1/8 NADIA U01 Effects of Adolescent Alcohol Exposure on Hippocampal Function in Adulthood

1/8 NADIA U01 青少年酒精暴露对成年后海马功能的影响

基本信息

批准号：
10227248
负责人：
H SCOTT SWARTZWELDER
金额：
$ 39.6万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10227248
关键词：
3-Dimensional ATAC-seq Acetylation Address Adolescent and Young Adult Adult Affective Alcohols Anxiety Aricept Astrocytes Behavioral Binding Sites Biological Brain Brain region CREB1 gene Cell Death Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Complement Confocal Microscopy Data Dendritic Spines Development Dorsal Ephrin-A3 Ephrins Epigenetic Process Equilibrium FMR1 Funding Future Gene Targeting Genes Goals Grain Hippocampal Formation Hippocampus (Brain)Histone Acetylation Histones Impairment Inflammatory Label Lentivirus Long-Term Effects Measures Mediation Memory Microinjections Molecular Morphology Nerve Degeneration Neuroimmune Neurons Pharmaceutical Preparations Pharmacology Phenotype Process Public Health Quantitative Reverse Transcriptase PCR Relapse Reporting Resolution Role Signal Transduction Site Specificity Structure Synapses Testing Vertebral column Viral Western Blotting adolescent alcohol effect adolescent alcohol exposure alcohol exposure alcohol use disorder anxiety-like behavior base brain behavior cell type density dentate gyrus donepezil experimental study follow-up gabapentin histone methylation inflammatory marker inflammatory milieu knock-down mRNA Expression neurogenesis neuroinflammation prevent protein activation protein expression reconstruction response sex stress reactivity synaptic function synaptogenesis therapy development underage drinking

项目摘要

The NADIA consortium is dedicated to identifying the mechanisms underlying the long-term effects of adolescent intermittent ethanol exposure (AIE) on brain and behavior and exploring approaches to prevent or reverse them. Component 1 has focused on the enduring effects of AIE on hippocampal structure and function and their behavioral sequelae. Based on our findings, our overarching hypothesis AIE causes an enduring but reversible compromise of hippocampal synaptic function driven by interacting epigenetic, neuroinflammatory, and glial mechanisms. During the last NADIA funding cycle we found that AIE produces a pro-inflammatory milieu in the hippocampal formation, alterations of dendritic spine density and morphology, altered histone acetylation and methylation, diminished astrocyte-synaptic proximity, decreases in neurogenesis, and increases in the mobilization cell death molecular machinery. Through NADIA collaborations, we further identified epigenetic changes that suggest specific molecular mechanisms underlying those effects. Importantly, we have also shown that many of those effects are reversible in adulthood with pharmacological agents in current clinical use. Our recent findings indicate that AIE results in a propensity toward anxiety-like behavior after environmental challenge, thus suggesting the need to expand our assessments to the ventral hippocampus. This has obvious translational implications because anxiety and stress reactivity are strong predictors of AUD development and relapse, and suggests that some of the AIE-induced changes we have observed in the dorsal hippocampus may be similar in the ventral region. Against this backdrop we propose three Specific Aims that will more fully characterize the AIE-induced phenotypes we have identified, identify mechanisms underlying them, and explore treatments to reverse them. Aim 1 will address the role of histone H3K27 acetylation, and other possible molecular mechanisms, in AIE- induced dendritic spine changes, and further characterize our previously-reported reversal of AIE-induced spine changes by donepezil. Aim 2 will follow-up our recent findings to identify mechanisms underlying AIE- induced induction of hippocampal inflammatory markers and corresponding reductions of neurogenesis and increased cell death cascade markers. Aim 3 is founded on preliminary data indicating that AIE causes a decrease in astrocyte-synaptic proximity that could be of functional synaptic significance. We will confirm and expand that finding, and assess its pharmacological reversibility in adulthood. Our goal is to explore possible interlacing mechanisms underlying AIE effects on synaptic, inflammatory, and glial function. These proposed studies are all based on distinct sets of preliminary data, will address specific epigenetic and molecular mechanisms underlying AIE effects on hippocampal structure and function, and will expand our understanding of translationally-relevant AIE-induced phenotypes.

纳迪亚联盟致力于确定长期影响的基础机制关于大脑和行为的青少年间歇性乙醇暴露（AIE），并探索预防或扭转它们。组件1的重点是AIE对海马结构和功能的持久影响及其行为后遗症。基于我们的发现，我们的总体假设AIE引起了持久但由相互作用的表观遗传，神经炎症驱动的海马突触功能的可逆折衷和神经胶质机制。在上一个纳迪亚的资金周期中，我们发现AIE产生了促炎性海马形成的环境，树突状脊柱密度和形态的改变，组蛋白改变乙酰化和甲基化，星形胶质细胞突触接近度减少，神经发生下降，而动员细胞死亡分子机械的增加。通过NADIA合作，我们进一步鉴定出表观遗传学变化，这些变化表明这些作用的特定分子机制。重要的是，我们还表明，与药理的成年后，许多这些作用都是可逆的当前临床用途的药物。我们最近的发现表明，AIE导致焦虑状的倾向环境挑战之后的行为，因此表明需要将我们的评估扩展到腹侧海马。这具有明显的翻译意义，因为焦虑和压力反应性很强 AUD开发和复发的预测因素，并建议我们进行的一些AIE诱导的变化在背侧海马中观察到的腹侧区域可能相似。在此背景下，我们提出了三个具体目标，这些目标将更充分地描述AIE引起的我们已经确定的表型，识别它们的基础机制，并探索治疗方法以扭转它们。 AIM 1将解决组蛋白H3K27乙酰化的作用，以及其他可能的分子机制，在AIE-中诱导的树突状脊柱变化，并进一步表征了我们先前报告的AIE诱导的逆转脊柱通过多奈替齐氏变化。 AIM 2将跟进我们最近的发现，以确定AIE的基础机制诱导海马炎症标志物的诱导以及神经发生和相应减少增加了细胞死亡级联标记。 AIM 3建立在初步数据上，表明AIE导致A 可能具有功能性突触显着性的星形胶质细胞突触接近性。我们将确认并扩大该发现，并评估其成年期的药理可逆性。我们的目标是探索可能 AIE对突触，炎症和神经胶质功能的影响的交织机制。这些拟议的研究都是基于不同初步数据集的，将解决特定 AIE对海马结构和功能的影响的表观遗传学和分子机制，并将扩展我们对翻译与AIE诱导的表型的理解。