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: 10207336
• 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/10207336
• 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; Pharmacology; 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; 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.

摘要 胎儿酒精谱系障碍(FASD)的一个共同特征是无法适当地集中注意力 并抑制对与可靠地导致阳性的刺激相似但不同的刺激的反应 结果。连续操作任务被用来测量注意抑制和反应抑制 受试者和五项选择连续操作任务(5C-CPT)被开发来检验这些 在啮齿类动物中以类似的方式进行加工。我们最近与我们的合作者一起验证了这一点 小鼠和人类受试者的任务行为，我们目前的数据显示，5C-CPT招募了类似的 啮齿动物和健康人额叶和顶叶皮质的脑电信号。在这里，我们建议测试 在妊娠早期和中期适度的酒精暴露是否会损害注意力和 触摸屏反应抑制5C-CPT。接下来，我们将同时进行类似脑电的硬脑膜休息 额叶和顶叶皮质的局域场电位(LFP)和深度记录法检查中度PAE 显著改变额叶和顶叶信号，以及这种信号是否与神经元放电的改变有关 模式或时机。这些方法的结合将使我们能够同时考虑单个单位的射击和 并将其与临床上相关的脑活动指标进行比较。最后，鉴于有证据表明 LFP振荡信号受快速尖峰蛋白阳性(FS-PV+)活性控制 中间神经元，我们将进行体内靶向记录FS-PV+神经元、免疫组织化学和体外培养 电生理学检查认知控制缺陷是否由中间神经元的改变所调节 数字和刺激性音调。我们的假设是，PAE通过丢失导致不适当的顶叶振荡音调 神经元间信号转导，总的结果是认知控制受损。总而言之， 这些目标的完成将使我们能够更好地了解长期损伤的机制 认知控制在FASD中出现，并为更有效的执行功能障碍治疗提供靶点。