The Novel Role for JNK in Memory and Synaptic Plasticity

描述(申请人提供)：创伤后应激障碍(PTSD)和急性应激障碍是导致背景恐惧记忆受损的焦虑症。例如，患有创伤后应激障碍的人报告说，由于压力导致的背景恐惧保持能力不足，例如无法回忆创伤事件的重要方面。应激导致记忆缺陷的信号机制仍不清楚。这一建议的中心假设是，急性应激诱导海马c-Jun-N末端激酶(JNK)信号通路的快速和持续激活。海马区JNK通路的这种激活是介导应激诱导的上下文条件记忆缺陷的机制之一。我们还假设，情境恐惧条件作用单独激活了海马JNKs。JNK激活代表了一种新的机制，用于调节背景恐惧记忆痕迹的巩固。该应用程序的目的是了解背景恐惧记忆形成的应激调节的细胞和分子基础，以便开发有效的治疗方法。我们将研究在急性应激和基线条件下，海马区JNKs在调节背景恐惧形成中的作用。我们将采用分子、电生理和行为分析的组合，并将行为水平上的变化与突触水平上的变化联系起来。使用结构性和条件性JNK转基因小鼠的额外实验将描绘特定的JNK亚型在调节恐惧记忆中的作用。该提案通过研究海马区JNKs在学习和记忆过程中的可能作用，为我们对学习和记忆的理解向前迈出了创新的一步。首先，该提案提供了一个模型，说明暴露在急性应激下如何过度激活JNK信号并产生记忆缺陷。其次，该提案评估了基线条件下背景恐惧条件下海马区JNK信号的变化，并将提供对压力和学习如何激活涉及共同蛋白激酶的部分重叠信号通路的综合理解。最后，这些研究将为包括创伤后应激障碍在内的各种焦虑症中观察到的记忆障碍的分子和电生理机制提供洞察力。 公共卫生相关性：本研究项目的目标是调查cJun NH2末端激酶(JNK)亚型在背景恐惧形成中的作用。特别是，这表明海马区JNK2和JNK3亚型在应激诱导的情境恐惧缺失中起关键作用，而海马区JNK1在这一行为任务中主要调节基线学习。该项目将深入了解在各种焦虑症中观察到的记忆功能障碍的分子机制，包括创伤后应激障碍。

DESCRIPTION (provided by applicant): Post Traumatic Stress Disorder (PTSD) and Acute Stress Disorder are anxiety disorders that produce impairment of contextual fear memory. For example, individuals suffering from PTSD report stress-induced deficits in retention of contextual fear, such as the inability to recall important aspects of the traumatic event. The signaling mechanisms underlying stress-induced memory deficits are still unclear. The central hypothesis of this proposal is that acute stress induces rapid and sustained activation of hippocampal c-Jun-N-terminal kinase (JNK) signaling pathways. This activation of hippocampal JNK pathways is one mechanism mediating stress-induced deficits of contextual conditioned memory. We also hypothesize that contextual fear conditioning alone activates hippocampal JNKs. JNK activation represents a novel mechanism for regulating consolidation of the contextual fear memory trace. The objective of the application is to gain understanding of the cellular and molecular bases of stress regulation of contextual fear memory formation such that effective therapies can be developed. We will examine the role of hippocampal JNKs in regulating contextual fear formation under both acute stress and baseline conditions. We will employ a combination of molecular, electrophysiological, and behavioral assays, and correlate alterations seen at the behavioral levels with those at the synaptic level. Additional experiments using constitutive and conditional JNK transgenic mice will delineate the contribution of specific JNK isoforms in mediating fear memory. The proposal offers an innovative step forward in our understanding of learning and memory by investigating the possible roles of hippocampal JNKs in these processes. First, the proposal provides a model for how exposure to acute stress could over-activate JNK signaling and produce memory deficits. Second, the proposal evaluates changes in hippocampal JNK signaling during contextual fear conditioning under baseline conditions, and will provide an integrated understanding of how stress and learning may activate partially overlapping signaling pathways involving common protein kinases. Finally, these studies will provide insight into the molecular and electrophysiological mechanisms responsible for memory dysfunction observed in various anxiety disorders, including PTSD. PUBLIC HEALTH RELEVANCE: The goal of this research project is to investigate the role of the cJun NH2-terminal kinase (JNK) isoforms in contextual fear formation. In particular, it suggests that hippocampal JNK2 and JNK3 isoforms are critically involved in stress-induced deficit of contextual fear, while hippocampal JNK1 mainly regulates baseline learning in this behavioral task. The project will provide insight into the molecular mechanisms responsible for memory dysfunction observed in various anxiety disorders, including Post-traumatic Stress Disorder.