At the right time and place – identifying epigenetic and molecular determinants of a developmental learning window

在正确的时间和地点 – 识别发育学习窗口的表观遗传和分子决定因素

• 批准号: 10575177
• 负责人: SARAH E LONDON
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575177
• 关键词: ATAC-seq; Adolescent; Adult; Age; Animal Model; Area; Auditory; Behavior; Behavioral; Birds; Brain; Brain region; Cells; Chromatin; Chromatin Structure; Data; Data Set; Development; Epigenetic Process; Explosion; Female; Foundations; Genomics; Goals; Immunohistochemistry; Individual; Investigation; Learning; Memory; Methods; Molecular; Molecular Biology; Molecular Profiling; Neuronal Plasticity; Outcome; Pattern; Phase; Phosphorylation; Population; Process; Productivity; Property; Prosencephalon; Publishing; RNA; Research; Research Personnel; Ribosomal Protein S6; Shapes; Songbirds; System; Techniques; Technology; Testing; Time; brain cell; cell type; developmental neurobiology; experience; hatching; innovation; insight; male; molecular marker; multiple omics; neural network; novel; programs; recruit; remediation; response; sex; single cell sequencing; spatial integration; trait; transcriptome sequencing; transcriptomics; zebra finch

Summary. Despite the plethora of ways that developmental experience influences long-term patterns of behavior, our mechanistic understanding of how this occurs is limited. The long-term goal of this research program is to elucidate the intersection of maturational and experience-dependent mechanisms that support behavioral acquisition across development. The objective of this application is to identify the epigenetic and molecular signatures of select cells recruited for developmental learning in juveniles. Here, we build on our recent preliminary data that repeatable, spatially-discreet cell populations initiate a molecular response required for memory formation at an age when learning is possible, but not before, and differently between males and females. This provides a unique opportunity to track the changes that occur within a brain region as development proceeds and comes “on-line” for encoding experience such that it determines adult behavioral patterns. In contrast to the explosion of sequencing technology-based discoveries about brain cells in adults, only a few factors are known to track with developmental learning. Identifying the properties of individual cells and their networks as they shift functionally across juvenile development would be useful for discovery of other brain systems that undergo developmental functional fluctuations and ultimately to move towards remediation efforts and enrichment programs targeted for peak phases of developmental receptivity to experience. The central hypothesis is that epigenetic and molecular regulatory processes define individual cells and their relationships differently depending on an individual’s age and sex, creating combinations that support learning at the onset of a natural learning phase. The PI has expertise in mechanisms of brain development and behavior including epigenetics and molecular biology as means to find causal relationships of juvenile experience to adult behavior. The co-Investigator’s expertise in single cell sequencing methods and analysis is complementary. The objectives will be accomplished by pursing two specific aims 1) To identify properties of the auditory forebrain that support molecular activation required for behavioral effects, and 2) To predict cell responsivity based on baseline chromatin accessibility and RNA profiles. A combination of state-of-the-art sequencing methods, and innovative analysis across platforms and datasets, will discover new relationships between chromatin structure and RNA populations, new cell subtypes, and the relationships between them, that predict the ability to learn in sex-specific ways. Using a molecular marker for cells recruited for learning, we will then co-localize these baseline cell features with functional ones. The proposed research thus begins to fill a void in developmental neurobiology by applying an unprecedented level of detail to the structural organization of functional networks. Elucidating and establishing mechanisms underlying the organization of developing brain to encode experience is the key to breaking through to a new productive era for testing novel ways that maturation and experience-dependent processes shape neural networks to promote or limit learning.

概括。 尽管有很多发展经验影响长期行为模式的方式，但我们 机械理解对这种情况的发生是有限的。该研究计划的长期目标是 阐明支持行为的成熟和经验依赖性机制的交集 在整个发展中获取。该应用的目的是识别表观遗传和分子 为少年招募的用于发育学习的精选细胞的特征。在这里，我们以最新为基础 可重复的，空间验证细胞种群的初步数据启动了所需的分子响应 在学习可能的年龄，但在男性和男性之间没有不同的时代的记忆形成 女性。这为跟踪大脑区域内发生的变化提供了一个独特的机会 开发进行并进行“在线”，用于编码经验，以决定成人行为 模式。与对成人脑细胞的基于测序的基于技术的发现的爆炸相反， 仅知道有少数因素可以通过发展学习来跟踪。识别单个单元的特性 他们的网络在少年开发中的功能上转移将有助于发现其他 经历发育功能波动并最终朝着补救发展的大脑系统 努力和丰富计划针对发展体验的发展峰阶段。 中心假设是表观遗传和分子调节过程定义了单个细胞及其 关系根据个人的年龄和性别而有所不同，创建支持学习的组​​合 在自然学习阶段的开始。 PI在大脑发育机制方面具有专业知识和 包括表观遗传学和分子生物学在内的行为，作为寻找少年因果关系的手段 成人行为的经验。共同研究器在单细胞测序方法和分析方面的专业知识是 完全地。目标将通过追求两个具体目标来实现1） 支持行为效应所需的分子激活的听觉前脑，2）预测细胞 基于基线染色质的可及性和RNA曲线的响应率。最先进的结合 测序方法以及跨平台和数据集的创新分析将发现新的关系 在染色质结构和RNA群体，新细胞亚型及其之间的关系之间 这可以预测以性别特定方式学习的能力。使用分子标记来进行学习的细胞， 然后，我们将与功能性元素共同定位这些基线单元格特征。因此，拟议的研究开始 通过在结构上应用前所未有的细节来填充发育神经生物学的空隙 功能网络的组织。阐明和建立组织的基础机制 开发大脑以编码体验是打破新生产时代的关键，以测试小说 成熟和依赖经验的过程塑造神经网络以促进或限制学习的方式。