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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该提案的总体目标是确定成人海马神经发生作为潜在的神经发生的相关性胎儿酒精谱系障碍 (FASD) 的治疗靶点，利用充分表征的小鼠模型产前酒精暴露（PAE）。成人海马神经发生作为潜在治疗方法的意义胎儿酒精谱系障碍 (FASD) 的目标基于临床前啮齿动物模型，该模型证明了长期发育性酒精暴露后神经发生的持久缺陷，神经发生的关键作用许多海马依赖性行为在临床 FASD 中也受到干扰，最近的证据表明人类海马体的神经发生贯穿整个生命周期。使用自愿饮酒范例进行建模 PAE 在小鼠中，我们的实验室之前证明了对富集的神经源性反应的明显损害与神经化学、形态学和电生理学破坏相关的环境（EE） EE介导的网络活动指数。本提案中概述的实验旨在测试整体假设 EE 介导的神经发生受损与行为和海马体缺陷有关 PAE 中的网络机制，并且可以使用遗传和/或药物治疗来恢复接近。该假设将通过解决以下具体目标进行检验。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能力受损。我们将利用两个复杂的神经发生依赖性在上下文和空间领域测试模式辨别/分离的认知任务。 PAE-EE 小鼠的行为表现将与受损的神经发生相关，并且与立即早期基因表达作为网络激活的读数。具体目标 2：确定 PAE 小鼠中 EE 介导的神经发生受损是否会导致 aDGC 传入突触输入的补偿性重塑。我们将利用神经解剖学方法包括基于狂犬病的逆行追踪，以确定树突复杂性和/或分布 PAE-EE 小鼠中 aDGC 的单突触传入输入被选择性改变。具体目标 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获得方法增强 aDGC 的存活率，试图恢复 PAE 小鼠中 EE 介导的神经发生。此外，我们将测试神经源性抗抑郁药氟西汀 (FLX) 是否可以恢复 EE 介导的神经发生以及 PAE 中的行为。如果是这样，神经发生和 FLX 介导的行为改善之间的因果关系将通过 aDGC 的选择性基因沉默进行测试。