Activity Dependent Changes in the Contextual Memory Engram

上下文记忆印迹中的活动依赖性变化

• 批准号: 10315420
• 负责人: Czarina Ramos
• 金额: $ 4.6万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-07 至 2025-01-06
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10315420
• 关键词: Activity; Dependent; Changes; Contextual; Memory

Project Summary The goal of this project is to determine the activity-dependent mechanisms involved in contextual memory formation in the hippocampal circuit of the CA3. Encoding memory requires activity-dependent changes to neuronal properties and circuits, and improper function of these processes is thought to contribute to many cognitive disorders. Contextual memory, in particular, requires the storage of environmental information accompanying a salient stimulus to encode the context in which an experience occurred. The CA3 region of the hippocampus is known to play a critical role in contextual memory due to extensive connections between its pyramidal neurons, the principal excitatory neurons of the circuit. Changes in the CA3 circuit during learning and memory, however, remain poorly understood. An emerging strategy in identifying active neuronal ensembles during learning and memory is through detecting expression of immediate early genes. Known to rapidly turn on upon the detection of cellular activity, immediate early gene expression is heterogenous across neuronal populations. The transcription factor Npas4, an IEG expressed upon neuronal depolarization, has recently been shown to activate during contextual memory tasks. Moreover, conditional knockout of Npas4 in the CA3 region impairs contextual memory recall, suggesting that activity in the Npas4+ neuronal ensemble in this circuit is required for proper contextual memory function. Recent evidence strongly suggest that contextual fear conditioning induces changes at dentate granule cell to Npas4+ CA3 pyramidal neuron synapses. The full extent to how CA3 pyramidal neurons in the Npas4+ ensemble changes through activity, however, remains unknown. Previous evidence in areas such as CA1 and sensory cortices suggest that Npas4+ neurons exhibit changes in both excitatory and inhibitory drive through synapse formation and elimination. To study the changes in neuronal function and circuit activity in the CA3 in the Npas4+ ensemble, an Npas4-specific Robust Activity Marking system (NRAM) will be employed to identify neurons active during a contextual memory task. Neurons recruited to the Npas4 ensemble will be assessed through electrophysiology and structural studies to determine changes in synaptic transmission, morphology, and intrinsic properties that contribute to memory formation. Changes in connectivity and circuit function will also be surveyed to determine larger scale changes to the CA3 network in the encoding of contextual memory. Finally, the necessity and sufficiency of the Npas4 neuronal ensemble, as well as its relevance in other cognitive functions will be determined. The work proposed will elucidate mechanisms of learning in the CA3 circuit, and provide a foundation in uncovering the molecular basis of memory.

项目摘要 这个项目的目标是确定参与语境记忆的活动依赖机制 在CA3的海马回路中形成。对记忆进行编码需要依赖于活动的变化， 神经元的特性和电路，以及这些过程的不适当功能被认为有助于许多 认知障碍尤其是情境记忆，需要储存环境信息 伴随着一个显著的刺激来编码一个经历发生的背景。的CA3区域。 已知海马体在上下文记忆中起着关键作用，这是由于海马体之间的广泛连接。 锥体神经元，回路的主要兴奋性神经元。学习期间CA3回路的变化， 然而，人们对记忆的了解仍然很少。一种识别活跃神经元系综的新策略 在学习和记忆过程中的作用是通过检测即刻早期基因的表达。已知会迅速开启 一旦检测到细胞活性，即刻早期基因表达在神经元细胞中是异质的。 人口。转录因子Npas4是一种在神经元去极化时表达的IEG，最近已经被研究。 在情境记忆任务中被激活。此外，在CA3区域中Npas4的条件性敲除可以在CA3区域中的Npas4的条件性敲除区域。 损害上下文记忆回忆，这表明该回路中Npas4+神经元集合的活动是 这是正确的上下文记忆功能所必需的。最近的证据有力地表明， 条件反射诱导齿状回颗粒细胞与Npas4+ CA3锥体神经元突触的变化。的最大限度 然而，Npas4+集合体中的CA3锥体神经元如何通过活动而变化仍然未知。 先前在CA1和感觉皮层等区域的证据表明，Npas4+神经元在海马神经元中表现出变化。 通过突触形成和消除的兴奋性和抑制性驱动。为了研究神经元的变化， Npas4+集合中CA3的功能和回路活动，一种Npas4特异性稳健活动标记 系统（NRAM）将用于识别在上下文记忆任务期间活跃的神经元。招募的神经元 将通过电生理学和结构研究来评估Npas4系综的变化， 在突触传递、形态学和有助于记忆形成的内在属性中。变化 此外，还将对CA3网络的连通性和电路功能进行调查，以确定 上下文记忆的编码。最后，Npas4神经元系综的必要性和充分性， 以及其在其他认知功能中的相关性将被确定。建议的工作将阐明 CA3回路中的学习机制，并为揭示CA3回路的分子基础提供基础。 记忆