Activity-dependent Transcriptional Pathways Underlying Synaptic Mechanisms for Memory Discrimination and Generalization.

记忆辨别和泛化突触机制下的活动依赖性转录途径。

• 批准号: 10320483
• 负责人: PABLO E CASTILLO
• 金额: $ 58.14万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320483
• 关键词: Adaptive Behaviors; Behavior; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Cells; Data; Discrimination; Disease; Electrophysiology (science); Equilibrium; Future; Gene Expression; Genetic Transcription; Health; Individual; Interneurons; Lateral; Lead; Learning; Light; Medial; Mediating; Memory; Modification; Molecular; Morphology; NPAS4 gene; Neurons; Output; Panic Disorder; Pathway interactions; Population; Post-Traumatic Stress Disorders; Process; Reporter; Research; Role; Stimulus; Synapses; Synaptic plasticity; Time; base; dentate gyrus; entorhinal cortex; experience; fear memory; granule cell; innovation; memory encoding; neural circuit; neuropsychiatric disorder; novel; recruit; research study; transcriptome sequencing; treatment strategy

PROJECT SUMMARY The ability of the brain to utilize information from past experiences to guide future decisions, termed adaptive behavior, is critical for survival. To effectively adapt behaviors, the brain applies stored memory to new but similar situations (generalization), while also maintaining the capacity to distinguish unique stimuli (discrimination). When these critical processes (memory generalization or discrimination) go awry, it can lead to maladaptive disorders such as post-traumatic stress disorder (PTSD) and panic disorder. Despite their importance, mechanisms underlying memory discrimination and generalization remain largely unknown. This proposal will investigate the dynamic processes that underlie the utilization of an encoded memory to guide future behaviors, in particular the molecular, synaptic, and circuit mechanisms that govern the balance between discrimination and generalization. We have collected very exciting preliminary data showing that individual contextual fear memories are represented in the dentate gyrus (DG) by multiple functionally distinct neuronal ensembles defined by different activity-dependent transcriptional pathways, and that these ensembles bi-directionally regulate the discrimination-generalization balance. Based on these exciting findings, we hypothesize that the activity- dependent pathways target specific synaptic inputs on DG granule cells to differentially control memory discrimination and generalization. We aim to (1) uncover novel forms of learning-induced synaptic plasticity; (2) reveal underlying circuit mechanisms for memory discrimination and generalization; and (3) identify the molecular players important for this experience-dependent behavioral adaptation. The proposed research is both conceptually and technically innovative. It will experimentally demonstrate for the first time functionally distinct active neuronal ensembles coexisting within the memory engram, shed light on the synaptic and circuit mechanisms by which encoded memories directly drive experience-dependent behavioral outputs, and may lead to new treatment strategies for neuropsychiatric disorders, such as PTSD and panic disorder, which are caused by the imbalance between memory discrimination and generalization.

项目概要 大脑利用过去经验的信息来指导未来决策的能力，称为适应性 行为，对于生存至关重要。为了有效地适应行为，大脑将存储的记忆应用到新的但相似的记忆中 情况（泛化），同时还保持区分独特刺激的能力（歧视）。 当这些关键过程（记忆泛化或辨别）出现问题时，可能会导致适应不良 创伤后应激障碍（PTSD）和恐慌症等疾病。尽管它们很重要， 记忆辨别和泛化背后的机制在很大程度上仍然未知。该提案将 研究利用编码记忆来指导未来行为的动态过程， 特别是控制辨别力之间平衡的分子、突触和电路机制 和概括。我们收集了非常令人兴奋的初步数据，表明个人情境恐惧 记忆在齿状回（DG）中由定义的多个功能不同的神经元群表示 通过不同的活性依赖性转录途径，并且这些整体双向调节 歧视-泛化平衡。基于这些令人兴奋的发现，我们假设该活动- 依赖通路针对 DG 颗粒细胞上的特定突触输入来差异控制记忆 歧视和概括。我们的目标是（1）发现学习引起的突触可塑性的新形式； (2) 揭示记忆辨别和泛化的底层电路机制； (3) 确定 分子参与者对于这种依赖经验的行为适应很重要。拟议的研究既是 在概念和技术上都有创新。它将首次通过实验证明功能上的不同 记忆印迹内共存的活跃神经元群，揭示了突触和回路 编码记忆直接驱动依赖于经验的行为输出的机制，并可能导致 针对神经精神疾病的新治疗策略，例如创伤后应激障碍和恐慌症，这些疾病是由 记忆辨别和泛化之间的不平衡。