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 我们有选择地记住与显着结果相关的感觉线索的机制是什么？ 显着的感觉体验在包括感觉皮质的区域中激活神经元的分布模式， 杏仁核和海马。据信，提示和结果的神经表现形式的联系 在感官体验和离线期间，在与提示和结果有关 随后的安静期间神经元的模式。提示结果的在线和离线方面 已经提出了关联学习，以涉及对这些投射的神经调节剂的共同激活 分布式大脑区域，这可能通过神经元中细胞内信号的作用促进神经可塑性 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结合皮层（LVAC）的几天和几周的过程 学习操作员GO-Nogo视觉歧视任务。 LVAC是连接海马的关键枢纽， 感觉皮质和杏仁核。在LVAC中沉默在线或离线活动的长期记忆 提示结果关联的合并和回忆。我们以前发现LVAC神经元提示反应 在学习过程中是高度塑料的，而LVAC对于执行我们的任务是必要的。我们证明了 随后将被给定的视觉提示激活的神经元的不同模式重新激活 〜100-200毫秒在安静醒来，早期学习期间的重新激活率较高，并且用于显着食物 - 预测与中性线索。食品证明的发生率，但不是中性提示重新激活的次数改善 在性能中。因此，涉及编码食物提示的神经元的集合的重新激活和 奖励预测参与神经元的第二天功能连通性的增强，提供了 潜在的皮质底物用于关联学习。该建议旨在定义神经调节性， 信号传导和上述发现的基础网络机制及其在学习中的因果作用。一个 密集支配LVAC并与显着性，可塑性和记忆巩固有关的大脑区域是 基因座（LC）。在线和离线LC活动指南都存储了哪些显着体验。 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，从而增强环状AMP （CAMP），促进突触可塑性的第二个使者。因此，我们假设增加了 在显着感官体验期间，从LC到LVAC的神经调节输入（AIM 1）驱动营地增加 LVAC神经元中的信号传导（AIM 2），并随后在激活的神经元的离线重新激活 这些经验，以修改第二天的网络活动和行为绩效的变化（目标 1-2）。然后，我们检查离线皮质重新激活的电生理相关性及其在因果关系中的作用 促进网络变化和学习（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，离线重新激活与关联可塑性之间的联系。