Although stimuli that are associated often overlap in time, previous events can also predict the occurrence of a later aversive stimulus and be associated with it to better guide future behavior. Associations of stimuli separated in time have been studied using discrete stimulus as the conditioned stimulus (CS) in trace conditioning or, more recently in our lab, using the context as the CS in contextual fear conditioning with temporal discontinuity (CFC-5s), a task that simultaneously includes the processing of time and space components. It is thought that fear memories are encoded by the strengthening of synaptic connections in a distributed neural network. However, it is unclear how this temporal factor, which may differentially require the maintenance of the stimulus over time, affects the interactivity between brain regions to form the association. Because the prelimbic cortex (PL) and the hippocampus have been individually engaged in trace conditioning, they may functionally interact to encode associations separated in time. This is anatomically supported by direct ipsilateral projections from the ventral hippocampal CA1 region (vCA1) to PL. The aim of the present study was to investigate the effect of the functional disconnection of vCA1 and PL on CFC-5s using pre-training asymmetric reversible inactivation with muscimol. For comparison, we also observed its effect on contextual fear conditioning (CFC). Results showed that the functional disconnection impaired the encoding of the CFC-5s, an association of stimuli separated in time, while did not affect the CFC, an association of stimuli overlapped in time. In addition, the preserved connection in one hemisphere was sufficient to support the encoding of CFC-5s. The time interval by itself did not increase freezing responses and both CFC and CFC tasks had similar generalization and higher freezing responses than unconditioned groups. These findings suggest that the time factor alters the requirement of the interactivity of the brain regions underlying fear conditioning and extend the relevance of hippocampal-prefrontal interactions in memory.

中文翻译：

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腹侧海马CA1区和前缘皮层的功能相互作用有助于及时分离刺激的上下文恐惧关联的编码。

尽管相关的刺激经常在时间上重叠，但先前的事件也可以预测较晚厌恶刺激的发生，并与之相关联以更好地指导未来的行为。已经研究了使用离散刺激作为跟踪条件中的条件刺激（CS），或者最近在我们的实验室中，使用上下文作为具有时间不连续性的上下文恐惧条件（CFC-5s）中的时间刺激，将时间分离的刺激关联起来。同时包含时间和空间成分处理的任务。人们认为，恐惧记忆是通过分布式神经网络中突触连接的增强来编码的。但是，目前尚不清楚这个时间因素如何随时间的流逝而不同地需要维持刺激，影响大脑区域之间的相互作用以形成关联。由于前肢皮层（PL）和海马体已分别参与痕量调节，因此它们可能在功能上相互作用以编码随时间分离的关联。从腹侧海马CA1区（vCA1）到PL的直接同侧投影在解剖学上对此提供了支持。本研究的目的是研究使用麝香酚进行预训练的不对称可逆失活对vCA1和PL功能断开对CFC-5的影响。为了进行比较，我们还观察到了它对情境恐惧调节的影响。结果表明，功能断开会损害CFC-5的编码，这是时间上分离的刺激物的关联，而没有影响CFC，这是时间上重叠的刺激物的关联。此外，一个半球中保留的连接足以支持CFC-5的编码。时间间隔本身不会增加冻结响应，并且CFC和CFC任务的泛化程度和冻结响应均高于无条件组。这些发现表明，时间因素改变了恐惧条件下大脑区域互动性的要求，并扩展了记忆中海马-前额叶相互作用的相关性。