Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders

胎儿酒精谱系障碍学习障碍的机制和治疗

基本信息

批准号：
10318975
负责人：
KAZUE HASHIMOTO-TORII
金额：
$ 40.16万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-25 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318975
关键词：
Acute Adolescent Affect Alcohols Behavior Behavioral Biological Assay Brain Calcium-Activated Potassium Channel Caregivers Cells Cerebrum Chromatin Cognitive Collaborations DNA Data Defect Early Intervention Elderly Electrophysiology (science)Epigenetic Process Exhibits Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal alcohol effects Gene Expression Genes Goals Heat-Shock Response Impairment Intervention Learning Mediating Methylation Molecular Motor Cortex Motor Skills Mus Neuronal Plasticity Neurons Outcome Patients Pharmacology Property RNA Reporter Response Elements Signal Transduction System Techniques Testing alcohol exposure base effective therapy embryonic alcohol exposure experience fetal genetic manipulation improved in vivo in vivo imaging knock-down learning ability migration motor learning motor skill learning multidisciplinary multiphoton imaging neurobehavior neurobehavioral new therapeutic target novel novel therapeutic intervention offspring overexpression postnatal prenatal prevent programs red fluorescent protein symptom treatment therapeutic target trait

项目摘要

Prenatal alcohol (ethanol) exposure (PAE) significantly impacts cognitive and behavioral abilities of the offspring. These conditions are defined as Fetal Alcohol Spectrum Disorders (FASD). Early intervention of such abnormalities is imperative for optimal outcomes; however, specific therapeutic targets and effective treatments are yet unavailable. The goal of this project is to elucidate the mechanisms underlying the long-term impacts of prenatal alcohol exposure and find effective treatments for the symptoms caused by such impacts in FASD. We have recently shown that the activation of heat shock signaling, which protects young neurons in the alcohol-exposed embryonic brain, can instead cause neuronal migration delay when it is hyperactivated. Our preliminary analysis has identified novel, long-term changes in gene expression associated with this prenatal hyperactivation of heat shock signaling, at the single-cell level within the brains of adolescent mice. These mice show gross and fine motor skills impairment, one of the earliest problems in FASD patients noticed by caregivers. Some of these changes were negatively correlated with the motor learning ability of these mice, and remarkably, reverting one of such altered factors, increased Kcnn2 (a calcium-activated potassium channel) function, improved the motor learning deficits. In addition, preliminary data suggested that overexpression of Kcnn2 in the motor cortex alone can cause motor learning defects. Based on these findings and preliminary data, we hypothesize that epigenetic changes associated with acute high-level activation of heat shock signaling in the fetal brain by PAE are involved in motor learning defects in later life. To test this hypothesis, we will first define the postnatal epigenetic traits specifically associated with the prenatal acute activation of heat shock signaling in the motor cortex of PAE mice, which display motor learning deficits (Aim 1). By investigating the specific effects of Kcnn2 overexpression in untreated mice and those of Kcnn2 knockdown in PAE mice, we will then define how increased Kcnn2 expression contributes to the learning deficits of PAE mice (Aim 2). We also test whether reverting the increased Kcnn2 function can be a novel therapeutic target to improve the deficits (Aim 3). Our multidisciplinary team puts our expertise to achieve these aims, by employing in vivo Kcnn2 manipulation, in vivo imaging and behavior analysis (Torii lab.), electrophysiology and epigenetic analyses (Hashimoto-Torii lab.). By combining a unique reporter system that we developed with these cutting-edge techniques, we will uncover hitherto unknown epigenetic mechanisms leading to neurobehavioral problems in FASD, and develop potentially novel interventions.

产前酒精（乙醇）暴露（PAE）显着影响后代。这些条件被定义为胎儿酒精谱系障碍（FASD）。早期干预这种异常对于最佳结果至关重要。但是，特定的治疗靶标和有效治疗尚不可用。该项目的目的是阐明长期的机制产前酒精暴露的影响，并找到有效的治疗症状 Fasd。我们最近表明，热电话信号的激活，可保护年轻神经元中的年轻神经元当酒精暴露的胚胎大脑过度激活时会导致神经元迁移延迟。我们的初步分析已经确定了与此相关的基因表达的新颖，长期变化热冲击信号传导的产前过度激活，在青少年小鼠大脑内的单细胞水平上。这些老鼠表现出严重的运动技能障碍，这是FASD患者最早的问题之一由看护人。这些变化中的一些与这些小鼠的运动学习能力负相关，值得注意的是，恢复了这种改变的因素之一，增加了KCNN2（钙激活的钾频道功能，改善运动学习缺陷。此外，初步数据表明仅运动皮层中KCNN2的过表达就会导致运动缺陷。基于这些发现和初步数据，我们假设表观遗传变化与 PAE在胎儿大脑中急性高水平激活的电动机参与电动机以后的学习缺陷。为了检验这一假设，我们将首先定义产后表观遗传特征与PAE运动皮层中热激信号的产前急性激活有关老鼠，显示运动学习缺陷（AIM 1）。通过研究KCNN2的特定作用未经治疗的小鼠的过表达以及Pae小鼠的KCNN2敲低的过表达，然后我们将定义如何定义 KCNN2表达增加有助于PAE小鼠的学习缺陷（AIM 2）。我们还测试是否恢复增加的KCNN2功能可能是改善缺陷的新型治疗靶标（AIM 3）。我们的多学科团队通过使用体内KCNN2操纵来实现我们的专业知识来实现这些目标体内成像和行为分析（Torii Lab。），电生理学和表观遗传学分析（桥本 - 托里实验室）。通过将我们与这些尖端技术开发的独特记者系统相结合，我们将发现迄今未知的表观遗传机制，导致FASD的神经行为问题，并发展潜在的新干预措施。