Roles of cortical neuromodulation and offline reactivation in memory consolidation of emotionally salient visual experiences

皮质神经调节和离线再激活在情感显着视觉体验的记忆巩固中的作用

• 批准号: 10392445
• 负责人: Mark L Andermann
• 金额: $ 35万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392445
• 关键词: Address; Affect; Amygdaloid structure; Area; Association Learning; Axon; Behavior; Behavioral; Biochemical; Brain region; Calcium; Cell physiology; Cells; Chronic; Coupled; Cues; Cyclic AMP; Darkness; Data; Dendrites; Dendritic Spines; Discrimination; Electrophysiology (science); Emotional; Event; Food; GTP-Binding Proteins; Hippocampus (Brain); Image; Investigation; Joints; Lateral; Learning; Link; Medial; Methods; Molecular; Mus; Neuromodulator; Neuronal Plasticity; Neurons; Norepinephrine; Outcome; Pattern; Performance; Population; Rewards; Role; Second Messenger Systems; Sensory; Signal Transduction; Synapses; Synaptic plasticity; Task Performances; Testing; Training; Vertebral column; Visual; association cortex; beta-adrenergic receptor; classical conditioning; cue reactivity; experience; in vivo; learning strategy; locus ceruleus structure; long term memory; memory consolidation; memory recall; nerve supply; neuroregulation; noradrenergic; optogenetics; real time monitoring; relating to nervous system; response; sensory cortex; tool; two-photon

Summary What are the mechanisms by which we selectively remember sensory cues associated with salient outcomes? Salient sensory experiences activate distributed patterns of neurons in regions including sensory cortex, amygdala, and hippocampus. The linking of neural representations of cues and outcomes is believed to occur both online, during the sensory experiences, and offline, during joint reactivation of cue- and outcome-related patterns of neurons during subsequent quiet periods. Both the online and offline aspects of cue-outcome association learning have been posited to involve co-activation of neuromodulators that project to these distributed brain regions, which may facilitate neural plasticity via actions on intracellular signaling in neuronal dendrites. We have recently developed methods to visualize these network, cellular and subcellular processes across days and weeks in lateral visual association cortex (LVAC) of behaving mice learning an operant Go-NoGo visual discrimination task. LVAC is a key hub that links the hippocampus, sensory cortex, and amygdala. Silencing of either online or offline activity in LVAC perturbs long-term memory consolidation and recall of cue-outcome associations. We previously found that LVAC neuron cue responses are highly plastic across learning and that LVAC is necessary for performance of our task. We showed that the same distinct pattern of neurons that was activated by a given visual cue was subsequently reactivated for ~100-200 ms during quiet waking, with higher reactivation rates during early learning and for salient food- predicting vs. neutral cues. Rates of food-cue but not neutral cue reactivation predicted next-day improvements in performance. Accordingly, reactivations involving ensembles of neurons encoding both the food cue and reward predicted strengthening of next-day functional connectivity of participating neurons, providing a potential cortical substrate for associative learning. This proposal seeks to define the neuromodulatory, signaling, and network mechanisms underlying the above findings, and their causal role in learning. A brain region that densely innervated LVAC and implicated in salience, plasticity, and memory consolidation is the locus coeruleus (LC). Both online and offline LC activity guides which salient experiences are stored. Noradrenaline released by LC neurons can act on beta-adrenergic receptors, thereby boosting cyclic AMP (cAMP), a second messenger that facilitates synaptic plasticity. Thus, we hypothesize that increased neuromodulatory input from LC to LVAC during salient sensory experiences (Aim 1) drives increases in cAMP signaling in LVAC neurons (Aim 2), and biases subsequent offline reactivation of neurons activated during these experiences, in order to modify next-day changes in network activity and behavioral performance (Aims 1-2). We then examine electrophysiological correlates of offline cortical reactivations and their causal role in facilitating network changes and learning (Aim 3). These cellular/subcellular investigations of neural activity and signaling in vivo will address links between neuromodulation, offline reactivation and associative plasticity.

概括 我们选择性地记住与显着结果相关的感官线索的机制是什么？ 显着的感觉体验激活了感觉皮层等区域神经元的分布模式， 杏仁核和海马体。人们相信线索和结果的神经表征之间会发生联系 在线（在感官体验期间）和离线（在与线索和结果相关的联合重新激活期间） 随后的安静时期的神经元模式。线索结果的线上和线下两个方面 联想学习被认为涉及神经调节剂的共同激活，这些神经调节剂投射到这些 分布的大脑区域，可能通过对神经元细胞内信号传导的作用来促进神经可塑性 树突。我们最近开发了可视化这些网络、细胞和亚细胞的方法 行为小鼠的横向视觉关联皮层 (LVAC) 中数天和数周的过程 学习操作性 Go-NoGo 视觉辨别任务。 LVAC 是连接海马体的关键枢纽， 感觉皮层和杏仁核。 LVAC 中在线或离线活动的沉默会扰乱长期记忆 线索-结果关联的巩固和回忆。我们之前发现 LVAC 神经元提示反应 在学习过程中具有高度可塑性，并且 LVAC 对于执行我们的任务是必要的。我们证明了 由给定的视觉提示激活的相同的不同神经元模式随后被重新激活 安静醒来时约 100-200 毫秒，早期学习和重要食物时的重新激活率较高 - 预测线索与中性线索。食物提示而非中性提示重新激活的比率预测第二天的改善 在性能上。因此，重新激活涉及编码食物线索和 奖励预测参与神经元第二天功能连接的加强，提供 联想学习的潜在皮质基质。该提案旨在定义神经调节， 上述发现背后的信号传导和网络机制，以及它们在学习中的因果作用。一个 LVAC 密集神经支配并与显着性、可塑性和记忆巩固有关的大脑区域是 蓝斑（LC）。线上和线下的LC活动指南都存储了重要的经验。 LC神经元释放的去甲肾上腺素可以作用于β-肾上腺素能受体，从而增强环AMP (cAMP)，促进突触可塑性的第二信使。因此，我们假设增加了 在显着感觉体验（目标 1）期间从 LC 到 LVAC 的神经调节输入驱动 cAMP 增加 LVAC 神经元中的信号传导（目标 2），并偏置随后激活的神经元的离线重新激活 这些经验，以便修改第二天网络活动和行为表现的变化（目标 1-2）。然后，我们检查离线皮质再激活的电生理相关性及其因果作用 促进网络变革和学习（目标 3）。这些神经活动的细胞/亚细胞研究 体内信号传导将解决神经调节、离线再激活和联想可塑性之间的联系。