Region-specific in vivo regulation of synaptic plasticity cell signalling following learning and memory

我的研究计划的长期目标是阐明与学习和记忆有关的主要神经元回路和分子突触过程。这样的基础研究对于理解在大脑老化和其他情况下观察到的损害是基本的。然而，由于有关突触可塑性的信息不完整，因此很难完全确定所观察到的放松调控的意义。因此，我们的工作将极大地受益于本次拨款中提出的研究。事实上，了解哪些脑区、神经系统和实际神经元确实参与了这些高级中枢神经系统(CNS)功能，以及正常情况下不同学习方式和记忆机制的时间顺序是至关重要的。这项应用的短期目标涉及到一种强大的转基因大鼠模型的产生和开发，该模型应该能够以动态的方式监测活动物中特定神经元和大脑区域的激活，作为学习和记忆处理的结果。神经元的激活将基于cAMP反应元件(CRE)调节的蛋白质合成，这是巩固中枢记忆形成的主要分子途径。我们的目标是1)建立和表征可行的转基因(TG)模型，在大脑中Cre调节的基因表达激活时产生发光信号。2)确定Cre介导的生物发光和荧光信号在TG大鼠中是否可以通过先进的成像技术进行监测，以及它们是如何以及在哪里被调制的，从而使TG大鼠接受学习和记忆任务。3)应用该模型研究特定脑区，特别是内侧前额叶皮质在近期记忆巩固和回忆中的参与程度。这些研究将为学习和记忆过程的复杂时空演变提供有价值的新知识。它将构成一项相当大的技术成就，并将提供实用工具来研究CRE信号通路参与大脑对其他刺激的反应，从而确保加拿大在神经科学领域的领先地位。

The long-term objectives of my research program are to elucidate the main neuronal circuits and molecular synaptic processes involved in learning and memory. Such basic research is fundamental for understanding impairments observed in brain aging and other conditions. However, it is difficult to fully establish the significance of the observed deregulations as the information on synaptic plasticity is fragmentary. Thus, our work will greatly benefit from the research proposed in the present grant. Indeed, it is essential to know which brain areas, neural systems and actual neurons do participate in these higher central nervous system (CNS) functions and in which temporal order for diverse modalities of learning and of memory mechanisms in normal conditions. The short-term goal of this application relates to the generation and exploitation of a robust transgenic rat model, which should allow the monitoring of the activation of defined neurons and brain areas in live animals, in a dynamic fashion, as a consequence of learning and memory processing. The activation of the neurons will be followed based on cAMP response element (CRE)-regulated protein synthesis, the predominant molecular pathway consolidating memory formation in the CNS. Our objectives are to 1) Generate and characterize viable transgenic (TG) models generating luminescent signals upon activation of the CRE-regulated gene expression in the brain. 2) Establish whether CRE-mediated bioluminescent and fluorescent signals in the TG rats can be monitored by advanced imaging techniques and how and where are they modulated exposing TG rats to learning and memory tasks. 3) Apply the model to investigate the extent of the participation of specific brain regions, in particular the medial prefrontal cortex, in recent memory consolidation and recall. These investigations will provide valuable novel knowledge on the complex spatial and temporal evolution of the learning and memory processes. It will constitute a considerable technological achievement and it will provide practical tools to investigate the involvement of CRE-signalling pathway in brain responses to other stimuli, thus securing Canada's position as a leader in the Neuroscience field.