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

摘要 我们选择性地记住与显著结果相关的感觉线索的机制是什么？ 显著的感觉体验激活了包括感觉皮质在内的区域神经元的分布模式， 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发生了。 在感觉体验期间在线，以及在与线索和结果相关的联合重新激活期间离线 在随后的静默期中神经元的模式。线索结果的线上和线下两个方面 联想学习被认为涉及到投射到这些神经元的神经调节剂的共同激活 分布的脑区，可能通过作用于神经元内的细胞内信号来促进神经可塑性 树枝状结构。我们最近开发了可视化这些网络的方法，包括细胞和亚细胞 行为小鼠外侧视觉联想皮质(LVAC)跨天和跨周的加工 学习一项可操作的Go-NoGo视觉辨别任务。LVAC是连接海马体的关键枢纽， 感觉皮质和杏仁核。LVAC中线上或线下活动的沉默扰乱了长时记忆 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 在整个学习过程中都具有高度的可塑性，而且LVAC对于我们的任务执行是必要的。我们展示了 由给定视觉线索激活的相同截然不同的神经元模式随后被重新激活 安静清醒时约100-200毫秒，早期学习和显著食物的再激活率较高- 预测线索与中性线索的对比。食物线索但不是中性线索重新激活率预测第二天的改善 在表演上。因此，涉及编码食物线索和蛋白质的神经元集合的重新激活 REWARD预测参与神经元的次日功能连接增强，提供 联想学习的潜在皮质基质。这项提议试图定义神经调节， 上述发现背后的信号和网络机制，以及它们在学习中的因果作用。一个 大脑区域密集地支配左心室，并与突显、可塑性和记忆巩固有关 蓝斑(LC)。线上和线下LC活动指南都存储了显著的体验。 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，从而增强环磷酸腺苷 (CAMP)，促进突触可塑性的第二信使。因此，我们假设增加了 在显著感觉体验(目标1)中从LC到LVAC的神经调制输入驱动cAMP的增加 LVAC神经元中的信号转导(AIM 2)，并偏向于随后激活的神经元的离线重新激活 这些体验，以便修改第二天网络活动和行为性能(AIMS)的变化 1-2)。然后，我们研究了离线皮质重新激活的电生理相关性及其在脑缺血中的因果作用。 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 体内的信号将解决神经调节、离线重新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.