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

项目概要 胎儿酒精谱系障碍 (FASD) 是非遗传性神经发育障碍的最常见原因 全世界的残疾。 FASD 的临床症状可能有所不同，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。延误 诊断与阴性临床结果相关，而早期干预可以提高患者的治疗质量 生活。 粗大和精细运动发育缺陷是 FASD 的一些最早可识别的临床症状。 患者。然而，产前酒精暴露导致早期运动技能缺陷的机制 目前尚不清楚。纹状体（基底神经节的输入核）内神经元的功能成熟是 与新生小鼠复杂运动的发生密切相关。 F30 中概述的实验 该提案将研究纹状体内 GABA 能中间神经元回路的异常发育如何可能 与产前酒精暴露后运动发育迟缓有关。我的初步数据表明，产前 酒精暴露会导致纹状体 GABA 能中间神经元的突触连接形成不足 产后前两周。具体目标 1 将利用全细胞膜片钳电生理学、光遗传学 和跨突触病毒方法来识别功能性突触形成缺陷的根源 传入纹状体 GABA 能中间神经元。具体目标 2 将确定如何观察产前酒精 暴露引起的纹状体 GABA 能中间神经元信号传导缺陷可能与形态和功能的改变有关 纹状体投射神经元的功能成熟和新生儿运动发育（通过一系列测量） 评估前两次期间粗大、精细和复杂运动能力的开始的简短行为任务 产后几周。 这个 F30 提案将使我能够实现我的长期目标，即为更好地理解 FASD 最早临床症状背后的生理变化，以便更好地识别 并为FASD患者提供针对性治疗。我完成拟议工作的目标是开发 作为 FASD 医师科学家进行研究所需的智力基础和技术技能 领域，重点关注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.