Vieira Philip A, Corches Alex, Lovelace Jonathan W, Westbrook Kevin B, Mendoza Michael, Korzus Edward
Department of Psychology & Neuroscience Program, University of California Riverside, CA 92521, USA.
Biomedical Sciences Program, University of California Riverside, CA 92521, USA.
Neurobiol Learn Mem. 2015 Mar;119:52-62. doi: 10.1016/j.nlm.2014.12.012. Epub 2015 Jan 20.
N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKIIα positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior.
N-甲基-D-天冬氨酸受体（NMDARs）在多种学习机制中起着关键作用，包括恐惧记忆的调节、大脑发育和脑部疾病。虽然NMDARs对内侧前额叶皮质（mPFC）的中间神经元和兴奋性神经元介导相反的作用，但NMDAR拮抗剂会引发深刻的皮质激活。本研究的目的是确定在mPFC依赖性适应性行为中，特别是恐惧辨别和恐惧消退中，特异性表达于兴奋性神经元的NMDARs的作用。为了实现这一目标，我们测试了从小鼠前额叶CaMKIIα阳性神经元中局部删除编码NMDAR必需的NR1亚基的Grin1基因的小鼠，观察它们在恐惧辨别测试中区分调频（FM）音调的能力。我们证明，在条件性恐惧最初泛化后，mPFC中依赖NMDAR的信号传导对于有效的恐惧辨别至关重要。虽然前额叶兴奋性神经元中NMDARs缺陷的小鼠对危险的恐惧条件刺激保持正常反应，但它们表现出异常的泛化递减。这些研究提供了证据表明，mPFC中依赖NMDAR的神经信号传导是一种神经机制的组成部分，该机制用于消除恐惧信号的含义，并通过保留适当的门控信息（即危险和无害线索）来支持辨别性恐惧学习。我们还发现，从mPFC兴奋性神经元中选择性删除NMDARs会导致听觉条件刺激的恐惧消退缺陷。这些研究表明，在兴奋性神经元中表达的前额叶NMDARs参与了适应性行为。
