Prefrontal interactions with hippocampus and amygdala during trace fear

描述（申请人提供）：前额叶皮层（PFC）在多个认知过程中起着关键作用。PFC功能障碍与多种疾病有关，包括阿尔茨海默病、创伤后应激障碍、精神分裂症和注意缺陷多动障碍。最近的研究已经开始关注PFC如何在功能明确的大脑结构网络中运作。特别是，PFC和内侧颞叶区域，如海马体，可能在记忆形成和恢复过程中协同工作。本项目将使用实验室大鼠的痕量恐惧条件反射（TFC）作为模型，以了解PFC和海马对新长期记忆形成的相对贡献。TFC与标准恐惧条件反射的不同之处在于，在听觉信号和脚震等厌恶结果之间插入了一个小的时间间隔，或称“追踪间隔”。大量研究表明，在微量条件作用下的正常学习需要PFC和海马体，但这两个结构的具体作用以及它们相互作用的原理目前尚不清楚。我们将量化细胞内信号通路的活动，这些通路在TFC训练中对PFC、海马体和杏仁核内的神经可塑性和学习起重要作用，并确定该网络中一个结构的神经活动如何影响与其相连的神经反应。我们还将确定巩固新的TFC记忆所需的每个大脑区域内从头合成蛋白质的程度。这项工作代表了该网络中记忆形成所需的分子事件的第一个系统研究，也是解决PFC和海马之间功能相互作用的极少数研究之一。

DESCRIPTION (provided by applicant): The prefrontal cortex (PFC) plays a critical role in multiple cognitive processes. Dysfunction in the PFC has been implicated in a wide range of disorders including Alzheimer's disease, post-traumatic stress disorder, schizophrenia, and attention deficit hyperactivity disorder. Recent research has begun to focus on understanding how the PFC operates within functionally defined networks of brain structures. In particular, the PFC and medial temporal lobe areas such as the hippocampus may work together during the formation and retrieval of memory. This project will use trace fear conditioning (TFC) in laboratory rats as a model to understand the relative contributions of the PFC and hippocampus to the formation of new long-term memories. TFC differs from standard fear conditioning in that a small temporal gap, or "trace interval", is inserted between an auditory signal and an aversive outcome such as foot shock. Numerous studies have shown that normal learning in trace conditioning requires both the PFC and hippocampus, but the specific contributions of each structure as well as the principles by which they interact are currently not known. We will quantify the activity of intracellular signaling pathways known to be important for neural plasticity and learning within the PFC, hippocampus and amygdala in response to TFC training and determine how neural activity in one structure within this network affects responses in those connected to it. We will also determine the degree to which de novo protein synthesis within each brain area is required for the consolidation of a new TFC memory. This work represents the first systematic investigation of the molecular events required for memory formation in this network and one of very few studies to address the functional interactions between the PFC and hippocampus. PUBLIC HEALTH RELEVANCE: The prefrontal cortex (PFC) plays a critical role in multiple cognitive processes, and dysfunction in the PFC has been implicated in a wide range of disorders including Alzheimer's disease, post-traumatic stress disorder, schizophrenia, and attention deficit hyperactivity disorder. This study will provide important new data about how the PFC interacts with medial temporal lobe structures and about how molecular events in PFC neurons contribute to normal cognition.