Acute stress effects on cognition and synaptic plasticity

我的发现资助计划旨在阐明体验对神经生理学和认知功能(如记忆)的影响的潜在机制。神经生理过程和记忆受到各种经历的强烈影响，例如急性应激。然而，经验对特定神经生理过程的影响，如突触可塑性的模式，与记忆之间缺乏明确的联系。本提案中的具体实验旨在确定一种特殊的经历--急性应激--对啮齿动物记忆恢复的影响。我们最近开发了敏感的行为测试，可以用来可靠地评估啮齿动物的两种类型的记忆--识别记忆和时序记忆。当这些测试在不同的刺激(空间信息或物体)下进行时，正常的记忆表现取决于人们很好地理解的、涉及许多大脑区域的可分离的回路，包括海马体、周围皮质和内侧前额叶皮质。在最初的一系列实验中，我们将检验这些测试中急性应激对记忆恢复的影响。我们认为，急性应激将扰乱这些测试中的正常记忆提取，从而提供关于急性应激影响的特定类型记忆和神经底物的新信息。在单独的电生理实验中，将表征急性应激对对这些测试的执行至关重要的神经回路中突触可塑性的影响。根据之前的实验结果，预计急性应激能够在海马体、周围皮质和内侧前额叶皮质诱导一种称为长期抑制的突触可塑性细胞模型。最后，在其他制剂中，一些已知可抑制长期抑郁的高度特异性抑制剂的效果将被用来阻断急性应激的电生理和行为影响。整合急性应激对学习和记忆的基本行为和电生理影响，将有助于发展关于在正常和具有挑战性的环境中调节认知的神经机制的理论。

My Discovery Grant Program is designed to elucidate the mechanisms underlying the effects of experience on neurophysiology and cognitive functions such as memory. Neurophysiological processes and memory are strongly influenced by a variety of experiences, such as acute stress. However, definitive links between the effects of experience on particular neurophysiological processes, such as patterns of synaptic plasticity, and memory are lacking. The specific experiments in the present proposal are designed to determine the effects of one particular experience, that of acute stress, on memory retrieval in rodents. We have recently developed sensitive behavioral tests that may be used to reliably assess two types of memory, recognition and temporal order memory, in rodents. When these tests are conducted with different stimuli (spatial information or objects), normal memory performance depends on well understood, dissociable circuits involving a number of brain areas including the hippocampus, perirhinal cortex, and medial prefrontal cortex. In an initial series of experiments, the effects of acute stress on memory retrieval in these tests will be examined. We believe that acute stress will disrupt normal memory retrieval on these tests thereby providing novel information regarding the specific types of memory and neural substrates influenced by acute stress. In separate electrophysiological experiments, the effects of acute stress on synaptic plasticity in the neural circuits important for performance of these tests will be characterized. Given the results of previous experiments, acute stress is predicted to enable the induction of a cellular model of synaptic plasticity known as long-term depression in the hippocampus, perirhinal cortex, and medial prefrontal cortex. Finally, the effects of a number of highly specific inhibitors known to inhibit long-term depression in other preparations will be used to block the electrophysiological and behavioral effects of acute stress. An integration of the fundamental behavioral and electrophysiological effects of acute stress on learning and memory will allow theories regarding the neural mechanisms mediating cognition in both normal and challenging circumstances to be developed.