Cortico-limbic circuits for learning and memory

这个nserc资助的研究项目的主要目标是扩展我们对神经机制的理解，通过神经机制，新学习的行为被实例化为长期记忆。使用一种小的“干扰肽”（专利申请中），我们能够阻断AMPA类嗜离子谷氨酸受体的内化，从而阻断一种称为长期电位（LTD）的突触可塑性形式所需的最后一步。我们将这种分子工具与复杂和行为测试结合使用，以评估突触可塑性在学习和记忆的特定方面的作用，其中一些我们在最近的研究中进行了改进。该研究计划将建立在最近成功的将LTD与负责反应灵活性和先前获得的记忆消失的过程联系起来的基础上。在最初的实验中，通过静脉注射药物，并在特定的行为测试中实现选择性记忆中断，随后的实验将试图定位神经结构，在该神经结构中，LTD的中断再现了全身给药所观察到的效果。随着这些操纵大脑中LTD的新工具的出现，我们现在可以通过诱导LTD直接检查LTP“去增强”对我们的脑刺激信号检测过程的功能影响。我们的工作假设认为，LTP后增强的信号检测将被“有限”刺激方案逆转，并且这种效果可以通过我们的“干扰肽”管理来阻断。该研究具有重要的理论意义，为研究大脑突触可塑性和信息加工提供了新的思路。

The main objective of this NSERC-funded research project is to extend our understanding of the neural mechanisms by which newly learned behaviours are instantiated into long-term memories. Using a small 'interference peptide' (patent-pending), we are able to block the internalization of the AMPA class of ionotropic glutamate receptors and thereby block the final step required for a form of synaptic plasticity called Long-term Potentation (LTD.) We use this molecular tool in conjunction with sophisticated and behavioural tests to assess the role of synaptic plasticity in specific aspects of learning and memory, several of which we have refined in our recent studies. This research program will build on recent success in linking LTD to processes responsible for response flexibility and extinction of previously acquired memory. Following initial experiments in which the drugs are injected via the intravenous route, and selective memory disruption achieved in a specific behavioural test, subsequent experiments will attempt to localize the neural structure(s) in which a disruption of LTD reproduces the effects observed with systemic drug administration. With the advent of these new tools for manipulating LTD in the brain, we can now examine directly the functional effects of 'depotentiation" of LTP, by induction of LTD, on our brain-stimulation signal detection procedure. Our working hypothesis maintains that enhanced signal detection following LTP will be reversed by an 'LTD' stimulation protocol and that this effect can be blocked by administration of our 'interference peptide'. This project has important theoretical implication and should provide new insights into synaptic plasticity and information processing in brain.