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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）显著影响新生儿的认知和行为能力