Prevailing theories posit that the hippocampus rapidly learns stimulus conjunctions during novel experiences, whereas the neocortex learns slowly through subsequent, off-line interaction with the hippocampus. Parallel evidence, however, shows that the medial prefrontal cortex (mPFC; a critical node of the neocortical network supporting long-term memory storage) undergoes rapid modifications of gene expression, synaptic structure, and physiology at the time of encoding. These observations, along with impaired learning with disrupted mPFC, suggest that mPFC neurons may exhibit rapid neural plasticity during novel experiences; however, direct empirical evidence is lacking. We extracellularly recorded action potentials of cells in the prelimbic region of the mPFC, while male rats received a sequence of stimulus presentations for the first time in life. Moment-to-moment tracking of neural ensemble firing patterns revealed that the prelimbic network activity exhibited an abrupt transition within 1 min after the first encounter of an aversive but not neutral stimulus. This network-level change was driven by ~15% of neurons that immediately elevated their spontaneous firing rates (FRs) and developed firing responses to a neutral stimulus preceding the aversive stimulus within a few instances of their pairings. When a new sensory stimulus was paired with the same aversive stimulus, about half of these neurons generalized firing responses to the new stimulus association. Thus, prelimbic neurons are capable of rapidly forming ensemble codes for novel stimulus associations within minutes. This circuit property may enable the mPFC to rapidly detect and selectively encode the central content of novel experiences.

SIGNIFICANCE STATEMENT During a new experience, a region of the brain, called the hippocampus, rapidly forms its memory and later instructs another region, called the neocortex, that stores its content. Consistent with this dominant view, cells in the neocortex gradually strengthen the selectivity for the memory content over weeks after novel experiences. However, we still do not know precisely when these cells begin to develop the selectivity. We found that neocortical cells were capable of forming the selectivity for ongoing events within a few minutes of new experiences. This finding provides support for an alternative view that the neocortex works with, but not follows, the hippocampus to form new memories.

普遍的理论认为，海马在新的经历中快速学习刺激性连词，而新皮层通过随后与海马的离线交互而缓慢学习。但是，并行证据表明，内侧前额叶皮层（mPFC；支持长期记忆存储的新皮质网络的关键节点）在编码时经历了基因表达，突触结构和生理的快速修饰。这些观察结果以及受干扰的mPFC导致学习障碍，表明mPFC神经元在新经历中可能表现出快速的神经可塑性。但是，缺乏直接的经验证据。我们在细胞外记录了mPFC前缘区域中细胞的动作电位，而雄性大鼠则是有史以来第一次接受一系列刺激提示。从神经元合奏模式的瞬间到瞬间的跟踪显示，前肢网络活动在第一次遇到厌恶而非中性刺激后的1分钟内表现出突然转变。这种网络水平的变化是由约15％的神经元驱动的，这些神经元会立即提高其自发放电频率（FRs），并在配对的少数情况下对厌恶刺激之前的中性刺激产生放电反应。当新的感觉刺激与相同的厌恶刺激配对时，这些神经元中约有一半会泛化对新刺激关联的激发反应。因此，前肢神经元能够在数分钟内迅速形成新的刺激关联的整体编码。

意义陈述在一种新的体验中，大脑的一个区域称为海马，迅速形成其记忆，然后指示另一个区域（称为新皮层）存储其内容。与此主导观点一致，新皮层中的细胞在经历数周后逐渐增强了对记忆内容的选择性。但是，我们仍然不清楚这些细胞何时开始形成选择性。我们发现新皮层细胞能够在新体验的几分钟内对正在进行的事件形成选择性。这一发现为新皮层与海马体共同发挥作用，但又不遵循海马体形成新记忆的观点提供了支持。