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Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders

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

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中文摘要
翻译
产前酒精(乙醇)暴露(PAE)显着影响胎儿的认知和行为能力 后代。这些病症被定义为胎儿酒精谱系障碍 (FASD)。早期干预 此类异常对于获得最佳结果至关重要;然而,具体的治疗目标和有效的 目前尚无治疗方法。该项目的目标是阐明长期的机制 产前酒精暴露的影响,并找到针对此类影响引起的症状的有效治疗方法 胎儿酒精谱系障碍。 我们最近发现热休克信号的激活可以保护年轻的神经元 暴露于酒精的胚胎大脑在过度活跃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 青春期小鼠大脑内单细胞水平的热休克信号产前过度激活。 这些小鼠表现出粗大和精细运动技能受损,这是 FASD 患者最早注意到的问题之一 由护理人员。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,恢复其中一个改变的因素后,Kcnn2(一种钙激活钾 通道)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 的过度表达就会导致运动学习缺陷。 根据这些发现和初步数据,我们假设表观遗传变化与 PAE 急性高水平激活胎儿大脑中的热休克信号,参与运动 以后生活中的学习缺陷。为了检验这个假设,我们首先定义出生后表观遗传特征 与 PAE 运动皮层热休克信号的产前急性激活特别相关 表现出运动学习缺陷的小鼠(目标 1)。通过考察Kcnn2的具体效果 未经治疗的小鼠中的过度表达以及 PAE 小鼠中 Kcnn2 敲低的小鼠,然后我们将定义如何 Kcnn2 表达增加会导致 PAE 小鼠的学习缺陷(目标 2)。我们还测试是否 恢复增强的 Kcnn2 功能可以成为改善缺陷的新治疗靶点(目标 3)。我们的 多学科团队利用我们的专业知识通过体内 Kcnn2 操作来实现这些目标 体内成像和行为分析(Torii 实验室)、电生理学和表观遗传分析(Hashimoto-Torii) 实验室。)。通过结合我们用这些尖端技术开发的独特报告系统,我们将 揭示迄今为止未知的导致 FASD 神经行为问题的表观遗传机制,并开发 潜在的新颖干预措施。
英文摘要
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.
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Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders
  • 批准号:
    10077809
  • 项目类别:
  • 资助金额:
    $40.16万
  • 财政年份:
    2019
  • 负责人:
    KAZUE HASHIMOTO-TORII
  • 依托单位:
Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders
  • 批准号:
    10543986
  • 项目类别:
  • 资助金额:
    $40.16万
  • 财政年份:
    2019
  • 负责人:
    KAZUE HASHIMOTO-TORII
  • 依托单位:
Roles of Primary Cilia in the Developing Cortex Exposed to Alcohol
  • 批准号:
    9245104
  • 项目类别:
  • 资助金额:
    $20.78万
  • 财政年份:
    2017
  • 负责人:
    KAZUE HASHIMOTO-TORII
  • 依托单位:
Biomarker for intellectual disability in children prenatally exposed to alcohol
  • 批准号:
    9391732
  • 项目类别:
  • 资助金额:
    $26.18万
  • 财政年份:
    2017
  • 负责人:
    KAZUE HASHIMOTO-TORII
  • 依托单位:
海外基金