Maturation of Circuits Underlying Learning and Memory

学习和记忆回路的成熟

• 批准号: RGPIN-2017-06344
• 负责人: ArrudaCarvalho, Maithe
• 金额: $ 2.4万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711576
• 关键词: Maturation; Circuits; Underlying; Learning; Memory

Our perceptual, cognitive and emotional abilities emerge at specific times during development and are critically shaped by experiences that occur during early life. Early development is also a period during which key brain areas involved in emotional processing, such as the hippocampus and prefrontal cortex, are maturing. This maturation coincides with the emergence of behaviours dependent on hippocampus-prefrontal cortex networks, such as the ability to generate long lasting memories, or memory persistence. Despite convergent evidence of volumetric, structural, and synaptic changes taking place in prefrontal cortex and hippocampus at the same time as memory persistence emerges, no study to date has looked at how the functional maturation of the hippocampus-prefrontal cortex circuit contributes to the ontogeny of memory persistence. To address this gap in knowledge we will use optogenetic tools to study how synaptic connectivity between hippocampus and prefrontal cortex changes across development. These are pressing research questions since presently there is no information on how the maturation of brain circuits underlying learning and memory might affect cognitive function in adulthood. To answer these questions, we will: (1) examine the maturation of basal synaptic transmission and anatomical connectivity within this microcircuit, (2) uncover the relationship between hippocampus-prefrontal cortex synaptic plasticity and the ontogeny of memory persistence, and (3) manipulate these plasticity changes in vivo to test whether this interferes with the onset of this behaviour. To fully describe hippocampus-prefrontal cortex functional maturation across development, we will use a combination of histological, electrophysiological and behavioural techniques. Despite the emergent use of optogenetics for the functional dissection of brain microcircuits, the use of this technique within the context of development is both powerful and as yet unexplored. This research will advance knowledge in three ways. First, it will establish a novel framework for the study of complex behaviour from the standpoint of the functional maturation of brain circuits, providing critical insight applicable to any number of developmentally regulated behaviours. Second, it will help define the circuit requirements necessary to sustain memory persistence, a process at the core of cognitive function. Third, identifying periods of heightened plasticity within the maturation of circuits underlying emotional learning has significant implications for interventions. Mapping the factors curtailing plasticity in learning and memory circuits will guide the design of circuit-specific interventions to enhance learning, improving the socioeconomic status of thousands of young Canadians in this and future generations.

我们的感知、认知和情感能力在发育过程中的特定时期出现，并受到早期生活经历的重要影响。早期发展也是一个时期，在此期间，参与情绪处理的关键大脑区域，如海马体和前额叶皮层，正在成熟。这种成熟与依赖于大脑前额叶皮层网络的行为的出现相吻合，例如产生持久记忆或记忆持久性的能力。尽管有证据表明，在记忆持久性出现的同时，前额叶皮层和海马体的体积、结构和突触发生了变化，但迄今为止还没有研究探讨前额叶皮层-前额叶皮层回路的功能成熟如何有助于记忆持久性的个体发生。为了解决这一知识差距，我们将使用光遗传学工具来研究海马和前额叶皮层之间的突触连接如何在发育过程中发生变化。这些都是迫切的研究问题，因为目前还没有关于大脑回路的成熟如何影响成年后的学习和记忆的信息。 为了回答这些问题，我们将：（1）检查这个微回路中基础突触传递的成熟和解剖学连接，（2）揭示海马-前额叶皮层突触可塑性与记忆持续性个体发生之间的关系，（3）在体内操纵这些可塑性变化，以测试这是否会干扰这种行为的发生。为了充分描述大脑前额叶皮层功能成熟的发展，我们将使用组织学，电生理学和行为技术的组合。尽管光遗传学在脑微电路功能解剖中的应用非常迅速，但在发育背景下使用这种技术既强大又尚未探索。 这项研究将通过三种方式推进知识。首先，它将建立一个新的框架，从大脑回路的功能成熟的角度来研究复杂的行为，提供适用于任何数量的发育调节行为的关键见解。其次，它将有助于定义维持记忆持久性所必需的电路要求，这是认知功能的核心过程。第三，识别情绪学习回路成熟过程中可塑性增强的时期对干预具有重要意义。绘制限制学习和记忆回路可塑性的因素将指导回路特定干预措施的设计，以提高学习，改善成千上万的年轻加拿大人在这一代和后代的社会经济地位。