Postnatal experience shapes gene expression and connectivity development in the cortex

产后经历影响大脑皮层的基因表达和连接发展

• 批准号: 10749679
• 负责人: Alexander Nevue
• 金额: $ 7.37万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749679
• 关键词: Acceleration; Address; Anatomy; Architecture; Auditory; Auditory area; Auditory system; Bar Codes; Behavior; Biological; Brain; Brain Stem; Cell Death; Cell Nucleus; Cell Shape; Cells; Central Nervous System; Chromosome Mapping; Complex; Data; Development; Diphtheria Toxin; Electrophysiology (science); Engineering; Gene Expression; Genetic; Genomics; Goals; Hair Cells; Hearing; Homeostasis; Impairment; Individual; Labyrinth; Maps; Measures; Methodology; Methods; Modeling; Molecular; Molecular Genetics; Mus; Outcome; Pathway interactions; Process; Property; RNA; Rabies; Rabies virus; Research Personnel; Sampling; Sensory; Sensory Deprivation; Sensory Hair; Shapes; Slide; Synapses; Technical Expertise; Techniques; Technology; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Tissues; Viral; brain cell; career; cell cortex; cell type; diphtheria toxin receptor; excitatory neuron; experience; genome-wide; in vivo; inhibitory neuron; molecular shape; mouse model; neural; neural circuit; new technology; normal hearing; novel; postnatal; postsynaptic neurons; presynaptic; programs; sensory cortex; sensory input; single nucleus RNA-sequencing; tool

PROJECT SUMMARY Postnatal sensory experience has a profound effect on the maturation, composition, and connectivity of cortical cell types, but systematic analyses of these changes have not yet been feasible. This lack of methods for systematic analysis had made it difficult to define principles in how neural activity re-wires brain circuits and whether connectivity changes precede or follow molecular changes in brain cell types. Systematically characterizing how neural activity from the sensory periphery shapes the molecular and synaptic properties of neural circuits in the brain would benefit from new technologies in which synaptic connectivity relationships and genome-wide RNAs could be measured in vivo from the same individual cells. High-throughput, single-cell resolved methods to profile gene expression and synaptic connectivity – including the barcoded rabies virus- based method called Slide-SBARRO method developed in the Saunders Lab - are well suited to study how sensory input influences cortical circuit formation. In Aim 1, I will use an inducible mouse model paired with single nucleus RNA sequencing of primary auditory cortex (A1) cells to determine how auditory input shapes cortical cell-type proportions and gene expression. In Aim 2, I will determine how auditory input shapes local synaptic relationships within A1 by reconstructing hundreds of spatially resolved and cell-type-specific monosynaptic networks using Slide-SBARRO. By comprehensively characterizing how auditory sensory input alters brain cell and circuit properties in A1, this proposal will enhance our understanding of the mechanisms through which cortex responds to damage in the sensory periphery. Finally, this proposal will allow me to develop new technical skills and intellectual approaches that I will use to study auditory circuit plasticity as an independent researcher.

项目概要 出生后的感官体验对皮质的成熟、组成和连接具有深远的影响 细胞类型，但对这些变化的系统分析尚不可行。这种缺乏方法 系统分析使得很难定义神经活动如何重新连接大脑回路和 连接性变化是否先于或随后脑细胞类型的分子变化。系统地 描述感觉外围的神经活动如何塑造分子和突触特性 大脑中的神经回路将受益于新技术，其中突触连接关系和 可以在体内从相同的单个细胞测量全基因组RNA。高通量、单细胞 解析基因表达和突触连接的方法 - 包括条形码狂犬病病毒 - Saunders 实验室开发的基于名为 Slide-SBARRO 方法的方法 - 非常适合研究如何 感觉输入影响皮质回路的形成。在目标 1 中，我将使用诱导小鼠模型与单 对初级听觉皮层 (A1) 细胞进行核 RNA 测序，以确定听觉输入如何塑造皮质 细胞类型比例和基因表达。在目标 2 中，我将确定听觉输入如何塑造局部突触 通过重建数百个空间分辨和细胞类型特异性的单突触，A1 内的关系 使用 Slide-SBARRO 的网络。通过全面表征听觉感觉输入如何改变脑细胞 和 A1 中的电路特性，该提案将增强我们对机制的理解 皮层对感觉外围的损伤做出反应。最后，这个提案将使我能够开发新技术 作为一名独立研究员，我将使用这些技能和智力方法来研究听觉回路可塑性。