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

项目总结/摘要 自闭症谱系障碍（ASD）是一组常见的神经发育障碍， 不同的表现，虽然感觉障碍是一贯注意到的。先前的工作已经 证明了感觉输入的要求，在形态成熟的亚型， 躯体感觉皮质中的中间神经元，但这对回路活动和区域活动的影响 输出未知。我们假设感觉输入招募选择的中间神经元亚型， 触发皮层回路的成熟，而这一过程的扰动会导致持久的 区域皮质输出的异常，这是脑缺血的病理生理学基础。 神经发育障碍为了验证我们的假设，我们将记录自发网络 活动的神经元亚群和感觉剥夺动物。我们将确定 用解剖示踪剂对这些细胞进行突触前输入。我们还将利用小鼠模型， 自闭症揭示了一个高风险的ASD基因在电路成熟中的功能， 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 ASD发病机制和遗传因素之间的相互作用的知识存在巨大差距， 背景和活动依赖的发展过程。ASD的全貌 发病机制尚不清楚。这个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发展，提供对疾病的机械见解 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.