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

总结 我们选择性地记住与显著结果相关的感官线索的机制是什么？ 显著的感觉体验激活了包括感觉皮层在内的区域的神经元分布模式， 杏仁核和海马体线索和结果的神经表征之间的联系被认为是 无论是在线，在感官体验，和离线，在联合重新激活的线索和结果相关的 神经元在随后的安静期的模式。线索-结果的线上和线下方面 联想学习被认为涉及神经调质的共同激活， 分布的大脑区域，这可能通过对神经元细胞内信号传导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的方法，细胞和亚细胞 行为小鼠的外侧视觉联合皮层（LVAC）中的跨天和周的过程 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扰乱了长期记忆 线索-结果关联的巩固和回忆。我们以前发现LVAC神经元的提示反应 在学习过程中具有高度的可塑性，LVAC对我们完成任务是必要的。我们发现， 被给定的视觉线索激活的神经元的相同的独特模式随后被重新激活， 安静清醒时约为100-200 ms，早期学习和显著食物的再激活率较高- 预测vs.中性线索。食物线索而非中性线索的再激活率预测了第二天的改善 在性能上。因此，涉及编码食物提示和 奖励预测参与神经元的第二天功能连接的加强，提供了一个 潜在的皮层基质进行联想学习。这个提议试图定义神经调节， 信号和网络机制，以及它们在学习中的因果作用。一 密集支配LVAC并与显著性、可塑性和记忆巩固有关的脑区， 蓝斑（LC）。在线和离线LC活动都指导存储哪些突出的经验。 LC神经元释放的去甲肾上腺素可作用于β-肾上腺素能受体，从而促进环AMP （cAMP），促进突触可塑性的第二信使。因此，我们假设， 在显著感觉体验期间从LC到LVAC的神经调节输入（Aim 1）驱动cAMP增加 LVAC神经元中的信号传导（Aim 2），并使随后的离线激活的神经元在 这些经验，以修改网络活动和行为性能的第二天变化（目的 1-2）。然后，我们研究了离线皮层再激活的电生理学相关性及其因果关系， 促进网络变化和学习（目标3）。这些对神经活动的细胞/亚细胞研究 而体内的信号传导将解决神经调节、离线再激活和关联可塑性之间的联系。

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.