Yau Joanna Oi-Yue, McNally Gavan P
School of Psychology, The University of New South Wales, Sydney 2052, New South Wales, Australia.
School of Psychology, The University of New South Wales, Sydney 2052, New South Wales, Australia
J Neurosci. 2015 Jan 7;35(1):74-83. doi: 10.1523/JNEUROSCI.3777-14.2015.
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.
巴甫洛夫条件反射涉及对条件刺激（CS）和无条件刺激之间预测关系的编码，从而使突触可塑性和学习受预测误差的指导。在此，我们运用药物遗传学技术来展示大鼠背内侧前额叶皮质（dmPFC）神经元的活动与恐惧预测误差之间的因果关系。我们在dmPFC中特异性表达了仅由设计药物（DREADD）激活的兴奋性hM3Dq设计受体，并通过关联阻断设计分离出预测误差的作用。大鼠在第一阶段通过与足部电击配对训练来恐惧视觉CS（CSA）。然后在第二阶段，大鼠接受视觉CSA和听觉CS（CSB）与足部电击的复合呈现。CSA的这种先前恐惧条件反射在第二阶段降低了预测误差，从而阻断了对CSB的恐惧学习。在第二阶段前接受用氯氮平 - N - 氧化物（CNO；3毫克/千克，腹腔注射）处理的AAV - hSYN-eYFP载体的大鼠组，在第二天无CNO的情况下测试时表现出阻断现象。相比之下，在第二阶段训练前接受用CNO处理的AAV - hSYN - hM3Dq和AAV - CaMKIIα - hM3Dq的大鼠组未表现出阻断；对CSB的学习得以恢复。预测误差和恐惧学习的这种恢复对CNO注射具有特异性，因为在第二阶段训练前注射载体的接受AAV - hSYN - hM3Dq和AAV - CaMKIIα - hM3Dq的大鼠组确实表现出阻断。这些效应并非归因于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，也不是改变了恐惧记忆检索。总之，这些结果确定了dmPFC在适应性行为特征中的因果作用：利用过去预测未来危险并从这些预测中的错误进行学习。
