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

项目总结 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，是生存的关键。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 在保持辨别独特刺激的能力(歧视)的同时，也保持对特定情况的识别(泛化)。 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 创伤后应激障碍(PTSD)和恐慌症等精神障碍。尽管它们很重要， 记忆歧视和泛化的潜在机制在很大程度上仍不清楚。这项提议将 研究利用编码内存来指导未来行为的动态过程， 尤其是支配辨别之间平衡的分子、突触和回路机制 和泛化。我们收集了非常令人兴奋的初步数据，表明个人背景恐惧 记忆在齿状回(DG)中由多个功能不同的神经元集合来表示 通过不同的活性依赖的转录途径，这些集成双向调节 歧视-泛化的平衡。基于这些令人兴奋的发现，我们假设这一活动- 依赖通路靶向DG颗粒细胞上的特定突触输入以差异控制记忆 歧视和泛化。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；以及(3)识别 分子玩家对这种依赖经验的行为适应很重要。拟议的研究既是 概念和技术上的创新。它将首次在实验中展示其独特的功能 活跃的神经元群共存于记忆印记中，揭示了突触和回路 编码记忆直接驱动经验依赖的行为输出的机制，并可能导致 到神经精神障碍的新治疗策略，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。

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.