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

摘要 尽管发展经验影响长期行为模式的方式很多，但我们的 对这是如何发生的机械理解是有限的。这项研究计划的长期目标是 阐明支持行为的成熟机制和经验依赖机制的交叉点 收购跨越发展。本申请的目的是鉴定表观遗传和分子生物学特征。 为青少年的发展学习而招募的精选细胞的特征。在这里，我们建立在我们最近的 初步数据表明，可重复的，空间离散的细胞群启动所需的分子反应， 记忆形成的年龄时，学习是可能的，但不是之前，和不同的男性和 女性这提供了一个独特的机会来跟踪大脑区域内发生的变化， 发展的过程中，来“在线”编码的经验，这样它就决定了成人的行为 模式.与基于测序技术的成人脑细胞发现的爆炸性增长相比， 已知只有少数因素可以追踪发展性学习。识别单个细胞的特性 他们的网络，因为他们在青少年发展的功能转移将有助于发现其他 大脑系统经历发育功能波动，最终走向修复 努力和丰富的计划，针对高峰阶段的发展接受经验。的 中心假设是表观遗传和分子调控过程定义了单个细胞及其 根据个人的年龄和性别，建立不同的关系，创造支持学习的组合 在自然学习阶段的开始。PI具有大脑发育机制方面的专业知识， 行为，包括表观遗传学和分子生物学作为手段，以寻找因果关系的青少年 成人行为的经验。合作研究者在单细胞测序方法和分析方面的专业知识是 互补的。这些目标将通过追求两个具体目标来实现：1）确定 支持行为效应所需分子激活的听觉前脑，以及2）预测细胞 基于基线染色质可及性和RNA谱的响应度。结合了最先进的 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 染色质结构和RNA群体之间的关系，新的细胞亚型，以及它们之间的关系， 来预测性别特异性学习的能力。使用一种分子标记来识别用于学习的细胞， 然后，我们将这些基线细胞特征与功能性特征共同定位。因此，拟议的研究开始 填补了发育神经生物学的空白，将前所未有的细节应用于结构上， 功能网络的组织。阐明和建立组织 开发大脑对经验进行编码是突破小说测试生产新时代的关键 成熟和经验依赖过程塑造神经网络以促进或限制学习的方式。

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.