Prenatal alcohol exposure, GABAergic interneuron circuitry, early motor behavior, and the developing striatum

项目摘要 胎儿酒精谱系障碍(FASD)是导致非遗传性神经发育的最常见原因 全球范围内的残疾。FASD的临床症状多种多样，但包括面部畸形、认知缺陷 和行为异常。FASD的临床表现多种多样，这给诊断带来了挑战。延迟 诊断与阴性临床结果相关，而早期干预可以提高患者的生活质量 生活。 粗大和精细运动发育缺陷是FASD最早可识别的临床症状之一 病人。然而，产前酒精暴露导致早期运动技能缺陷的机制 目前还不清楚。纹状体内神经元的功能成熟，纹状体是基底神经节的输入核 与新生小鼠复杂运动的开始密切相关。本F30中概述的实验 该提案将研究纹状体内GABA能神经元间回路的异常发育如何 与产前酒精暴露后的发育运动迟缓有关。我的初步数据显示，产前 酒精暴露导致纹状体GABA能中间神经元突触连接形成缺陷 出生后的头两周。具体目标1将利用全细胞膜片钳电生理学、光遗传学 以及跨突触病毒方法识别功能性突触形成缺陷的来源 纹状体GABA能中间神经元的传入。具体目标2将确定如何观察产前饮酒 暴露诱导的纹状体GABA能中间神经元信号转导缺陷可能与改变的形态和 纹状体投射神经元功能成熟与新生儿运动发育的系列研究 在前两个阶段评估粗略、精细和复杂运动能力的简短行为任务 出生后几周。 这份F30建议将使我能够实现我的长期目标，即更好地了解 FASD最早临床症状的生理变化以提高对FASD的识别 FASD患者并提供有针对性的治疗。我完成拟议工作的目标是开发 在FASD作为内科科学家进行研究所需的智力基础和技术技能 领域，重点是产前酒精暴露如何影响神经回路的发育并导致 早期行为的改变。

Project Summary Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of non-genetic neurodevelopmental disability worldwide. Clinical symptoms of FASD can vary, but include facial dysmorphology, cognitive deficits and behavioral abnormalities. The variable clinical presentation of FASD makes diagnosis a challenge. Delayed diagnosis is associated with negative clinical outcomes, while early intervention can improve patients’ quality of life. Deficits in gross and fine motor development are some of the earliest identifiable clinical signs of FASD in patients. However, the mechanism by which prenatal alcohol exposure contributes to deficits in early motor skills is not yet known. Functional maturation of neurons within the striatum, the input nucleus of the basal ganglia, is closely associated with onset of complex movements in neonatal mice. The experiments outlined in this F30 proposal will investigate how aberrant development of GABAergic interneuron circuitry within the striatum may relate to developmental motor delays after prenatal alcohol exposure. My preliminary data suggest that prenatal alcohol exposure results in deficient formation of synaptic connections to striatal GABAergic interneurons during the first two postnatal weeks. Specific Aim 1 will leverage whole cell patch clamp electrophysiology, optogenetic and trans-synaptic viral approaches to identify the source of deficits in the formation of functional synaptic afferents to striatal GABAergic interneurons. Specific Aim 2 will establish how observed prenatal alcohol exposure-induced deficits in striatal GABAergic interneuron signaling may relate to altered morphological and functional maturation of striatal projection neurons, and neonatal motor development as measured by a series of brief behavioral tasks assessing the onset of gross, fine, and complex motor abilities during the first two postnatal weeks. This F30 proposal will allow me to fulfill my long-term objective of contributing to a better understanding of the physiological changes underlying the earliest clinical symptoms of FASD in order to improve efforts to identify FASD patients and provide targeted treatment. My goals in completing the proposed work are to develop the intellectual foundations and technical skills necessary to conduct research as physician scientist in the FASD field, with a focus on how prenatal alcohol exposure can affect the development of neural circuits and result in changes in early behaviors.