并抑制对与那些可靠地导致积极的刺激相似但不同的刺激的反应 结果。连续表现任务已被用来测量注意力和反应抑制 人类受试者和五选择连续表现任务（5C-CPT）的开发是为了检查这些 啮齿类动物的过程也类似。我们最近与我们的合作者一起验证了这一点 在小鼠和人类受试者中进行任务行为，我们当前的数据表明 5C-CPT 招募了类似的 来自啮齿动物和健康人类受试者额叶和顶叶皮层的脑电图信号。在这里，我们建议测试一下 在妊娠早期和中期适度接触乙醇是否会损害注意力和 触摸屏5C-CPT上的反应抑制。接下来，我们将进行同步脑电图硬脑膜休息 额叶和顶叶皮层的局部场电位 (LFP) 和深度记录，以检查是否存在中度 PAE 显着改变额叶和顶叶信号传导，并且该信号传导是否与神经元放电的改变有关 模式或时间安排。这些方法的结合将使我们能够同时研究单个单位的射击和 区域活动并将其与临床相关的大脑活动测量进行比较。最后，给出证据表明 LFP 振荡信号由快速尖峰小清蛋白阳性 (FS-PV+) 的活性控制 中间神经元，我们将进行 FS-PV+ 神经元的靶向体内记录、免疫组织化学和离体记录 电生理学检查认知控制缺陷是否是由中间神经元的改变介导的 数字和兴奋语气。我们的假设是 PAE 通过损失导致不适当的顶叶振荡音调 中间神经元信号传导的影响，总体结果是认知控制受损。综合起来， 完成这些目标将使我们能够更好地了解长期损害的机制。 FASD 中的认知控制为执行功能障碍的更有效治疗提供了目标。