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参与学习和记忆的主要神经元回路和分子突触过程。这些基础研究对于理解大脑老化和其他情况下观察到的损伤至关重要。然而，由于突触可塑性的信息是零碎的，因此很难完全确定所观察到的失调的意义。因此，我们的工作将大大受益于本补助金中提出的研究。事实上，必须知道哪些脑区、神经系统和实际神经元参与这些高级中枢神经系统（CNS）功能，以及在正常条件下不同的学习和记忆机制模式的时间顺序。本申请的短期目标涉及稳健的转基因大鼠模型的产生和开发，其应当允许以动态方式监测活体动物中作为学习和记忆处理的结果的限定神经元和脑区域的激活。神经元的激活将基于cAMP反应元件（CRE）调节的蛋白质合成来进行，这是巩固CNS中记忆形成的主要分子途径。我们的目标是1）产生和表征在脑中激活CRE调节的基因表达时产生发光信号的可行转基因（TG）模型。2)确定是否可以通过先进的成像技术监测TG大鼠中的CRE介导的生物发光和荧光信号，以及它们如何以及在何处被调制，将TG大鼠暴露于学习和记忆任务。3)应用该模型来研究特定大脑区域，特别是内侧前额叶皮层，在最近的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空间和时间演变提供有价值的新知识。这将是一项相当大的技术成就，它将提供实用的工具，以调查CRE-signaling途径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导地位。

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.