Shobe Justin L, Bakhurin Konstantin I, Claar Leslie D, Masmanidis Sotiris C
Department of Neurobiology,
Neuroscience Interdepartmental Program.
J Neurosci. 2017 Sep 27;37(39):9415-9423. doi: 10.1523/JNEUROSCI.0572-17.2017. Epub 2017 Aug 28.
Discrete cues can gain powerful control over behavior to help an animal anticipate and cope with upcoming events. This is important in conditions where understanding the relationship between complex stimuli provides a means to resolving situational ambiguity. However, it is unclear how cortical circuits generate and maintain these signals that conditionally regulate behavior. To address this, we established a Pavlovian serial feature-negative conditioning paradigm, where male mice are trained on a trial in which a conditioned stimulus (CS) is presented alone and followed by reward, or a feature-negative trial in which the CS is preceded by a feature cue indicating there is no reward. Mice learn to respond with anticipatory licking to a solitary CS, but significantly suppress their responding to the same cue during feature-negative trials. We show that the feature cue forms a selective association with its paired CS, because the ability of the feature to transfer its suppressive properties to a separately rewarded cue is limited. Next, to examine the underlying neural dynamics, we conduct recordings in the orbitofrontal cortex (OFC). We find that the feature cue significantly and selectively inhibits CS-evoked activity. Finally, we find that the feature triggers a distinct OFC network state during the delay period between the feature and CS, establishing a potential link between the feature and future events. Together, our findings suggest that OFC dynamics are modulated by the feature cue and its associated conditioned stimulus in a manner consistent with an occasion setting model. The ability of patterned cues to form an inhibitory relationship with ambiguously rewarded outcomes has been appreciated since early studies on learning and memory. However, it was often assumed that these cues, despite their hierarchical nature, still made direct associative links with neural rewarding events. This model was significantly challenged, largely by the work of Holland and colleagues, who demonstrated that under certain conditions cues can inherit occasion setting properties whereby they modulate the ability of a paired cue to elicit its conditioned response. Here we provide some of the first evidence that the activity of a cortical circuit is selectively modulated by such cues, thereby providing insight into the mechanisms of higher order learning.
离散线索能够对行为产生强大的控制作用，以帮助动物预测并应对即将发生的事件。这在理解复杂刺激之间的关系可为解决情境模糊性提供一种手段的情况下非常重要。然而，尚不清楚皮质回路是如何产生并维持这些有条件地调节行为的信号的。为了解决这个问题，我们建立了一种巴甫洛夫式序列特征负性条件反射范式，在该范式中，雄性小鼠接受训练，在一个试验中，单独呈现一个条件刺激（CS），随后给予奖励，或者在一个特征负性试验中，CS之前有一个特征线索，表明没有奖励。小鼠学会对单独的CS做出预期性舔舐反应，但在特征负性试验中会显著抑制对相同线索的反应。我们表明，特征线索与其配对的CS形成了选择性关联，因为该特征将其抑制特性转移到另一个单独给予奖励的线索上的能力是有限的。接下来，为了研究潜在的神经动力学，我们在眶额皮质（OFC）进行记录。我们发现特征线索显著且选择性地抑制CS诱发的活动。最后，我们发现该特征在特征与CS之间的延迟期触发了一个独特的OFC网络状态，在该特征与未来事件之间建立了潜在联系。总之，我们的研究结果表明，OFC动力学以与情境设定模型一致的方式受到特征线索及其相关条件刺激的调节。自早期关于学习和记忆的研究以来，有模式的线索与模糊奖励结果形成抑制关系的能力就已得到认可。然而，人们通常认为这些线索尽管具有层级性质，但仍然与神经奖励事件直接建立关联。这个模型受到了很大挑战，主要是由于霍兰德及其同事的工作，他们证明在某些条件下，线索可以继承情境设定特性，借此调节配对线索引发其条件反应的能力。在这里，我们提供了一些首批证据，表明皮质回路的活动受到此类线索的选择性调节，从而为高阶学习机制提供了见解。
