The Novel Role for JNK in Memory and Synaptic Plasticity

JNK 在记忆和突触可塑性中的新作用

• 批准号: 8264538
• 负责人: Cedomir Todorovic
• 金额: $ 17.27万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-16 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264538
• 关键词: AMPA Receptors; Acute; Anxiety Disorders; Behavioral; Behavioral Assay; Chemicals; Data; Emotional; Event; Exposure to; Fright; Functional disorder; Goals; Hippocampus (Brain); Impairment; Individual; Inflammatory; Ischemic Brain Injury; Knock-in Mouse; Learning; Long-Term Potentiation; MAPK10 gene; MAPK8 gene; MAPK9 gene; Mediating; Memory; Memory impairment; Mental disorders; Mitogen-Activated Protein Kinase 9; Modeling; Molecular; Mus; Mutation; N-terminal; Pathway interactions; Phosphotransferases; Post-Traumatic Stress Disorders; Process; Protein Isoforms; Protein Kinase; Publishing; Regulation; Reporting; Research Project Grants; Role; Signal Pathway; Signal Transduction; Stress; Synapses; Synaptic plasticity; Testing; Transgenic Mice; Work; activating transcription factor; acute stress; acute traumatic stress disorder; base; chemical genetics; conditioned fear; cytokine; design; effective therapy; innovation; insight; memory process; novel; psychologic; public health relevance; research study; response; stress-activated protein kinase 1; stressor

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.

描述（由申请人提供）：创伤后应激障碍（PTSD）和急性应激障碍是焦虑症，会导致背景恐惧记忆受损。例如，患有创伤后应激障碍的个体报告在保持背景恐惧方面的压力诱导的缺陷，例如无法回忆创伤事件的重要方面。应激诱导记忆障碍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，上下文恐惧条件单独激活海马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。 本申请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，从而可以开发有效的治疗方法。我们将研究海马JNK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、电生理和行为分析的组合，并将在行为水平上观察到的改变与在突触水平上观察到的改变相关联。使用组成型和条件性JNK转基因小鼠的额外实验将描绘特定JNK亚型在介导恐惧记忆中的贡献。 该提案通过研究海马JNKs在这些过程中的可能作用，为我们理解学习和记忆提供了创新的一步。首先，该提案为暴露于急性应激如何过度激活JNK信号传导并产生记忆缺陷提供了一个模型。其次，该提案评估了在基线条件下情境恐惧条件反射过程中海马JNK信号的变化，并将提供一个综合的理解，即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。最后，这些研究将提供深入了解的分子和电生理机制负责记忆功能障碍中观察到的各种焦虑症，包括创伤后应激障碍。 公共卫生关系：本研究项目的目标是调查cJun NH 2-末端激酶（JNK）亚型在情境恐惧形成中的作用。特别是，它表明，海马JNK 2和JNK 3亚型是关键参与应激诱导的背景恐惧的赤字，而海马JNK 1主要调节基线学习在这个行为任务。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。

项目成果

Small-conductance Ca2+-activated potassium type 2 channels regulate the formation of contextual fear memory.

小电导 Ca2 激活的钾 2 型通道调节情境恐惧记忆的形成。

• DOI: 10.1371/journal.pone.0127264
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Murthy,SaravanaRK;Sherrin,Tessi;Jansen,Chad;Nijholt,Ingrid;Robles,Michael;Dolga,AmaliaM;Andreotti,Nicolas;Sabatier,Jean-Marc;Knaus,Hans-Guenther;Penner,Reinhold;Todorovic,Cedomir;Blank,Thomas
• 通讯作者: Blank,Thomas