The Novel Role for JNK in Memory and Synaptic Plasticity

描述（由申请人提供）：创伤后应激障碍（PTSD）和急性应激障碍是导致情境恐惧记忆受损的焦虑障碍。例如，患有创伤后应激障碍的人报告说，压力引起的对情境恐惧的保留缺陷，比如无法回忆起创伤事件的重要方面。应激诱发记忆缺陷的信号机制尚不清楚。该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JNK通路的激活是介导应激诱导的情境条件记忆缺陷的一种机制。我们还假设情境恐惧条件反射单独激活了海马体的JNKs。JNK激活代表了一种调节情境恐惧记忆痕迹巩固的新机制。该应用程序的目的是了解情境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。我们将研究海马JNKs在急性应激和基线条件下调节情境恐惧形成中的作用。我们将采用分子、电生理和行为分析相结合的方法，并将行为水平上的变化与突触水平上的变化联系起来。另外的实验使用组成和条件JNK转基因小鼠将描述特定JNK亚型在介导恐惧记忆中的作用。通过研究海马JNKs在学习和记忆过程中的可能作用，这一建议为我们对学习和记忆的理解提供了创新的一步。首先，该研究为暴露于急性应激下如何过度激活JNK信号并产生记忆缺陷提供了一个模型。其次，该研究评估了基线条件下情境恐惧条件下海马JNK信号的变化，并将提供对压力和学习如何激活涉及常见蛋白激酶的部分重叠信号通路的综合理解。最后，这些研究将提供对包括创伤后应激障碍在内的各种焦虑症中观察到的记忆功能障碍的分子和电生理机制的见解。

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.