Pharmacogenetic Excitation of Dorsomedial Prefrontal Cortex Restores Fear Prediction Error
Pharmacogenetic Excitation of Dorsomedial Prefrontal Cortex Restores Fear Prediction Error
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DOI：
10.1523/jneurosci.3777-14.2015
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发表时间：
2015-01
期刊：
影响因子：
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通讯作者：
J. Yau;G. McNally
中科院分区：
文献类型：
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作者：
J. Yau;G. McNally
巴甫洛夫条件反射涉及编码条件刺激和非条件刺激之间的预测关系，因此突触的可塑性和学习是由预测误差来指导的。在这里，我们使用药物遗传学技术来证明大鼠背内侧前额叶皮质(DmPFC)神经元的活动与恐惧预测错误之间的因果关系。我们在dmPFC中表达了兴奋性hM3Dq Designer受体，并用联合阻断设计分离了预测错误的作用。在阶段I，通过配对足部电击训练大鼠恐惧视觉CS(CSA)。然后在第二阶段，大鼠接受视觉CSA和听觉CS(CSB)加足电击的复合呈现。这种对CSA的预先恐惧条件作用减少了第二阶段的预测误差，从而阻止了对CSB的恐惧学习。AAV-hSYN-EYFP载体+氯氮平-N-氧化物(CNO；3 mg/kg，i.p.)组。在第二阶段之前，第二天在没有CNO的情况下进行测试时显示阻塞。相反，在第二阶段训练前接受CNO治疗的AAv-hSYN-hM3Dq和AAv-CaMKIIα-hM3Dq组没有表现出阻断；对CSB的学习恢复。这种预测错误和恐惧学习的恢复是注射CNO所特有的，因为在第二阶段训练之前注射车辆的AAv-hSYN-hM3Dq和AAv-CaMKIIα-hM3Dq组确实显示出阻断。这些效果不是由于DREADD操作增强了学习或唤醒，增加了恐惧记忆强度或恐惧学习的渐近水平，或改变了恐惧记忆的提取。总而言之，这些结果确定了dmPFC在适应行为特征中的因果作用：利用过去预测未来的危险，并从这些预测中的错误中学习。
Pavlovian conditioning involves encoding the predictive relationship between a conditioned stimulus (CS) and an unconditioned stimulus, so that synaptic plasticity and learning is instructed by prediction error. Here we used pharmacogenetic techniques to show a causal relation between activity of rat dorsomedial prefrontal cortex (dmPFC) neurons and fear prediction error. We expressed the excitatory hM3Dq designer receptor exclusively activated by a designer drug (DREADD) in dmPFC and isolated actions of prediction error by using an associative blocking design. Rats were trained to fear the visual CS (CSA) in stage I via pairings with footshock. Then in stage II, rats received compound presentations of visual CSA and auditory CS (CSB) with footshock. This prior fear conditioning of CSA reduced the prediction error during stage II to block fear learning to CSB. The group of rats that received AAV–hSYN–eYFP vector that was treated with clozapine-N-oxide (CNO; 3 mg/kg, i.p.) before stage II showed blocking when tested in the absence of CNO the next day. In contrast, the groups that received AAV–hSYN–hM3Dq and AAV–CaMKIIα–hM3Dq that were treated with CNO before stage II training did not show blocking; learning toward CSB was restored. This restoration of prediction error and fear learning was specific to the injection of CNO because groups that received AAV–hSYN–hM3Dq and AAV–CaMKIIα–hM3Dq that were injected with vehicle before stage II training did show blocking. These effects were not attributable to the DREADD manipulation enhancing learning or arousal, increasing fear memory strength or asymptotic levels of fear learning, or altering fear memory retrieval. Together, these results identify a causal role for dmPFC in a signature of adaptive behavior: using the past to predict future danger and learning from errors in these predictions.