The Instruction of Sensory Inputs in Inhibitory Circuit Maturation in the Somatosensory Cortex

项目摘要/摘要 自闭症谱系障碍(ASD)是一组常见的神经发育障碍 表现多样，但始终注意到感觉障碍。以前的工作有 证明了感官输入在亚型的形态成熟中的要求 躯体感觉皮层的中间神经元，但这对回路活动和局部区域的影响 输出未知。我们假设感觉输入招募特定的中间神经元亚型来 触发大脑皮层回路的成熟，这一过程的扰动导致持续 区域皮质输出的异常，这是其病理生理学基础 神经发育障碍。为了检验我们的假设，我们将记录自发的网络 神经元亚群和感觉剥夺动物的活动。我们将确定 使用解剖示踪剂将突触前信息输入到这些细胞。我们还将利用一个小鼠模型 自闭症揭示高危ASD基因在回路成熟过程中的功能 抑制性中间神经元和皮质内投射神经元。这项调查将填补一个 对ASD发病机制和基因间相互作用的认识存在很大差距 背景和依赖活动的发育过程。ASD的完整图景 发病机制尚不清楚。该项目旨在描述神经元活动如何引导电路 在遗传风险增加的背景下的发展，提供对疾病的机械性洞察 开发并为早期诊断和新的治疗靶点奠定基础。

PROJECT SUMMARY/ABSTRACT Autism Spectrum Disorders (ASD) are a group of common neurodevelopmental disorders of diverse presentation, though sensory disturbances are consistently noted. Previous work has demonstrated a requirement for sensory input in the morphological maturation of subtypes of interneurons in the somatosensory cortex, but the effect this has on circuit activity and regional output is unknown. We hypothesize that sensory inputs recruit select interneuron subtypes to trigger the maturation of cortical circuits and that perturbations of this process cause lasting abnormalities in regional cortical output, which underlie the pathophysiology of neurodevelopmental disorders. To test our hypothesis, we will record the spontaneous network activity of subpopulations of neurons and in sensory deprived animals. We will identify the presynaptic inputs to these cells with an anatomical tracer. We will also utilize a mouse model of autism to reveal the function of a high-risk ASD gene in the maturation of circuits involving inhibitory interneurons and intracortical projection neurons. This investigation will fill a substantial gap in knowledge of ASD pathogenesis and the interaction between genetic background and activity-dependent developmental processes. The complete picture of ASD pathogenesis remains unclear. This project aims to describe how neuronal activity guides circuit development in the context of increased genetic risk, providing mechanistic insight into disease development and laying the groundwork for earlier diagnosis and novel treatment targets.