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.

项目摘要 大脑利用过去经验中的信息来指导未来决策的能力，称为适应性 行为对生存至关重要。为了有效地适应行为，大脑将存储的记忆应用于新的但相似的行为。 在这种情况下（泛化），同时也保持区分独特刺激的能力（歧视）。 当这些关键过程（记忆概括或辨别）出错时，可能会导致适应不良 例如创伤后应激障碍（PTSD）和惊恐障碍。尽管它们很重要， 记忆辨别和泛化的潜在机制在很大程度上仍然未知。这项建议会 研究利用编码记忆指导未来行为的动态过程， 特别是控制辨别力和认知力之间平衡的分子、突触和电路机制。 和概括。我们已经收集了非常令人兴奋的初步数据，表明个人的背景恐惧， 记忆在齿状回（DG）中由多个功能不同的神经元集合来代表，这些神经元集合被定义为 通过不同的活性依赖性转录途径，这些集合双向调节 区分-泛化平衡基于这些令人兴奋的发现，我们假设- 依赖性通路靶向DG颗粒细胞上的特定突触输入以差异地控制记忆 区分和概括。我们的目标是（1）发现学习诱导的突触可塑性的新形式;（2） 揭示记忆辨别和概括的潜在电路机制;（3）识别 对这种依赖经验的行为适应很重要的分子。这项研究的目的是， 概念和技术创新。它将首次通过实验证明 同时存在于记忆印迹中的活跃的神经元集合，揭示了突触和回路 编码记忆直接驱动依赖经验的行为输出的机制，并可能导致 神经精神疾病的新治疗策略，如创伤后应激障碍和恐慌症， 记忆辨别和概括之间的不平衡。