Maturation of Circuits Underlying Learning and Memory

我们的知觉、认知和情感能力在发育过程中的特定时间出现，并受到早期生活中发生的经验的关键塑造。早期发育也是大脑中参与情绪处理的关键区域，如海马体和前额叶皮质成熟的时期。这种成熟与依赖于海马体-前额叶皮质网络的行为的出现不谋而合，例如产生持久记忆的能力，或记忆持久性。尽管有一致的证据表明，在记忆持续出现的同时，前额叶皮质和海马区也发生了体积、结构和突触的变化，但到目前为止，还没有研究关注海马-前额叶皮质回路的功能成熟如何有助于记忆持续的个体发生。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体和前额叶皮质之间的突触连接如何在发育过程中发生变化。这些都是迫在眉睫的研究问题，因为目前还没有关于作为学习和记忆基础的大脑回路的成熟如何影响成年后的认知功能的信息。*为了回答这些问题，我们将：(1)检查该微电路内基础突触传递和解剖连接的成熟度，(2)揭示海马-前额叶皮质突触可塑性与记忆持久性个体发育之间的关系，以及(3)在体内操纵这些可塑性变化，以测试这是否干扰这种行为的开始。为了全面描述海马体-前额叶皮质在发育过程中的功能成熟，我们将综合使用组织学、电生理学和行为学技术。尽管光遗传学被紧急用于大脑微电路的功能解剖，但在发展的背景下，这种技术的使用既强大又尚未探索。*这项研究将从三个方面推进知识。首先，它将建立一个从大脑回路功能成熟的角度研究复杂行为的新框架，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需的电路要求，这是认知功能的核心过程。第三，确定情绪学习基础回路成熟期的高度可塑性对干预具有重要意义。绘制出降低学习和记忆电路可塑性的因素图，将指导专门针对电路的干预措施的设计，以增强学习，改善这一代和未来几代加拿大年轻人的社会经济地位。

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.