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

产前酒精暴露、GABA能中间神经元回路、早期运动行为和发育中的纹状体

• 批准号: 10618358
• 负责人: Adelaide R Tousley
• 金额: $ 5.27万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-25 至 2026-05-24
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618358
• 关键词: Affect; Alcohols; Animal Model; Area; Basal Ganglia; Behavior; Behavioral; Birth; Cells; Child; Clinical; Cognitive; Cognitive deficits; Complex; Corpus striatum structure; DNA cassette; Data; Development; Diagnosis; Disease; Dysmorphology; Early Intervention; Electrophysiology (science); Embryo; Ethanol; Exposure to; Face; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fishes; Foundations; Frequencies; Ganglia; Glutamates; Goals; Injections; Internal Ribosome Entry Site; Interneurons; LoxP-flanked allele; Measures; Medial; Mediating; Membrane; Morphology; Motor; Motor Cortex; Motor Skills; Movement; Mus; Neocortex; Neonatal; Neurodevelopmental Disability; Neurons; Outcome; Patients; Phenotype; Physicians; Physiological; Pilot Projects; Play; Property; Quality of life; Reporter; Research; Role; School-Age Population; Scientist; Series; Signal Transduction; Source; Symptoms; Synapses; Synaptic plasticity; Technical Expertise; Teratogens; Testing; Thalamic structure; Transgenic Mice; Vertebral column; Viral; Work; alcohol exposure; biocytin; cholinergic; experimental study; gamma-Aminobutyric Acid; improved; inducible Cre; insight; migration; motor behavior; motor control; motor deficit; mouse model; neocortical; neonatal mice; neural circuit; neurodevelopment; non-genetic; novel marker; optogenetics; patch clamp; postnatal; pregnant; prospective; sensory cortex; sensory input; somatosensory; synaptic function; targeted treatment; voltage clamp

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.

项目摘要 胎儿酒精谱系（FASD）是非遗传神经发育的最常见原因 全球残疾。 FASD的临床症状可能会有所不同，但包括面部畸形，认知缺陷 和行为异常。 FASD的可变临床表现使诊断成为挑战。延迟 诊断与负临床结果有关，而早期干预可以提高患者的质量 生活。 总体运动和精细运动发育的缺陷是FASD的一些最早可识别的临床迹象 患者。但是，产前酒精暴露有助于定义早期运动技能的机制 尚不清楚。纹状体内神经元的功能成熟，基底神经节的输入核us为 与新生小鼠的复杂运动的发作密切相关。此F30中概述的实验 提案将调查纹状体内GABA能中间神经元电路的异常发展可能如何 与产前酒精暴露后发育延迟有关。我的初步数据表明产前 酒精暴露会导致在纹状体GABA能中间神经元中确切形成突触连接 前两个后几周。特定的目标1将利用全细胞斑块夹电生理学，光遗传学 和反式突触病毒方法，以识别功能突触形成的定义来源 纹状体GABA能中间神经元的传入。特定的目标2将确定观察到的产前酒精 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学改变有关 纹状体投影神经元的功能成熟和新生儿运动发育，如一系列 简短的行为任务评估了前两项总体，精细和复杂运动能力的发作 产后周。 该F30提案将使我能够实现我的长期目标，以更好地理解 FASD最早的临床症状的身体变化，以提高努力以识别 FASD患者并提供目标治疗。我完成拟议工作的目标是开发 在FASD中作为物理科学家进行研究所必需的知识基础和技术技能 领域，重点是产前酒精暴露如何影响神经回路的发展，并导致 早期行为的变化。