Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders

产前酒精暴露(PAE)显著影响老年人的认知和行为能力 后代。这些情况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不可少的；然而，具体的治疗目标和有效的 目前还没有治疗方法。这个项目的目标是阐明长期的 胎儿期酒精暴露的影响，并寻找有效的治疗方法 FASD。 我们最近已经证明，热休克信号的激活，它保护年轻的神经元在 暴露在酒精中的胚胎大脑，当过度激活时，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、长期的变化 在青春期小鼠大脑中的单细胞水平上，出生前热休克信号的过度激活。 这些小鼠表现出粗略和精细的运动技能障碍，这是FASD患者最早注意到的问题之一 由照顾者提供。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，逆转这种改变的因素之一，增加了Kcnn2(一种钙激活的钾 通道)功能，改善运动学习障碍。此外，初步数据显示， 仅在运动皮质中Kcnn2的过度表达就会导致运动学习障碍。 基于这些发现和初步数据，我们假设表观遗传变化与 PAE对胎脑中热休克信号的急性高水平激活参与运动 晚年的学习缺陷。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 与PAE运动皮质中热休克信号的产前急性激活有关 小鼠，表现出运动学习障碍(目标1)。通过研究Kcnn2的具体作用 在未经处理的小鼠中过表达，以及在PAE小鼠中Kcnn2基因敲除的那些，然后我们将定义 Kcnn2表达增加导致PAE小鼠学习障碍(目标2)。我们还测试了 恢复增加的Kcnn2功能可以成为改善缺陷的新的治疗目标(目标3)。我们的 多学科团队将我们的专业知识用于实现这些目标，通过在体内使用Kcnn2操作，在 活体成像和行为分析(Torii实验室)、电生理学和表观遗传学分析(Hashimoto-Torii 实验室)。通过将我们开发的独特的记者系统与这些尖端技术相结合，我们将 揭示迄今未知的导致FASD神经行为问题的表观遗传机制，并开发 潜在的新干预措施。

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.