Institute of Systems Neuroscience, National Tsing Hua University, Kuang-Fu Rd, Sec 2, No 101, Hsinchu, 30013, Taiwan.
Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
Brain Struct Funct. 2022 Sep;227(7):2529-2541. doi: 10.1007/s00429-022-02545-3. Epub 2022 Aug 2.
Inappropriate fear expression and failure of fear extinction are commonly seen in patients with post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD). Among the patients, aberrant and asymmetric activation of the lateral orbitofrontal cortex (lOFC) is reported in some clinical cases. In this study, we aimed to examine the role of lOFC activation in extinction acquisition and explore the potential functional lateralization of lOFC on extinction. We bilaterally or unilaterally activated the lOFC with N-methyl--aspartate (NMDA) before fear extinction acquisition in rats. Our data suggested that both left and bilateral lOFC activation interfered with the in-session expression of conditioned fear, whereas activation of the right lOFC did not. In addition, pre-extinction unilateral or bilateral activation of the lOFC, regardless of the side, impaired the acquisition of fear extinction. We also quantified the neuronal activities during the late phase of extinction with immunohistochemical approach. Our data showed that activation of the lOFC increased the neuronal activities on the injection side(s) in the medial prefrontal cortex (mPFC), the lateral amygdala (LA), the basolateral amygdala (BLA; preferentially the non-GABAergic neurons), and the medial intercalated cells (mITC; preferentially the right side). To conclude, aberrant activation of the lOFC during extinction disturbed the excitatory/inhibitory balance of neuronal activities in fear-related brain regions, which interfered with the expression of conditioned fear and impaired the acquisition of fear extinction.
在创伤后应激障碍 (PTSD) 和强迫症 (OCD) 患者中，常可见不适当的恐惧表达和恐惧消退失败。在这些患者中，一些临床病例报告显示外侧眶额皮层 (lOFC) 的异常和不对称激活。在这项研究中，我们旨在研究 lOFC 激活在消退获得中的作用，并探索 lOFC 对消退的潜在功能偏侧化。我们在大鼠进行恐惧消退获得之前，通过 N-甲基-D-天冬氨酸 (NMDA) 双侧或单侧激活 lOFC。我们的数据表明，左和双侧 lOFC 的激活均干扰了条件性恐惧的会话表达，而右 lOFC 的激活则没有。此外，消退前单侧或双侧 lOFC 的激活，无论哪一侧，均损害了恐惧消退的获得。我们还通过免疫组织化学方法量化了消退后期的神经元活动。我们的数据显示，lOFC 的激活增加了内侧前额叶皮层 (mPFC)、外侧杏仁核 (LA)、基底外侧杏仁核 (BLA；优先是非 GABA 能神经元) 和内侧中间神经元 (mITC；优先是右侧) 注射侧的神经元活动。总之，消退期间 lOFC 的异常激活扰乱了与恐惧相关脑区神经元活动的兴奋/抑制平衡，干扰了条件性恐惧的表达，并损害了恐惧消退的获得。
