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 胎儿酒精谱系障碍（FASD）是非遗传性神经发育障碍最常见的原因。 全世界的残疾人。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的临床表现多变，使诊断成为一个挑战。延迟 诊断与阴性临床结局相关，而早期干预可改善患者的 生活 粗大和精细运动发育缺陷是FASD最早可识别的临床体征之一， 患者然而，产前酒精暴露导致早期运动技能缺陷的机制 目前还不清楚。纹状体是基底神经节的输入核， 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。我的初步数据显示产前 酒精暴露导致纹状体GABA能中间神经元的突触连接形成不足， 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 和跨突触病毒方法来鉴定功能性突触形成中缺陷的来源， 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酒精 纹状体GABA能中间神经元信号转导中的应激诱导缺陷可能与改变的形态学和 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 简单的行为任务评估粗，精细，和复杂的运动能力的开始，在前两个 产后几周 这个F30提案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，以提高识别FASD的努力。 FASD患者并提供针对性治疗。我完成拟议工作的目标是开发 知识基础和必要的技术技能进行研究，作为医生科学家在FASD 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。