Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders

产前酒精（乙醇）暴露（PAE）显着影响的认知和行为能力， 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是必要的;然而，特定的治疗靶点和有效的治疗靶点是必要的。 目前还没有治疗方法。该项目的目标是阐明长期的潜在机制， 产前酒精暴露的影响，并找到有效的治疗这种影响引起的症状， FASD。 我们最近发现，热休克信号的激活，保护年轻的神经元， 暴露于酒精的胚胎大脑，当它过度激活时，反而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的长期变化。 在青春期小鼠脑内的单细胞水平上，产前热休克信号过度激活。 这些小鼠表现出粗大和精细运动技能障碍，这是FASD患者最早注意到的问题之一 照顾者。其中一些变化与这些小鼠的运动学习能力呈负相关， 值得注意的是，恢复了其中一个改变的因子，增加了Kcnn 2（一种钙激活的钾离子通道）， 通道）功能，改善运动学习障碍。此外，初步数据显示， Kcnn 2在运动皮层中的单独过表达可导致运动学习缺陷。 基于这些发现和初步数据，我们假设， 与急性高水平激活的热休克信号在胎脑中的PAE参与运动 在以后的生活中学习缺陷。为了验证这一假设，我们将首先定义出生后的表观遗传特征 特异性地与PAE运动皮层中的热休克信号的产前急性激活相关 显示运动学习缺陷的小鼠（Aim 1）。通过研究Kcnn 2的特异性作用， 在未处理的小鼠中的Kcnn 2过表达和在PAE小鼠中的Kcnn 2敲低，然后我们将定义 增加的Kcnn 2表达导致PAE小鼠的学习缺陷（目的2）。我们还测试了 恢复增加的Kcnn 2功能可以是改善缺陷的新的治疗靶点（目的3）。我们 多学科团队将我们的专业知识，以实现这些目标，通过采用体内Kcnn 2操纵， 体内成像和行为分析（Torii实验室），电生理学和表观遗传学分析（桥本鸟居 实验室）。通过将我们开发的独特报告系统与这些尖端技术相结合，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，并开发 潜在的新干预。

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.