Prenatal alcohol exposure and corticostriatal mediation of behavioral flexibility

产前酒精暴露和皮质纹状体对行为灵活性的调节

• 批准号: 10093976
• 负责人: Jonathan L Brigman
• 金额: $ 33.51万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093976
• 关键词: Adult; Animals; Area; Behavior; Behavior Control; Behavioral; Behavioral Assay; Cognition; Cognitive deficits; Complex; Corpus striatum structure; Data; Development; Dorsal; Electrophysiology (science); Environment; Executive Dysfunction; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Individual; Lateral; Lead; Learning; Longevity; Mediating; Mediation; Memory; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Physiology; Play; Reversal Learning; Rewards; Rhodopsin; Rodent Model; Role; Secondary to; Signal Transduction; Slice; Social Behavior; Synaptic plasticity; Testing; Transgenic Mice; Update; alcohol exposure; behavioral impairment; brain circuitry; drinking; effective therapy; excitatory neuron; executive function; flexibility; functional disability; functional restoration; in vivo; optogenetics; receptor expression; receptor function; recruit; restoration; tool; touchscreen

Abstract There is growing evidence that moderate exposure to alcohol during development can lead to behavioral and cognitive deficits that can persist throughout the lifespan. Cognitive impairments associated with Fetal Alcohol Spectrum Disorders (FASD) include abnormalities in learning and memory, executive control and social behaviors and are often characterized by a hyper-focus on one particular task or aspect of a task, to the detriment of other important behaviors. We have recently shown that moderate prenatal alcohol exposure (PAE) can impair executive control in adulthood and that behavioral impairments are accompanied by significant alterations in coherence in the orbitofrontal cortex during choice. Both behavioral deficits and cortical alterations are found when GluN2B subunit containing N-Methyl-D-Aspartate receptors (NMDAR) are lost in the OFC. Given preliminary data that GluN2B is significantly reduced in the OFC after PAE, we propose to investigate whether impairments in behavioral flexibility are driven by alterations in cortical coherence mediated by alterations in NMDAR expression and function and whether these deficits can be rescued. We propose to integrate a well-established voluntary drinking paradigms for moderate PAE with touch-screen behavioral assays, in vivo and ex vivo electrophysiology and optogenetic stimulation. First, we will express channel rhodopsin (ChR2) in the cortex of PAE and SAC mice and examine whether direct stimulation will rescue behavioral flexibility impairments in PAE mice. Next, given evidence that GluN2B is downregulated after PAE and that his subunit contributes to establishing cortical coherence, we will investigate whether behavioral deficits in the model are mediated by alterations in GluN2B subunit expression and recruitment required to induce plasticity and support behavioral flexibility. Finally, we will examine whether changes in connectivity between OFC and dS drives asynchrony and perseveration. We will use retrograde expression to fluorescently tag OFC-dS neurons and characterize function of NMDAR via ex vivo slice physiology. Then we will utilize retrograde expression of ChR2 to test if stimulation restricted to OFC-dS neurons is sufficient to rescue the behavioral deficits. Taken together the completion of these aims will elucidate the mechanisms of cognitive impairment in FASD and provide an important tool for developing more effective therapies for executive dysfunction.

摘要 越来越多的证据表明，在发育过程中适度饮酒会导致行为和 认知缺陷可能会持续一生。与胎儿酒精相关的认知障碍 谱系障碍(FASD)包括学习和记忆、执行控制和社交方面的异常 行为，通常的特征是过度关注一个特定的任务或任务的方面，到 危害其他重大行为的。我们最近的研究表明，胎儿期适度饮酒 (PAE)会损害成年期的执行控制，行为障碍伴随着 在选择的过程中，眶前皮质的连贯性发生了显著变化。行为缺陷和 当含有N-甲基-D-天冬氨酸受体(NMDAR)的GluN2B亚单位被 在OFC迷路了。鉴于初步数据显示，PAE后OFC中GluN2B显著减少，我们建议 研究行为灵活性的损害是否由大脑皮层连贯性的改变驱动 通过NMDAR表达和功能的改变以及这些缺陷是否可以被挽救来介导。我们 建议将成熟的中度PAE自愿饮酒模式与触摸屏相结合 行为分析、体内和体外电生理学和光遗传刺激。首先，我们将表示 通道视紫红质(ChR2)在PAE和SAC小鼠大脑皮层的表达，并检测直接刺激是否会 拯救PAE小鼠的行为灵活性损伤。接下来，鉴于有证据表明GluN2B受到下调 在PAE和他的亚基有助于建立皮质一致性之后，我们将调查是否 模型中的行为缺陷是由GluN2B亚单位表达和募集的改变所介导的 诱导可塑性和支持行为灵活性所必需的。最后，我们将检查是否会更改 OFC和DS之间的连接推动了异步性和持久性。我们将使用逆行表达式来 荧光标记Fc-ds神经元，通过体外切片生理学研究NMDAR的功能。那我们 将利用ChR2的逆行表达来测试仅限于OFC-DS神经元的刺激是否足以 挽救行为缺陷。综上所述，这些目标的完成将阐明 FASD的认知功能障碍，为开发更有效的治疗方法提供了重要工具 执行功能障碍。