Molecular mechanisms of infantile learning and memory

项目摘要 行为学研究表明，早期生活经历对大脑能力的发展有重要影响。 因此，如果早期经历是高度不平衡的，例如，如果它们是在慢性疾病的影响下发生的， 挑战或压力，个人的个性会发展出特定的特征，包括一些 与严重的精神病有关尽管有这些广泛的行为特征， 已知的生物学机制的基础学习和记忆在早期的生活，除了 创伤和压力的影响。了解大脑中学习和记忆的机制 早期发育是理解学习和记忆系统是如何建立的关键， 功能，以及更好地阐明与神经发育相关的缺陷， 残疾。 大脑中最重要的运作系统之一是内侧颞叶依赖性记忆 系统，它处理有关情节，空间，上下文和社会经验的信息。直到最近 据信这种记忆系统在婴儿期不起作用是因为它在发育上不成熟， 并且在发育后期才开始参与。然而，最近在啮齿动物模型中的研究，包括我们的 他的研究表明，情景和空间形式的学习需要生物机制的功能， 背侧海马（dHC），一个主要区域，连同内侧前额叶皮质（mPFC），内侧 颞叶记忆系统尽管最近取得了这一进展， 缺乏婴儿期的、依赖于大脑的学习和记忆机制。 为了填补这一知识空白，我们建议采用啮齿动物模型的情节和空间学习，遗传 基因工程小鼠模型、分子成像技术、空间转录组学和RiboTag小鼠 技术与组学分析相结合，以追求以下具体目标：（1）绘制分布图， 婴儿期情景学习激活的细胞网络的系统水平（dHC和mPFC） 在记忆恢复中的作用，并测试恢复的可塑性和作用。 幼儿记忆在成人行为中的作用(2)为了全面分析在以下条件下的原位dHC和mPFC基因表达， 整个转录组的水平，以及获得一个全面的翻译组专门调控， 兴奋性和抑制性神经元，对婴儿和成人大脑的学习做出反应。 这些实验将提供前所未有的大量关于生物学和 婴儿学习和记忆的系统级机制，以及一个宝贵的来源， 关于神经发育和成人认知障碍的新假说的知识。

Project Summary Behavioral studies have shown that early life experience significantly shapes the development of brain abilities. Accordingly, if early experiences are highly unbalanced, e.g. if they occur under the influence of chronic challenges or stresses, the individual's personality will develop specific traits, including some that are associated with severe psychopathologies. Despite these extensive behavioral characterizations, very little is known about the biological mechanisms underlying learning and memory in early life, with the exception of the effects of trauma and stress. Understanding the mechanisms underlying learning and memory in early development is key for comprehending how the learning and memory systems are built and function throughout life, as well as to better elucidate the deficits associated to neurodevelopmental disabilities. One of the most important systems operating in the brain is the medial temporal lobe-dependent memory system, which processes information about episodic, spatial, contextual and social experiences. Until recently it was believed that this memory system does not function in infancy because it is developmentally immature, and only begins to be involved late in development. However, recent studies in rodent models, including our own, showed that episodic and spatial forms of learning require the function of biological mechanisms in the dorsal hippocampus (dHC), a main region, together with the medial prefrontal cortex (mPFC), of the medial temporal lobe memory system. Despite this recent progress, knowledge of the biological and system-level mechanisms of infantile, hippocampus-dependent learning and memory is lacking. To fill this knowledge gap we propose to employ rodent models of episodic and spatial learning, genetically engineered mouse models, molecular imaging technology, spatial transcriptomics and RiboTag mouse technology combined with omic analyses to pursue the following specific aims: (1) To map the distribution at a system level (dHC and mPFC) of the cellular networks activated in response to episodic learning in infancy and in memory recovery following reminders at later ages, and to test the malleability and roles of recovered infantile memories in adult behavior. (2) To comprehensively profile in situ dHC and mPFC gene expression at the level of the whole transcriptome, as well as obtain a comprehensive translatome specifically regulated in excitatory and inhibitory neurons, in response to learning in both infant and adult brains. These experiments will provide an unprecedented amount of novel information regarding the biological and system-level mechanisms underlying infantile learning and memory, as well as an invaluable source of knowledge for generating novel hypotheses regarding neurodevelopmental and adult cognitive disorders.