Network mechanisms of impaired adult hippocampal neurogenesis in a mouse model of prenatal alcohol exposure

产前酒精暴露小鼠模型中成年海马神经发生受损的网络机制

• 批准号: 10455050
• 负责人: Lee Anna Cunningham
• 金额: $ 34.09万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455050
• 关键词: Address; Adolescence; Adult; Affect; Animals; Antidepressive Agents; Behavior; Behavioral; Brain; Clinical; Cognition; Cognitive; Complex; Data; Development; Discrimination; Discrimination Learning; Educational Intervention; Electrophysiology (science); Emotional; Experimental Models; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fluoxetine; Gene Expression; Genetic; Goals; Hippocampus (Brain); House mice; Human; Immediate-Early Genes; Impairment; Individual; Intellectual functioning disability; Intervention; Label; Laboratories; Lead; Learning; Life; Mediating; Memory; Mental Health; Methods; Modeling; Moods; Morphology; Mus; Neurological outcome; Neuronal Plasticity; Newborn Infant; Outcome; Pattern; Performance; Pharmacology; Publications; Rabies; Reporting; Research; Rodent Model; Role; Saccharin; Synapses; Testing; Therapeutic; adult neurogenesis; alcohol exposure; base; behavioral response; clinical diagnosis; cognitive task; design; drinking; emerging adult; environmental enrichment for laboratory animals; experimental study; flexibility; gain of function; granule cell; improved; indexing; mood regulation; mouse model; nervous system disorder; neurochemistry; neurogenesis; pre-clinical; progenitor; response; stress resilience; therapeutic target

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to establish the relevance of adult hippocampal neurogenesis as a potential therapeutic target for fetal alcohol spectrum disorder (FASD), utilizing a well-characterized mouse model of prenatal alcohol exposure (PAE). The significance for adult hippocampal neurogenesis as a potential therapeutic target in fetal alcohol spectrum disorder (FASD) is based on preclinical rodent models that demonstrate long- lasting deficits in neurogenesis following developmental alcohol exposure, the critical role of neurogenesis in many hippocampal-dependent behaviors that are also disrupted in clinical FASD, and recent evidence that neurogenesis continues throughout life in the human hippocampus. Using voluntary drinking paradigms to model PAE in mice, our laboratory previously demonstrated marked impairment of the neurogenic response to enriched environment (EE) that is associated with disruption of neurochemical, morphological and electrophysiological indices of EE-mediated network activity. Experiments outlined in this proposal are designed to test the overall hypothesis that impaired EE-mediated neurogenesis is relevant for deficits in behavior and hippocampal network mechanisms in PAE, and can be restored using genetic and/or pharmacological therapeutic approaches. This hypothesis will be tested by addressing the following specific aims. Specific Aim 1: To determine whether impaired EE-mediated neurogenesis is directly correlated with impaired pattern discrimination learning in PAE mice. We will utilize two complex neurogenesis-dependent cognitive tasks in which pattern discrimination/separation is tested in both contextual and spatial domains. Behavioral performance will be correlated with impaired neurogenesis in PAE-EE mice, and with immediate early gene expression as a readout of network activation. Specific Aim 2: To determine whether impaired EE-mediated neurogenesis in PAE mice leads to compensatory remodeling of afferent synaptic input to aDGCs. We will utilize neuroanatomical approaches including rabies-based retrograde tracing to determine whether dendritic complexity and/or the distribution of monosynaptic afferent inputs to aDGCs are selectively altered in PAE-EE mice. Specific Aim 3: To determine whether sensitivity to EE-mediated neurogenesis in PAE mice is restored by genetic and/or pharmacological intervention. We will utilize a genetic gain-of-function approach to augment the survival of aDGCs in an attempt to restore EE-mediated neurogenesis in PAE mice. In addition, we will test whether the neurogenic antidepressant, fluoxetine (FLX), restores EE-mediated neurogenesis and behavior in PAE. If so, causal relationships between neurogenesis and FLX-mediated behavioral improvement will be tested by selective, genetic silencing of aDGCs.

项目摘要/摘要 这项建议的总体目标是建立成年海马神经发生的相关性，作为潜在的 胎儿酒精谱障碍(FASD)的治疗靶点，利用具有良好特性的小鼠模型 产前酒精暴露(PAE)。成人海马区神经发生作为一种潜在治疗手段的意义 胎儿酒精谱系障碍(FASD)的靶点是基于临床前啮齿动物模型，该模型显示长期的 发育性酒精暴露后神经发生的持续性缺陷，神经发生在 许多海马区依赖的行为在临床FASD中也被破坏，最近的证据表明 在人类的海马体中，神经发生贯穿整个生命。使用自愿饮酒范式进行建模 在小鼠的PAE中，我们的实验室先前证实了浓缩物对神经源性反应的显著损害 与神经化学、形态和电生理紊乱相关的环境(EE) EE介导的网络活跃度指数。本提案中概述的实验旨在测试总体 EE介导的神经发生受损与行为和海马区缺陷相关的假说 PAE中的网络机制，并可通过遗传和/或药物治疗恢复 接近了。这一假设将通过解决以下具体目标来检验。 具体目标1：确定EE介导的神经发生受损是否与 PAE小鼠的模式辨别学习障碍。我们将利用两个复杂的神经发生依赖 在认知任务中，模式辨别/分离在语境和空间两个领域都被测试。 PAE-EE小鼠的行为表现将与受损的神经发生相关，并与即刻早期相关 基因表达作为网络激活的读数。 特定目标2：确定EE介导的PAE小鼠神经发生受损是否导致 ADGC传入突触的代偿性重构。我们将利用神经解剖学的方法 包括基于狂犬病的逆行追踪以确定树突状细胞的复杂性和/或 在PAE-EE小鼠中，对aDGC的单突触传入输入被选择性地改变。 特异性目标3：确定PAE小鼠对EE介导的神经发生的敏感性是否恢复 通过遗传和/或药物干预。我们将利用遗传功能增益方法来 增加aDGC的存活率，试图恢复EE介导的PAE小鼠的神经发生。此外，我们 将测试神经源性抗抑郁剂氟西汀(Floxetine)是否恢复EE介导的神经发生和 PAE中的行为。如果是这样的话，神经发生和Flx介导的行为改善之间的因果关系 将通过选择性的基因沉默aDGC进行测试。