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.

NADIA 联盟致力于确定长期影响的潜在机制青少年间歇性乙醇暴露（AIE）对大脑和行为的影响，并探索预防或预防方法扭转它们。第 1 部分重点关注 AIE 对海马结构和功能的持久影响以及他们的行为后遗症。根据我们的发现，我们的总体假设 AIE 导致了持久但由相互作用的表观遗传、神经炎症、和神经胶质机制。在上一个 NADIA 资助周期中，我们发现 AIE 产生促炎物质海马结构中的环境、树突棘密度和形态的改变、组蛋白的改变乙酰化和甲基化、星形胶质细胞突触邻近性减少、神经发生减少，以及动员细胞死亡分子机制的增加。通过与 NADIA 的合作，我们进一步确定的表观遗传变化表明这些影响背后的特定分子机制。重要的是，我们还表明，其中许多影响在成年后可以通过药物逆转目前临床使用的药物。我们最近的研究结果表明，AIE 会导致类似焦虑的倾向环境挑战后的行为，因此表明需要将我们的评估扩大到腹侧海马体。这具有明显的转化意义，因为焦虑和压力反应性很强 AUD 发展和复发的预测因素，并表明我们已经发现一些 AIE 引起的变化在背侧海马中观察到的情况可能与在腹侧区域中观察到的相似。在此背景下，我们提出了三个具体目标，以更全面地描述 AIE 引起的我们已经确定了表型，确定了它们背后的机制，并探索了逆转它们的治疗方法。目标 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- 诱导的树突棘变化，并进一步表征了我们之前报道的 AIE 诱导的逆转多奈哌齐会改变脊柱。目标 2 将跟进我们最近的发现，以确定 AIE 的潜在机制—— 诱导海马炎症标记物的诱导和相应的神经发生的减少细胞死亡级联标记物增加。目标 3 的基础是初步数据表明 AIE 会导致星形胶质细胞与突触的接近度降低，这可能具有功能性突触意义。我们将确认并扩大这一发现，并评估其在成年后的药理学可逆性。我们的目标是探索可能 AIE 对突触、炎症和神经胶质功能影响的交错机制。这些拟议的研究均基于不同的初步数据集，将解决具体问题 AIE 对海马结构和功能影响的表观遗传和分子机制，并将扩大我们对翻译相关的 AIE 诱导表型的理解。