Systems and molecular mechanisms of retrieval-dependent memory destabilization

检索依赖性记忆不稳定的系统和分子机制

• 批准号: 9229599
• 负责人: FRED J HELMSTETTER
• 金额: $ 36.94万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229599
• 关键词: 26S proteasome; Address; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Area; Attention; Auditory; Basal Ganglia; Behavior; Biochemical; Biological Models; Brain; Brain region; Cell Nucleus; Cells; Clinical; Complex; Cues; Data; Disease; Emotional; Exposure to; Female; Fright; Gene Expression; Goals; Immediate-Early Genes; Intervention; Knowledge; Laboratory Animals; Lateral; Learning; Link; Measures; Medial; Memory; Mental Health; Modeling; Modification; Molecular; Neurons; Organism; Outcome; Phosphorylation; Post-Translational Protein Processing; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Rattus; Reaction; Retrieval; Role; Shock; Signal Transduction; Stimulus; Synapses; System; Testing; Thalamic structure; Time; Training; Ubiquitin; Up-Regulation; Update; Work; behavioral response; calmodulin-dependent protein kinase II; classical conditioning; conditioned fear; experience; fear memory; flexibility; long term memory; memory process; memory recall; memory retrieval; men' s group; midbrain central gray substance; multicatalytic endopeptidase complex; neuroregulation; optogenetics; prevent; relating to nervous system; response; sound; targeted treatment

Fear conditioning is an excellent model system for understanding how the brain responds to threat. When organisms learn that an auditory cue predicts danger, the formation of this emotional memory requires plastic changes at synapses in the amygdala. Importantly, the subsequent retrieval and use of this memory involves activity-dependent synaptic destabilization. The functional significance of memory destabilization at retrieval is yet to be fully understood, but this process is likely to be important for memory updating and flexibility under normal conditions. Understanding and control of memory destabilization may open new avenues for clinical interventions in anxiety disorders. Our recent work has focused on the critical role of the ubiquitin-proteasome system (UPS) in controlling synaptic stability when existing memories are recalled. While destabilization is well documented at amygdala synapses, very few data exist related to the factors that control this process. In this project we use optogenetic silencing and stimulation to control neural activity during memory retrieval in behaving animals while quantifying biochemical signals related to destabilization in the amygdala. These signals include proteasome activity and activity-driven phosphorylation of Rpt6 regulatory subunits. Aim 1 is focused on altering activity within specific amygdala nuclei or connections. Studies in Aim 2 assess the role of prelimbic medial prefrontal cortex (PL) activity in triggering memory destabilization and address functional interactions between PL and the amygdala. In Aim 3 we address the role of the ventral periaqueductal gray and some of its reciprocal connections with the amygdala. The knowledge gained here may ultimately be applied to the targeted destabilization and erasure of traumatic memories.

恐惧条件反射是一个很好的模型系统，可以用来理解大脑如何对 威胁当有机体知道听觉线索预示着危险时， 情绪记忆需要杏仁核突触的可塑性变化。重要的是 这种记忆随后检索和使用涉及依赖于活动的突触 不稳定记忆不稳定在提取时的功能意义尚未完全阐明。 理解，但这个过程可能对内存更新和灵活性很重要， 正常情况下。了解和控制记忆不稳定可能会打开新的 焦虑症的临床干预途径。我们最近的工作集中在 泛素-蛋白酶体系统（UPS）在控制突触稳定性中的关键作用， 现有的记忆被唤醒。虽然杏仁核突触的不稳定性得到了很好的证明， 关于控制这一过程的因素的数据很少。在这个项目中，我们使用 光遗传学沉默和刺激以控制在记忆恢复期间的神经活动 行为动物，同时量化与不稳定相关的生化信号， 杏仁核这些信号包括蛋白酶体活性和活性驱动的磷酸化， Rpt 6调节亚单位。Aim 1的重点是改变特定杏仁核内的活动， 连接.目的2中的研究评估了前边缘内侧前额叶皮层（PL）活动的作用 在触发记忆不稳定和地址之间的功能相互作用PL和 杏仁核在目标3中，我们讨论了腹侧导水管周围灰质及其一些作用 与杏仁核的相互联系在这里获得的知识最终可能是 应用于有针对性的破坏和消除创伤记忆。