Connectivity of Adult-Generated Dentate Granule Cells in a Mouse Model of Prenatal Alcohol Exposure

产前酒精暴露小鼠模型中成年齿状颗粒细胞的连接性

• 批准号: 9755190
• 负责人: Kymberly Cheyanne Gustus
• 金额: $ 4.5万
• 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: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755190
• 关键词: Address; Adult; Age; Alcohols; Anatomy; Anxiety; Autopsy; Axon; Behavioral; Brain; Carbon; Cells; Clinical; Cognition; Cognitive; Coupled; Cytoplasmic Granules; Dendritic Spines; Development; Electrophysiology (science); Environment; Evoked Potentials; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Genomic DNA; Goals; Hippocampus (Brain); Housing; Human; Impairment; Intellectual functioning disability; Interneurons; Knowledge; Label; Laboratories; Lead; Learning; Life; Mediating; Memory; Mentors; Methods; Mission; Modeling; Moods; Morphology; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurological outcome; Neurons; Neurosciences; New Mexico; Newborn Infant; Output; Pregnancy; Preparation; Process; Pyramidal Cells; Regulation; Research; Research Training; Resolution; Rodent Model; Slice; Stress; Structure; Synapses; System; Techniques; Temporal Lobe; Testing; Therapeutic; Vertebral column; Work; alcohol exposure; alcohol measurement; alcohol related problem; alcohol research; base; confocal imaging; critical period; design; environmental enrichment for laboratory animals; experience; flexibility; fluorescence imaging; granule cell; in vivo; mood regulation; mossy fiber; mouse model; neurobehavioral; neurogenesis; neuroimaging; novel; optogenetics; postnatal; pre-clinical; preclinical study; reconstruction; response; restoration; vector

PROJECT SUMMARY/ABSTRACT The overall goal of the proposed research is to characterize alterations in network connectivity of adult- generated dentate granule cells (aDGCs) in a mouse model of prenatal alcohol exposure (PAE). If successful, these studies may reveal mechanisms that underlie deficits in hippocampal function associated with fetal alcohol spectrum disorders (FASDs). The current proposal is designed to test the overall hypothesis that PAE disrupts experience-dependent remodeling of connectivity of newborn dentate granule neurons in the adult hippocampus. The proposal is premised on previous work demonstrating that exposure to even moderate levels of alcohol throughout gestation leads to an impaired neurogenic response to enriched environment and altered synaptic activity of aDGCs as assessed electrophysiologically. I will utilize a well-characterized limited access gestational exposure model in mice to characterize the impact of PAE on circuit connectivity of aDGCs. Specifically, I will utilize a combination of dual-vector tracing, high-resolution confocal imaging, electrophysiological and optogenetic approaches to address the following aims. Specific Aim 1. To test the hypothesis that PAE disrupts EE-mediated remodeling of afferent synaptic input to aDGCs. Here we will assess the impact of PAE on the distribution of monosynaptic afferent input to aDGCs using a dual vector tracing system (Aim 1.1), morphological analysis of dendritic complexity and spine maturation in aDGCs (Aim 1.2), and functional synaptic input to aDGCs using whole-cell patch slice recordings of evoked synaptic activity (Aim 1.3). Specific Aim 2. To test the hypothesis that PAE disrupts EE-mediated remodeling of efferent synaptic output from aDGCs. Here, I will assess the impact of PAE on excitatory efferent connections of aDGCs with CA3 pyramidal cells and interneurons using a neuroanatomical approach (Aim 2.1), coupled with optogenetic stimulation of aDGCs in hippocampal slice preparations (Aim 2.2). These aims coincide with the mission of the NIAAA to attain fundamental knowledge for the improvement of alcohol-related problems, since understanding how PAE impacts hippocampal connectivity may reveal opportunities for novel circuitry-based therapeutic approaches to mitigate neurobehavioral consequences in clinical FASDs. Importantly, the proposed research provides a framework for research training in alcohol-related neuroscience utilizing state-of-the art approaches within an outstanding mentoring team and research environment within the New Mexico Alcohol Research Center.

项目总结/摘要 拟议研究的总体目标是描述成人网络连接的变化， 在产前酒精暴露（PAE）的小鼠模型中产生齿状颗粒细胞（aDGC）。如果成功， 这些研究可能揭示了与胎儿酒精相关的海马功能缺陷的机制 谱系障碍（FASD）。目前的提案旨在测试PAE破坏 成年海马中新生齿状颗粒神经元连接的经验依赖性重塑。 这项建议是基于先前的工作，表明即使是中等程度的酒精暴露， 在整个妊娠期间，导致对丰富环境的神经原性反应受损， 电生理学评估的aDGC活性。我会利用一个特征明确的 小鼠中的暴露模型，以表征PAE对aDGC的电路连接性的影响。具体来说，我会 利用双矢量跟踪、高分辨率共聚焦成像、电生理和 光遗传学方法来解决以下目标。具体目标1.为了验证PAE 破坏EE介导的对aDGC的传入突触输入的重塑。在这里，我们将评估 使用双向量追踪系统对aDGC的单突触传入输入分布的PAE（目的1.1）， aDGC中树枝状复杂性和棘成熟的形态学分析（目的1.2）以及功能性突触 使用诱发的突触活动的全细胞贴片切片记录的aDGC输入（目的1.3）。具体目标2。 为了验证PAE破坏EE介导的传出突触输出重塑的假设， aDGC。在这里，我将评估PAE对aDGC与CA 3锥体神经元兴奋性传出连接的影响。 细胞和中间神经元使用神经解剖学方法（目的2.1），加上光遗传学刺激， 海马切片制备物中的aDGC（目的2.2）。这些目标与NIAAA的使命一致， 改善酒精相关问题的基本知识，因为了解PAE如何影响 海马连接可能揭示了新的基于电路的治疗方法的机会， 临床FASD的神经行为后果。重要的是，拟议的研究提供了一个框架， 在酒精相关的神经科学研究培训利用国家的最先进的方法在一个杰出的 指导团队和新墨西哥州酒精研究中心的研究环境。